REVIEW

Mitochondrial function and epigenetic outlook in Leber's

Hereditary Optic Neuropathy (LHON)

S. Mohana Devia,⁎

, Aswathy P Naira, I. Mahalaxmib, V. Balachandarc

a SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Sankara Nethralaya, Chennai 600 006, Indiab Livestock Farming and Bioresource Technology, Tamil Nadu, Indiac Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, India

Received 21 May 2021; accepted 12 July 2021

Available online 20 July 2021

KEYWORDSEpigenetics;Leber's hereditaryoptic neuropathy;Mitochondrialcomplex 1;Neurodegenerativediseases;Nuclear encodedmitochondrial proteins

Abstract

Introduction: Neurodegenerative diseases are reliant on neurons which demand high energy for

its functioning, which depends on systems like mitochondrial oxidative phosphorylation

(OXPHOS). This energy generated by mitochondria occurs through different respiratory

complexes ranging from complex I to IV. Complexes are also known as NADH, including complex

I because it is the first enzyme and largest chain of the given respiratory chain; however,

complex 1 is called the ubiquinone oxidoreductase. Majority of neurodegenerative cases

demonstrate irresistible evidence of plenty of mitochondrial subtleties that are impaired, as

inhibition of complex 1 could lead to excessive reactive oxygen species (ROS) production.

Development: In this review we try to discuss on how epigenetic modifications could cause a

drift in smooth functioning of mitochondria and its function leading to neurodegenerative

diseases like Leber's hereditary optic neuropathy (LHON). The reference articles were collected

from NCBI-Pubmed, Scopus and Web of science. This review tries to deliver a summarizing

overview related to Complex 1 mediated mitochondrial dysfunction and studies done so far in

this aspect, along with the epigenetic modifications.

Conclusion: In this review we discussed the different roles of mitochondria and its related

dysfunction in the pathogenesis of neurodegenerative diseases.

n 2021 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. This is an open

access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/

by-nc-nd/4.0/).

⁎Corresponding author.E-mail address: geneticmohana@gmail.com (S. Mohana Devi).

NEUROLOGYPERSPECTIVES

www.journals.elsevier.com/neurology-perspectives

Neurology Perspectives 1 (2021) 220–232

https://doi.org/10.1016/j.neurop.2021.07.003

2667-0496/n 2021 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PALABRAS CLAVEEpigenética;Neuropatía ópticahereditaria de Leb;Complejomitocondrial I;Enfermedadesneurodegenerativas;Proteínasmitocondrialescodificadas en elnúcleo

Función de las mitocondrias y consideraciones epigenéticas en la neuropatía óptica

hereditaria de Leber

Resumen

Introducción: Las neuronas necesitan grandes cantidades de energía para su funcionamiento y

dependen de sistemas como la fosforilación oxidativa mitocondrial. Dicha energía se genera en

las mitocondrias a través de diferentes complejos respiratorios (complejos I-IV). El complejo I,

también conocido como nicotinamida adenina dinucleótido (NADH por sus siglas en inglés) o

ubiquinona oxidorreductasa, es la primera enzima y el mayor complejo de la cadena

respiratoria. La mayoría de enfermedades neurodegenerativas se asocian de forma inequívoca

a una gran variedad de alteraciones mitocondriales, como la inhibición del complejo I, que

podría desencadenar una sobreproducción de especies reactivas de oxígeno.

Desarrollo: El objetivo de nuestra revisión es analizar cómo las modificaciones epigenéticas

pueden alterar el funcionamiento normal de las mitocondrias, lo que puede a su vez favorecer el

desarrollo de enfermedades neurodegenerativas como la neuropatía óptica hereditaria de

Leber. Hemos usado las bases de datos PubMed, Scopus y Web of Science para identificar

artículos relacionados. Esta revisión presenta un resumen de la evidencia disponible hasta la

fecha sobre la disfunción del complejo I mitocondrial y las modificaciones epigenéticas

identificadas.

Conclusión: Analizamos el papel de las mitocondrias y las disfunciones mitocondriales en la

patogénesis de las enfermedades neurodegenerativas.

n 2021 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. Este es un

artículo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/

by-nc-nd/4.0/).

Introduction

Mitochondrial diseases are inherited genetically whichoccurs when mitochondria is unable to proceed oxidativephosphorylation. This happens due to mutations in mito-chondrial genes and nuclear genes which encodes structuralmitochondrial proteins. Mitochondrial DNA mutations aretransmitted by maternal inheritance and nuclear DNAmutations may follow an autosomal dominant, autosomalrecessive or X-linked inheritance pattern. Mitochondrialdiseases prevalence is estimated around 1 in 5000 inadults.1 Deficiency of complex 1 due to pathogenic muta-tions leads to various mitochondrial diseases. Variousnuclear gene as well as mitochondrial gene mutations havebeen identified which has been associated with mitochon-drial complex 1 deficiency. Mutations in genes which codesfor structural subunit and assembly factors of complex 1 isreferred as Primary complex 1 defects.2 Factors such asmitochondrial dysfunction, oxidative stress and apoptosishave an important role in various ocular diseases whereasoxidative stress and mutations in mitochondrial proteinencoding genes are associated with several neurodegenerativediseases.3 Epigenetic regulation among nuclear geneswhichencodes for complex 1 subunitswould make evidentchanges inexpression of complex 1 subunit. This changes in mitochondrialprotein level would lead to defective oxidative phosphorylationand energy depletion in cells.

Focusing on the range of genomic mechanism which notonly relies on the sequence of DNA but also other factors isepigenetics. It is important to integrate cues from theenvironment in order to understand the development ofregulated genetic complication and control homeostasis.

There are various studies carried out in epigenetics againstembryology, cellular differentiation and aging. In the lastdecade there are many pioneering studies focusing on epige-netics that include acetylation, methylation, ubiquitylation andphosphorylation which are natural occurring processes thattake place in every organism, and changes in these can causeunwanted effects on health leading to various diseases/disorders.4 Researches in epigenetic regulation of nuclearencodedmitochondrial genes will lead to better understandingof various mitochondrial diseases and increases the chances tofind out better therapeutics in future.

Mitochondria and oxidative phosphorylation

Oxidative phosphorylation consists of five enzyme com-plexes which are embedded in the inner mitochondrialmembrane.5 Mitochondria is the only one organelle ineukaryotic cell which have their own genome separately.The mtDNA is located in the matrix and each mitochondriacontain several identical copies of mtDNA.6 Other than theenergy production, mitochondria have several unique functionin control of cell cycle, regulating cell signaling, maintainingcell death and other cellular metabolism.7 Oxidative phosphor-ylation is a complex process and OXPHOS system that requires alarge group of mitochondrial as well as nuclear encodedproteins to function accurately.8 OXPHOS system includescomplex I (CI or NADH:ubiquinone oxidoreductase), complex II(CII or succinate:ubiquinone oxidoreductase), complex III (CIIIor ubiquinol:cytochrome-c oxidoreductase), complex IV (CIV orcytochrome-c oxidase) and Complex V (FOF1-ATP-synthase).The flow of electrons from NADH/FADH2 to O2 through this

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subunits located in the mitochondrial inner membrane leads tothe pumping of protons out of the mitochondrial matrix and itsgenerate ATP.9

Role of complex 1 in oxidative phosphorylation

OXPHOS subunit Complex I (NADH:ubiquinone oxidoreduc-tase) is the largest subunit and C1 is boot shaped structure of~1 MDa and being composed of the hydrophobic membranearm and the hydrophilic matrix arm perpendicular to eachother. The matrix arm consists mostly of the nuclear-encoded subunits, FMN, three iron–sulfur clusters and sitefor internal ubiquinone. The membrane arm has all mtDNA-encoded subunits, one iron–sulfur cluster and catalytic sitefor the substrate ubiquinone.10 Central C1 subunits arrangedas three functional modules: 1) N module, the electron inputmodule that oxidizes NADH 2) Q module that reducesubiquinone and 3) P module that translocate proton acrossthe membrane.11 N module comprising NDUFV1, NDUFV2,NDUFS1 subunits, in which electron entering to N modulethrough FMN from NADH. FMN is non-covalently bound toNDUFV1 and it transfers the electron to Fe–S clusters N3,N1b, N4, and N5.12 The Q module is composed of NDUFS2,NDUFS3, NDUFS8, and NDUFS7 subunits and it acceptselectrons from the iron–sulfur clusters of the N module andtransfers the electrons through iron–sulfur clusters N6a, N6band N2 to ubiquinone.13 Study has been reported aboutcomplex 1 deficiency in drosophila model which is caused byhomoplasmic mutation in ND2 gene. This mutant modelexhibits phenotypes that resemble symptoms of mitochon-drial disease, short lifespan, progressive neurodegeneration,altered mitochondrial membrane potential and low levelATP production.14 P module is membrane embedded and itmediates proton pumping. P module comprising the sevenmitochondrial DNA-encoded CI subunits (ND1, ND2, ND3,ND4, ND4L, ND5, ND6), ND1 at the base of the Q-module,followed by ND3, ND6 and ND4L, and the antiporter-likesubunits ND2, ND4 and ND5.11,15 Majority of the complex 1subunit proteins for assembly and accessory factors areencoded by nuclear genes, those proteins are synthesized incytosol and imported into the mitochondria through trans-location machineries.16

There are studies which show that biosynthesis ofcomplex 1 is a complicated process and many assemblyfactors are involved in each step of the process.17 Manystudies have been conducted to understand the differentstages of complex 1 assembly process and its integration intothe respiratory chain super complexes.18 Recent studyproving that modules of complex 1 were found to form fivedifferent subassemblies, comprising all 14 central and 18accessory subunits corresponding to almost 80% of the totalmass of fully assembled complex I.18 The N module coresubunits NDUFV1, NDUFV2 and NDUFS1 and accessorysubunits NDUFV3, NDUFS4, NDUFS6 and NDUFA12 areintegrated at last to form complex 1 functional holo-enzyme.19 Accessory subunits form a scaffold around thecore subunit to prevent ROS generation and for theprotection against oxidative damage by shielding redoxgroups from reaction with oxygen, in binding of the CI tothe membrane, and in the stabilization of the enzyme. Also,more specific functions in the regulation of activity or the

assembly of other subunits into the holocomplex have beenimplied.20 The Complex I assembly factors NDUFAF1, ACAD9,ECSIT, TMEM126B, and TIMMDC1 form the MCIA complex,which was identified in human osteosarcoma 143B cells bycomplexome profiling.21

Complex 1 mediated ROS production andoxidative stress

Oxidative stress is the imbalance between reactive oxygenspecies (ROS)/reactive nitrogen species (RNS) generationand the biological antioxidant defense system. The accumu-lation of ROS in cells and changes in functional level ofmacromolecules leads to damage of tissue to organ andcontributes to pathogenensis of many diseases.22 ROSproduction can happen in mitochondria in two differentways: (1) In results of complex 1 inhibition, the electrons arebacked up within the Fe–S cluster of complex 1. (2) Reverseelectron transfer, where electrons are going backward tocomplex 1 from complex II via ubiquinone which generatesuperoxide from semi-ubiquinone at the quinine-bindingsite.23 Mitochondrial inner membrane is the major site ofROS production and mitochondrial DNA (mtDNA) are moreprompt for ROS damage. mtDNA damage is more substantialand persist longer than mutations in nuclear DNA.24 mtDNA ismore susceptible for oxidative stress than nDNA because ofits close proximity to the inner mitochondrial membrane:major production of ROS site as well as mtDNA is notprotected with histone or any other associated proteins andintronless regions, all these factors enhance the oxidativemodification in the genome. Effect of mitochondrial damagereflects on the mtDNA as well as mtRNA transcrits reducedlevel and alterations in mitochondrial function.25 ROS alsoattacks structural and enzymatic proteins through theoxidation of aminoacids, prosthetic group, formation ofcross links and proteolysis. Inhibition of key proteins canlead to serious consequences in the metabolic pathways.mtDNA can be displaced to intra- and extracellular com-partments in response to various stress conditions. Displace-ment of mtDNA from mitochondria is still unclear and studiesare indicating that through the generation and release ofextracellular vesicles mtDNA transfer to extracellular com-partment is possible.26,27

Studies have illustrated that several mitochondrialdiseases are associated with ROS mediated mtDNA mutation.In MELAS, hydroxyl radical damage to mtDNA and it canaccelerate the mitochondrial genotype associated with thedisease.28 In MELAS and MERRF patients, intracellular ROSlevel and oxidative damage to macromolecules wereincreased in skin fibroblast cells.29 ROS associated telome-rase shortening have been observed in patients with MELAS-related mitochondriopathy and patient with LHON.30 InLeber's hereditary optic neuropathy (LHON), all associatedpoint mutations such as ND1, ND4 and ND6 are enhancingROS production.31 Increased or decreased ROS productionleads to oxidative stress condition in cells and it inducesmitochondrial DNA mutations, damage the mitochondrialrespiratory chain, amend membrane permeability and it hasimpact on Ca2+ homeostasis and mitochondrial defensesystems.32 As a consequence of LHON point mutation,oxidative stress is responsible for cellular damage and

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activates apoptosis in RGCs.33 Oxidative stress cause DNAdamage and level of DNA damage marker (8OH2'dG) has beenshown raised in LHON patient leukocyte.34 Human osteosar-coma cybrid cells with LHON mutations were also showedreduced GSH activity.35 In animal model study showed ATPproduction remains same while oxidative stress remains as highindicating the role of ROS as a source of RGC degeration.36

Diseases associated with mutations in mito-chondrial complex 1 dysfunction

Assembly defects in complex 1 lead to improper functioningof electron transport chain and severe disease conditions.Various mutations in mitochondrial and nuclear genesassociated with complex 1 cause most of the mitochondrialdiseases.37 Almost 25 genes have been identified forcomplex 1 deficiency in which 6 genes are nuclear encodedaccessory protein genes and 19 mitochondrial genes codesfor complex 1 subunits. Proper assembly of subunits andaccessory proteins are required for the stability andfunctioning of complex 1.38 Pathogenic mutations havebeen identified in mitochondrial genes for Leigh syndrome,multisystem disorders such as MELAS (mitochondrial enceph-alopathy with lactic acidosis and stroke like episodes), orMELAS/LHON overlap syndromes,39 Leber's Hereditary OpticNeuropathy (LHON), and MERRF (myoclonic epilepsy andragged red fibers), Mitochondrial Encephalomyopathy, Lac-tic Acidosis and Stroke-like episodes.

Syndrome resembling strokes are associated with severecomplex I deficiency caused by mitochondrial DNA (mtDNA)mutations.12 Among mitochondrial disorders, MELAS syn-drome is considered as one of the most common maternallyinherited diseases and the pathogenicity of MELAS is still notwell understood.40 Study using MELAS neuronal cybrid cellsreported a homoplasmic m.3243A > G mutation which is ametabolic switch towards glycolysis with the production oflactic acid. It shows severe defects in respiratory chainactivity and complex I disassembly with an accumulation ofassembly intermediates. Studies showed that Ketone Bodies(KB) exposure during 4 weeks associated with glucosedeprivation significantly restored complex I stability andactivity, increased ATP synthesis and reduced NADH/NAD+ratio, mtDNA copy number were significantly increased withKB. KB may constitute an alternative and promising therapyfor MELAS syndrome, and could be beneficial for othermitochondrial diseases caused by complex I deficiency.41

Mutations in nuclear encoded structural subunit genesand in assembly factor genes are associated with severeclinical presentations like Leigh syndrome, Leigh likesyndrome, leukoencephalopathy with macrocephaly,leukoencephalopathy, lethal infantile mitochondrial dis-ease, cardiomyopathy and encephalopathy, unspecified en-cephalomyopathy, progressive cavitating leukoencephalopathy,hypertrophic cardiomyopathy and encephalomyopathy areassociated with mutations in nuclear encoded complex 1sub-units.42,43 In 1998, first study about mutation in nDNA encodedcomplex 1 subunit was reported and the study was onheterozygous mutation in NDUFS8 gene in a patient with Leighsyndrome with complex 1 enzyme deficiency in muscle tissueand cultured skin fibroblast.44 Leigh syndrome is the mostcommon clinical presentation of mitochondrial diseases in

children and mutation causing Leigh syndrome have beendetected in almost all complex 1 gene including both nuclearand mitochondrial genes.45 The emerging use of whole exomesequencing (WES) has become an essential tool in identificationof the heterogeneous molecular background of complex Ideficiency and discovery of novel disease genes underlying thiscondition.46

Oxidative stress and complex 1 associatedneurodegenerative diseases

Brain tissue has high energy demand and central nervoussystem functions strongly depending on efficient mitochondrialfunction. Mutations in mitochondrial genome, alterations inmitochondrial dynamics, ROS generation, pathologic proteinaggregations and environmental factors may alter energymetabolism and it leads to neurodegenerative diseases.73

Oxidative stress mediate mitochondrial alterations whichmight be a major reason for neurodegeneration.74 Neurode-generative diseases are a heterogeneous group of disorderscharacterized by gradually progressive, selective loss ofneuronal systems which are physiologically or anatomicallyrelated. The most common chronic neurodegenerative diseasesassociated with aging and aggregation of misfolded proteins areAD, PD, HD and ALS. Many studies have proved that complex 1activity significantly decrease in cortex, cerebellum andbrainstem mitochondria from aged sample group compared toyoung control group.75,76 Neuronal damage occurs as the effectof imbalance of ATP production, membrane potential andcalcium uptake, in neurodegenerative processes, increasedROS leads to all these imbalance conditions. In 1990, first studyhas been reported about the role of mitochondria in neurode-generative process associated with Parkinson's disease wherecomplex I deficiency was observed in substantia nigra andplatelet mitochondria of patients.77 Mitochondrial complex 1activity is reduced in the substantia nigra of PD patients andstudy using complex I inhibitors such as rotenone, MPTP andpesticides cause neurological changes similar to PD.78 Partialinhibition of complex I in nerve terminals is sufficient formitochondria to generate more ROS. H2O2 plays a major role ininhibiting complex I as well as ketoglutarate dehydrogenasewhich results in higher ROS production in dopaminergic neuronsleading to excessive oxidative stress and ATP deficiency thateventually will result in cell death in the nigro-striatalpathway.79 In a PD related study demonstrated that complex1 inhibition increased free radicals and reduced proteasomalactivity via adenosine triphosphate (ATP) depletion and itincreases neuronal vulnerability.80 Combinational effect ofdecreased complex 1 activity, reduced cellular ATP levels,increased ROS levels lead to reduced ATP dependent axonaltransport, reduced proteosomal degradation and cytoplasmicaccumulation of the tau protein. Hyperphosphorylated tau maybe one of the factor that contribute to the apoptosis processand its sufficient to cause neurodegeneration.81 Accumulationof mutant aggregate-prone proteins induced by proteasomalinhibition in neurodegenerative diseases results in impairmentof the mitochondrial respiratory chain complexes activity.82

In AD, membrane-associated oxidative stress, increasedfree radical production and perturbed Ca2+ homeostasishave been observed and also COX activity is reduced andneurons exhibit mitochondrial damage and apoptosis.83

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Table 1 List of diseases with mutations in nuclear encoding genes for mitochondrial complex 1 subunits and assembly factors.

Disease Complex 1

subunit

Mutation Study sample Reference

Leigh syndrome

Leigh syndrome

Leigh syndrome

NDUFS1

L23N

del 222

D252G

M707V

R241W

R557W

One large-scale deletion

L23N

Skin fibroblast

Blood sample

47

48

NDUFV1 Y204C

C206G

E214K

IVS 8 + 4

A432P

del nt 989–990

Skin fibroblast 47

NDUFS2

D446N

M292T

Fibroblast cells 49

50

NDUFS3 T145I

R199W

Skin fibroblast 51

NDUFS4

Splicing mutation of intron 1

(IVS1nt −1) c

Homozygous 5 bp duplication

C316T

G44A

homozygous c.462delA

Skin fibroblast

Skin fibroblast

Skin fibroblast

Skin fibroblast

Patient blood

52

53

54

55

56

NDUFS7

V122 M

(c.17–1167 C > G) Exon 1

Skin fibroblast

Patient blood

57

58

NDUFS8

P79L/R102H

P85L

R138H

Skin fibroblast

Skeletal muscle and lymphoblast DNA

44

59

NDUFA2 skipping of exon 2 Skin fibroblast and muscle tissue 60

NDUFA10 Q142R Fibroblast and muscle tissue 61

NDUFAF2 p.Y38X)

c.l03delA

p.W74X

Fibroblast cells 62

FOXRED1 N430S

Q232X

R352W

Skeletal muscle and liver cells 63

Leukoencephalopathy

NDUFV1 A341V Skin fibroblast 64

NDUFS1 Q522K Fibroblast 65

NDUFA1

G32R

c.94G > C

Lymphoblast cells

Blood and fibroblast cells

66

67

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Changes in oxidative metabolism in AD showed as a result ofchanges in gene expression of nuclear and mitochondrialgenes encoding for complex 1 enzyme. Decreased complex 1activity as the result of down regulation of mitochondrialgenes have been found in AD brain specimens.84,85 Decreasedgene expression of ND4 subunit of complex 1 also has beenreported in the temporal cortex of AD patients.86 Appearanceof h Aβ aggregation and Tau pathologies correlate withmitochondrial dysfunctions in neurons in AD.Elevated Ca2+and ROS levels during mitochondrial dysfunction both con-tribute to the accumulation of pTau aggregates. In 2007,Melov et al. showed that mitochondrial SOD2 deficiency canresult in pTau aggregation in mice, a symptom that isreversible by the administration of antioxidants.87

Other neurological disorders like bipolar disorder andschizophrenia are also linked to mitochondrial dysfunctionand oxidative stress. It still remains unclear whethermitochondrial dysfunction is specifically associated withcomplex I impairment or associated with increased oxidativedamage and, if so, whether this relationship is specific tobipolar disorder.88 Levels of NDUFS7 and complex I activitywere decreased significantly in patients with bipolardisorder but were unchanged in those with depression andschizophrenia compared with controls88 (Table 1).

Leber's Hereditary Optic Neuropathy (LHON)and epigenetic studies in LHON

Ocular diseases also involved in mitochondrial diseases andocular changes are noticeable feature in various mitochon-drial diseases. Eye is high energy demanding organ andmitochondrial DNA damage as the result of oxidative stressstudied in pathogenesis of various opathalmologic diseasessuch as diabetic retinopathy (DR), age-related maculardegeneration (AMD) and glaucoma.89 First study in DRdemonstrate the overall mtDNA damage in the retina inanimal models and shows that this damage continues evenafter hyperglycemia is reversed, suggesting a strong role formtDNA damage in the development, and also in themetabolic memory associated with the progression of DR.90

Mitochondrial abnormality in ophthalmic disease associatedwith complex 1 dysfunction in LHON leads to optic nervedamage specifically involving retinal ganglion cells.

Leber's Hereditory Optic Neuropathy (LHON) is a mater-nally inherited mitochondrial disorder which leads tobilateral vision loss by degeneration of retinal ganglioncells. Point mutations in the mtDNA which code for NADHdehydrogenase subunit of Complex 1 in the ETC causes theprogressive vision loss.91 The three common primary mito-chondrial mutations are m.11778G4A in MT-ND4 gene,m.3460G4A in MT-ND1gene and m.14484T4C in MT-ND6gene. The prevalence for the disease is estimated to1:3000 and LHON begins generally in the mean age onsetbetween 18 and 35, it happens around 50% in male and 10%–50% in females.92 In the earlier stage of the disease, acute orsubacute, painless vision loss in one eye and gradually withinfew weeks it will affect the second eye also. Majority ofpatient will remain blind and it affect the overall quality oftheir life.93 Sometimes LHON misdiagnosed as optic neuritisat early stage due to acuity of onset, age at presentation.94

Recently one study has been reported, a case with painfulunilateral optic neuritis pave the way for the onset of LHON.It is not clear whether any mechanism are commonly sharingwith these diseases or optic neuritis acted as a activatingfactor for LHON disease condition.95 Both the incompletepenetrance and the male predominance in LHON are notfully explained yet.

There is no proper treatment to prevent the vision losscaused by LHON till now but medicines are available topromote ATP and decrease the oxidative stress.96,97 Recentstudy gives evidence that use of idebenone may bebeneficial for LHON treatment and it has influential effecton visual acuity (VA) and visual evoked potential (VEP) inLHON patients.98 LHON is considered as a multifactorialdisease with complex genetic and environmental interac-tion. Apart from the mitochondrial mutations, epigeneticfactors play an important role in the disease pentrance andexpression of the disease. On the basis of clinical studies,several environmental factors have been proposed toprompt LHON. Mitochondrial genetic variants associatedwith various diseases have been given in Table 2.

Some of the papers have suggested that alcohol andtobacco consumption are one of the main environmentalfactors which trigger vision loss in LHON.99–104 Tobaccosmoke contains mixture of toxic contents including freeradicals which make alterations in the ETC mechanism and itcould make a synergic effect with alcohol in the LHON

Table 1 (continuación)

Disease Complex 1

subunit

Mutation Study sample Reference

Mitochondrial

encephalopathy

NDUFAF2 R45X

M1L

Fibroblast cells 62

NUBPL G56R

Skeletal muscle and liver cells

68

ACAD9 R532W

R417C

Fibroblast 69

NDUFV2 (IVS2 + 5_ + 8delGTAA Skin fibroblast 70

NDUFV1 R45X Fibroblast cells 71

Fatal infantile lactic

acidosis

NDUFA11 IVS15g-a

Leaky mutation

Fibroblast cells 72

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condition.99 Reports showed that persons who have mt.3460and mt.14484 LHON mutations have high chances to getdisease condition by high consumption of alcohol andtobacco102,105,106 reported that smoking is significantlyassociated with disease penetrance, degree of smoking andnumber of years smoked correlated with increased risk ofdeveloping symptoms. In contradictory to this reports, astudy of affected and unaffected siblings from 80 sibshipswith LHON did not show any significant deleterious associ-ation between alcohol or tobacco consumption with visionloss in diseased condition.107

Other than the tobacco and alcohol consumption, someother environmental factors are also involved in the epige-netic mechanism of LHON. Antiretroviral drugs of thenucleoside analog (zidovudine) class are known to beassociated with mitochondrial toxicity.108 Clinical studies arereported in some individual cases of LHON associated withantiretroviral therapy for human immunodeficiency virus (HIV)infection.109–111 HIV patients with family history of LHON whorequire antiretroviral therapy are more triggered for thesevere vision loss.112 Je Hyun Seo et al. proposed antituber-culosis medication might be an epigenetic factor of LHON inpatients with primary mutation.113 In one of the case, reportshowed clinical expression of LHON precipitated by carbonmonoxide poisoning who have mitochondrial primary muta-tion.114 Long exposure to n-hexane and other organic solventuncouples mitochondrial respiration and impairs ATP synthe-sis, this suggest that these compounds could be a triggeringepigenetic factor for LHON.115 Occupational exposure topolycyclic aromatic hydrocarbons (PAH) may provide pro-oxidative effect to the mitochondrial dysfunction for theperson who has primary LHON mutation and it causes visionloss. Studies have been reported vision loss by LHON after theperson had been exposed to rubber tire fire and suggestingthat it could be a factor to trigger epigenetic mechanism inLHON.116,117 More validated data and research studies arerequired to confirm these factors and epigenetics as a causefor LHON. Understanding and identification of clinical andenvironmental factors and its mechanism of epigeneticchanges would help to open a novel therapeutic method andmore understanding of the disease condition.

Epigenetic modification of nuclear genes in-volved in mitochondrial diseases

According to proteomics survey, approximately 67% ofmitochondrial proteins are present in the mitochondrialmatrix, followed by 21% located within the inner mitochon-drial membrane, 6% of proteins reside in the inner

Table 2 Mitochondrial genetic variants associated with

various diseases.

Disease Mitochondrial genetic variant

Leigh syndrome (LS)

MT-ND1 m.4142 G > T

MT-ND3

m.10158 T > C

m.10191 T > C

m.10197G > A

MT-ND4

m.11777 C > A

m.11778 G > A

MT-ND5

m.13513G > A

m.12706 T > C

m.13094 T > C

m.12706 T > C

MT-ND6

m.14487T > C

m.14453 G > A

m.14459 G > A

m.14600G > A

MT-ATP6

m.8993 T > G

m.8993 T > C

m.9176 T > G

m.9176 T > C

m.9185 T > C

m.9191 T > C

MT-TK m.8363A > G

MT-TW m.5537insT

MT-CO3 m.9537insC

MELAS

MT-ND1

m.3697G > A

m.3946G > A

m.3949 T > C

m.3308 T > C

m.3376G > A

m.3481G > A

m.3959G > A

m.3995A > G

MT-ND4

m.12015 T > C

m.11084A > G

m.11470A > C

MT-ND5 m.12770A > G

m.13046 T > C

m.13063G > A

MT-ND6 m.14453G > A

MT-TL1 m.3243A > G

m.3271 T > C

MT-CO3 m.9957 T > C

m.9997 T > C

MT-CO1 m.6597C > A

MT-CYB m.14787del4

Mitochondrial

Encephalomyopathy

MT-TL1 m.3242G > A

MT-ND6 m.14487 T > C

MT-ND3 m.10197G > A

Myoclonic epilepsy with

ragged-red fibers

(MERRF)

MT-TK

m.8344A > G

m.8356 T > C

Table 2 (continuación)

Disease Mitochondrial genetic variant

Lethal Infantile

Mitochondrial Disease

MT-TW m.5567 T > C

Leber's Hereditary Optic

Neuropathy (LHON)

MT-ND1 m.3460G > A

MT-ND4 m.11778G > A

MT-ND6 m.14484 T > C

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membrane space and 4% present in the outer mitochondrialmembrane and 99% of these mitochondrial proteins areencoded by nuclear genome.118 Changes in mitochondrialprotein expression leads to defective oxidative phosphory-lation and ATP synthesis which leads to cell death andenergy deficiency in cells. This metabolic changes could bethe reason for many mitochondrial diseases and othercomplex disorders. nDNAs are protected with histones butnot in mtDNA, that is the major difference between thesetwo genomes. Post-translational histone modification andvarious DNA methylations regulate nuclear gene expressionand protein synthesis in the cell. This kind of epigeneticchange will also happen for nuclear encoded mitochondrialgenes, which results in decreased level of mitochondrialproteins and leads to dysfunction of mitochondria. Adequateepigenetic studies help to perceive the relevance of eachmitochondrial protein associated with the complex diseases.Researches in epigenetic regulation of nuclear encodedmitochondrial genes will lead to better understanding ofvarious diseases and increases the chances for bettertherapeutics in future. But the epigenetic research is stillnot much explored in nuclear encoded mitochondrialproteins in disease conditions (Fig. 1).

Manganese Superoxide Dismutase (SOD2), encoded bynuclear gene sod2, is an important mitochondrial antioxi-dant enzyme whose activity has broad implications in healthand disease. Many studies have been done in epigeneticregulation of this gene in cancer biology with free radicaltheory. Studies have reported that reduced SOD activity withCpG methylation in the intronic enhancer region119 and withreduced H3K4me2 histone modification at intronic enhancerwhich leading to the altered expression of MnSOD.120 Indiabetic condition , sod2 is modified with methyl H4K20 andH3K9 acetylation in the promoter region.121 H3K4 histone

methylation of retinal sod2 gene has crucial role in develop-ment of diabetic retinopathy.122 These studies raise thepossibility to use therapeutic targeted towards regulation ofmethylation status of histones to prevent inhibition of MnSODand protect mitochondrial damage. In paraganglioma diseasecondition, succinate dehydrogenase(SDH) gene expressiondownregulated with H3K27me3 histone modification in thenuclear gene and it can be reversed by overexpression of theJMJD3 histone demethylase.123 Abnormal hypermethylation inthe promoter region of the VDAC (Voltage Dependent AnionChannels) gene shows reduced expression of VDAC porinprotein and it causes low sperm motility in athenospermiacondition in men.124 Neurodegenerative diseases are morewith multifactorial etiology having a very high ability to makechanges in quality and standards of life.125–128 Along withmitochondrial dysfunctions and epigenetics changes, evi-dences are indicating that various metabolic pathways havebeen involved in progression and development of neurode-generative condition.129–132

Epigenetic regulation of nuclear encoded mitochondrialgene has an important role in the disease progression andcell functioning. Studies have been focused on variousaspects of epigenetics play a distinguished role in variousocular neurodegenerative diseases.133 Downregulation ofmitochondrial proteins leads to abnormal metabolic condi-tion in cell through damaged oxidative phosphorylation andfree radical formation. Cell-based approaches on oculardiseases are a new dimension towards treatment approachestreatment.134 This condition will cause cell death and leadsto severe diseases. But still more research is needed toclarify the actual mechanisms. So understanding of epige-netic mechanism and designing therapeutic for the epige-netic targets will improve the treatment efficiency invarious diseases.

Figure 1 Illustration of how epigenetics involved in mitochondrial disease progression. Epigenetic factors modify histone proteins

in chromatin and it affects gene regulation. Altered gene expression leads to depletion in protein level which results improper

assembly of subunits in complex 1. This will affect the functioning of mitochondria and oxidative stress takes place. Mitochondrial

damage leads to cell death and it causes various degenerative diseases.

Neurology Perspectives 1 (2021) 220–232

227

Conclusion

The purpose of this review was to find out the possible waysof how epigenetics can affect the process of mitochondrialoxidative phosphorylation leading to various diseases focus-ing on ocular diseases. There is a solid incentive to knowmore about epigenetics and reconnoiter the role ofepigenetics in terms of mitochondrial diseases becausethese are the factors that has the potential to understandvariable penetrance, phenotypic heterogeneity and environ-mental factors that induce disorders from this group. Thecurrent technology has the ability to directly evaluateepigenetic discrepancy in the nuclear genome or mitochon-dria. These situations have ultimately led to the urge ofbeing able to find a permanent solution. Therefore, ourfocus is to develop on the idea of epigenetic modificationsinvolved in mitochondrial diseases leading to various opticalneuropathies, especially LHON.

Funding

The authors would like to thank the Science and EngineeringResearch Board (SERB) for providing Early Career ResearchAward (ECR/2018/000718), India to complete this articlesuccessfully.

Declaration of Competing Interest

The authors declare no conflict of interest.

References

1. Bannwarth S, Procaccio V, Lebre AS, et al. Prevalence of rare

mitochondrial DNA mutations in mitochondrial disorders.J Med Genet. 2013;50(10):704–14. https://doi.org/10.1136/

jmedgenet-2013-101604.

2. Rodenburg RJ. Mitochondrial complex I-linked disease.Biochim Biophys Acta - Bioenerg. 2016;1857(7):938–45.

https://doi.org/10.1016/j.bbabio.2016.02.012.

3. Cenini G, Lloret A, Cascella R. Oxidative stress in neurodegen-

erative diseases: from a mitochondrial point of view. Oxid MedCell Longev. 2019;2019:2105607. https://doi.org/10.1155/

2019/2105607.

4. Moosavi A, Motevalizadeh Ardekani A. Role of epigenetics in

biology and human diseases. Iran Biomed J. 2016;20(5):246–58. https://doi.org/10.22045/ibj.2016.01.

5. Hatefi Y. The mitochondrial electron transport and oxidative

phosphorylation system. Annu Rev Biochem. 1985;54(1):1015–

69. https://doi.org/10.1146/annurev.bi.54.070185.005055.6. Taanman J-W. The mitochondrial genome: structure,

transcription, translation and replication. Biochim Biophys

Acta - Bioenerg. 1999;1410(2):103–23. https://doi.org/10.1016/S0005-2728(98)00161-3.

7. McBride HM, Neuspiel M, Wasiak S. Mitochondria: more than

just a powerhouse. Curr Biol. 2006;16(14):R551–60. https://

doi.org/10.1016/j.cub.2006.06.054.8. Koopman WJH, Distelmaier F, Smeitink JAM, Willems PHGM.

OXPHOS mutations and neurodegeneration. EMBO J. 2013;32(1):

9–29. https://doi.org/10.1038/emboj.2012.300.

9. Hanna MG, Nelson IP. Genetics and molecular pathogenesis ofmitochondrial respiratory chain diseases. Cell Mol Life Sci C.

1999;55(5):691–706. https://doi.org/10.1007/s000180050327.

10. Tuschen G, Sackmann U, Nehls U, Haiker H, Buse G, Weiss H.Assembly of NADH: Ubiquinone reductase (complex I) in Neuros-

pora mitochondria: independent pathways of nuclear-encoded and

mitochondrially encoded subunits. J Mol Biol. 1990;213(4):845–57.

https://doi.org/10.1016/S0022-2836(05)80268-2.11. Brandt U. Energy converting NADH: quinone oxidoreductase

(Complex I). Annu Rev Biochem. 2006;75(1):69–92. https://

doi.org/10.1146/annurev.biochem.75.103004.142539.12. Janssen RJRJ, Nijtmans LG, van den Heuvel LP, Smeitink JAM.

Mitochondrial complex I: structure, function and pathology.

J Inherit Metab Dis. 2006;29(4):499–515. https://doi.org/10.

1007/s10545-006-0362-4.13. Zickermann V, Kerscher S, Zwicker K, Tocilescu MA,

Radermacher M, Brandt U. Architecture of complex I and its

implications for electron transfer and proton pumping.

Biochim Biophys Acta. 2009;1787(6):574–83. https://doi.org/10.1016/j.bbabio.2009.01.012.

14. Burman JL, Itsara LS, Kayser E-B, et al. A Drosophila model of

mitochondrial disease caused by a complex I mutation thatuncouples proton pumping from electron transfer. Dis Model

Mech. 2014;7(10):1165–74. https://doi.org/10.1242/dmm.015321.

15. Stroud DA, Surgenor EE, Formosa LE, et al. Accessory subunits

are integral for assembly and function of human mitochondrialcomplex I. Nature. 2016;538(7623):123–6. https://doi.org/

10.1038/nature19754.

16. Lightowlers RN, Taylor RW, Turnbull DM. Mutations causing

mitochondrial disease: what is new and what challengesremain? Science (80-). 2015;349(6255):1494 LP–1499.

https://doi.org/10.1126/science.aac7516.

17. Andrews B, Carroll J, Ding S, Fearnley IM, Walker JE. Assemblyfactors for the membrane arm of human complex I. Proc Natl

Acad Sci. 2013;110(47):18934 LP–18939. https://doi.org/10.

1073/pnas.1319247110.

18. Guerrero-Castillo S, Baertling F, Kownatzki D, et al. Theassembly pathway of mitochondrial respiratory chain complex

I. Cell Metab. 2017;25(1):128–39. https://doi.org/10.1016/j.

cmet.2016.09.002.

19. Mckenzie MRM. Assembly factors of human mitochondrialcomplex I and their defects in disease. IUBMB Life. 2010;62(7):

497–502.

20. De Rasmo D, Palmisano G, Scacco S, et al. Phosphorylation

pattern of the NDUFS4 subunit of complex I of the mammalianrespiratory chain. Mitochondrion. 2010;10(5):464–71. https://

doi.org/10.1016/j.mito.2010.04.005.

21. Heide H, Bleier L, Steger M, et al. Complexome profilingidentifies TMEM126B as a component of the mitochondrial

complex I assembly complex. Cell Metab. 2012;16(4):538–49.

https://doi.org/10.1016/j.cmet.2012.08.009.

22. Sies H. Oxidative stress: From basic research to clinicalapplication. Am J Med. 1991;91(3, Supplement 3):S31–8.

https://doi.org/10.1016/0002-9343(91)90281-2.

23. Stepanova A, Konrad C, Guerrero-Castillo S, et al. Deactivation

of mitochondrial complex I after hypoxia-ischemia in theimmature brain. J Cereb Blood Flow Metab. 2019;39(9):1790–

802. https://doi.org/10.1177/0271678X18770331.

24. Yakes FM, Van Houten B. Mitochondrial DNA damage is moreextensive and persists longer than nuclear DNA damage in

human cells following oxidative stress. Proc Natl Acad Sci U S

A. 1997;94(2):514–9. https://doi.org/10.1073/pnas.94.2.514.

25. Clayton DA. Transcription of the mammalian mitochondrialgenome. Annu Rev Biochem. 1984;53(1):573–94. https://doi.

org/10.1146/annurev.bi.53.070184.003041.

26. Pérez-Treviño P, Velásquez M, García N. Mechanisms of

mitochondrial DNA escape and its relationship with differentmetabolic diseases. Biochim Biophys Acta - Mol Basis Dis.

1866;2020(6):165761. https://doi.org/10.1016/j.bbadis.2020.

165761.

S. Mohana Devi, Aswathy P Nair, I. Mahalaxmi, et al.

228

27. Picca A, Guerra F, Calvani R, et al. Generation and release ofmitochondrial-derived vesicles in health, aging and disease. J Clin

Med. 2020;9(5):1440. https://doi.org/10.3390/jcm9051440.

28. Ihara M, Tanaka H, Yashiro M, Nishimura Y. Mitochondrial

myopathy, encephalopathy, lactic acidosis, and stroke-likeepisodes (MELAS) with chronic renal failure: report of mother-

child cases. Rinsho Shinkeigaku. 1996;36(9):1069–73. http://

europepmc.org/abstract/MED/8976130.29. Wei YH, Lu CY, Wei CY, Ma YSLH. Oxidative stress in human

aging and mitochondrial disease-consequences of defective

mitochondrial respiration and impaired antioxidant enzyme

system. Chin J Physiol. 2001;44(1):1–11.30. Oexle K, Zwirner A. Advanced telomere shortening in respira-

tory chain disorders. Hum Mol Genet. 1997;6(6):905–8.

https://doi.org/10.1093/hmg/6.6.905.

31. Lin CS, Sharpley MS, Fan W, et al. Mouse mtDNA mutant modelof Leber hereditary optic neuropathy. Proc Natl Acad Sci U S

A. 2012;109(49):20065–70. https://doi.org/10.1073/pnas.

1217113109.32. Guo Y, Li C-I, Sheng Q, et al. Very low-level heteroplasmy

mtDNA variations are inherited in humans. J Genet Genomics.

2013;40(12):607–15. https://doi.org/10.1016/j.jgg.2013.10.

003.33. Carelli V, Rugolo M, Sgarbi G, et al. Bioenergetics shapes

cellular death pathways in Leber's hereditary optic neuropa-

thy: a model of mitochondrial neurodegeneration. Biochim

Biophys Acta - Bioenerg. 2004;1658(1):172–9. https://doi.org/10.1016/j.bbabio.2004.05.009.

34. Yen MY, Kao SH, Wang AGWY. Increased 8-hydroxy-2′-

deoxyguanosine in leukocyte DNA in Leber's hereditary opticneuropathy. Invest Ophthalmol Vis Sci. 2004;45(6):1688–91.

35. Ghelli A, Porcelli AM, Zanna C, Martinuzzi A, Carelli V, Rugolo

M. Protection against oxidant-induced apoptosis by exogenous

glutathione in Leber hereditary optic neuropathy cybrids.Invest Ophthalmol Vis Sci. 2008;49(2):671–6. https://doi.org/

10.1167/iovs.07-0880.

36. Zhuo Y, Luo H, Zhang K. Leber hereditary optic neuropathy and

oxidative stress. Proc Natl Acad Sci. 2012;109(49):19882–3.https://doi.org/10.1073/pnas.1218953109.

37. Antonicka H, Leary SC, Guercin G-H, et al. Mutations in COX10

result in a defect in mitochondrial heme A biosynthesis and

account for multiple, early-onset clinical phenotypes associ-ated with isolated COX deficiency. Hum Mol Genet. 2003;12

(20):2693–702. https://doi.org/10.1093/hmg/ddg284.

38. Calvo SE, Mootha VK. The mitochondrial proteome and humandisease. Annu Rev Genomics Hum Genet. 2010;11:25–44.

https://doi.org/10.1146/annurev-genom-082509-141720.

39. Malfatti E, Bugiani M, Invernizzi F, et al. Novel mutations of ND

genes in complex I deficiency associated with mitochondrialencephalopathy. Brain. 2007;130(7):1894–904. https://doi.

org/10.1093/brain/awm114.

40. Koga Y, Ishibashi M, Ueki I, et al. Effects of <span class=&quot;

sc&quot;>l</span>-arginine on the acute phase of strokes inthree patients with MELAS. Neurology. 2002;58(5):827–8.

https://doi.org/10.1212/WNL.58.5.827.

41. Frey S, Geffroy G, Desquiret-Dumas V, et al. The addition ofketone bodies alleviates mitochondrial dysfunction by restor-

ing complex I assembly in a MELAS cellular model. Biochim

Biophys Acta - Mol Basis Dis. 2017;1863(1):284–91. https://

doi.org/10.1016/j.bbadis.2016.10.028.42. Pagniez-Mammeri H, Rak M, Legrand A, Bénit P, Rustin P,

Slama A. Mitochondrial complex I deficiency of nuclear origin:

II. Non-structural genes. Mol Genet Metab. 2012;105(2):173–9.

https://doi.org/10.1016/j.ymgme.2011.10.001.43. Triepels RH, Van den Heuvel LP, Trijbels JMSJ. Respiratory

chain complex I deficiency. Am J Med Genet. 2001;106(1):

37–45.

44. Loeffen J, Smeitink J, Triepels R, et al. The first nuclear-encoded complex I mutation in a patient with Leigh Syndrome.

Am J Hum Genet. 1998;63(6):1598–608. https://doi.org/10.

1086/302154.

45. Rahman S, Blok RB, Dahl HH, Danks DM, Kirby DM, Chow CW,Christodoulou JTD. Leigh syndrome: clinical features and

biochemical and DNA abnormalities. Ann Neurol. 1996;39(3):

343–51.46. Piekutowska-Abramczuk D, Assouline Z, Mataković L, et al.

NDUFB8 mutations cause mitochondrial complex I deficiency in

individuals with Leigh-like encephalomyopathy. Am J Hum

Genet. 2018;102(3):460–7. https://doi.org/10.1016/j.ajhg.2018.01.008.

47. Bénit P, Chretien D, Kadhom N, et al. Large-scale deletion and

point mutations of the nuclear NDUFV1 and NDUFS1 genes in

mitochondrial complex I deficiency. Am J HumGenet. 2001;68(6):1344–52. https://doi.org/10.1086/320603.

48. Martín MA, Blázquez A, Gutierrez-Solana LG, et al. Leigh

syndrome associated with mitochondrial complex I deficiencydue to a novel mutation in the NDUFS1 gene. Arch Neurol.

2005;62(4):659–61. https://doi.org/10.1001/archneur.62.4.

659.

49. Ngu L-H, Nijtmans L, Distelmaier F, et al. A catalytic defect inmitochondrial respiratory chain complex I due to a mutation in

NDUFS2 in a patient with Leigh syndrome. Biochim Biophys

Acta. 1822;2012:168–75. https://doi.org/10.1016/j.bbadis.

2011.10.012.50. Tuppen HAL, Hogan VE, He L, et al. The p.M292T NDUFS2

mutation causes complex I-deficient Leigh syndrome in

multiple families. Brain. 2010;133(10):2952–63. https://doi.org/10.1093/brain/awq232.

51. Bénit P, Slama A, Cartault F, et al. Mutant NDUFS3 subunit of

mitochondrial complex I causes Leigh syndrome. J Med Genet.

2004;41(1):14–7. https://doi.org/10.1136/jmg.2003.014316.52. Bénit P, Steffann J, Lebon S, et al. Genotyping microsatellite

DNA markers at putative disease loci in inbred/multiplex

families with respiratory chain complex I deficiency allows rapid

identification of a novel nonsense mutation (IVS1nt −1) in theNDUFS4 gene in Leigh syndrome. Hum Genet. 2003;112(5):563–

6. https://doi.org/10.1007/s00439-002-0884-2.

53. van den Heuvel L, Ruitenbeek W, Smeets R, et al. Demonstra-

tion of a new pathogenic mutation in human complex Ideficiency: a 5-bp duplication in the nuclear gene encoding

the 18-kD (AQDQ) subunit. Am J Hum Genet. 1998;62(2):262–

8. https://doi.org/10.1086/301716.54. Budde SMS, van den Heuvel LPWJ, Janssen AJ, et al. Combined

enzymatic complex I and III deficiency associated with

mutations in the nuclear encoded NDUFS4 gene. Biochem

Biophys Res Commun. 2000;275(1):63–8. https://doi.org/10.1006/bbrc.2000.3257.

55. Petruzzella V, Vergari R, Puzziferri I, et al. A nonsense

mutation in the NDUFS4 gene encoding the 18 kDa (AQDQ)

subunit of complex I abolishes assembly and activity of thecomplex in a patient with Leigh-like syndrome. Hum Mol

Genet. 2001;10(5):529–36. https://doi.org/10.1093/hmg/10.

5.529.56. Anderson SL, Chung WK, Frezzo J, et al. A novel mutation in

NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family.

J Inherit Metab Dis. 2008;31(2):461–7. https://doi.org/10.

1007/s10545-008-1049-9.57. Triepels RH, Van Den Heuvel LP, Loeffen JLCM, et al. Leigh

syndrome associated with a mutation in the NDUFS7 (PSST)

nuclear encoded subunit of complex I. Ann Neurol. 1999;45(6):

787–90. https://doi.org/10.1002/1531-8249(199906)45:6<787::AID-ANA13>3.0.CO;2-6.

58. Lebon S, Minai L, Chretien D, et al. A novel mutation of the

NDUFS7 gene leads to activation of a cryptic exon and

Neurology Perspectives 1 (2021) 220–232

229

impaired assembly of mitochondrial complex I in a patient withLeigh syndrome. Mol Genet Metab. 2007;92(1):104–8. https://

doi.org/10.1016/j.ymgme.2007.05.010.

59. Procaccio V, Wallace DC. Late-onset Leigh syndrome in a

patient with mitochondrial complex I NDUFS8 mutations.Neurology. 2004;62(10):1899–901. https://doi.org/10.1212/

01.wnl.0000125251.56131.65.

60. Hoefs SJG, Dieteren CEJ, Distelmaier F, et al. NDUFA2 complexI mutation leads to Leigh disease. Am J Hum Genet. 2008;82

(6):1306–15. https://doi.org/10.1016/j.ajhg.2008.05.007.

61. Hoefs SJG, van Spronsen FJ, Lenssen EWH, et al. NDUFA10

mutations cause complex I deficiency in a patient with Leighdisease. Eur J Hum Genet. 2011;19(3):270–4. https://doi.org/

10.1038/ejhg.2010.204.

62. Hoefs SJG, Dieteren CEJ, Rodenburg RJ, et al. Baculovirus

complementation restores a novel NDUFAF2 mutation causingcomplex I deficiency. Hum Mutat. 2009;30(7):E728–36.

https://doi.org/10.1002/humu.21037.

63. Hoefs SJG, Dieteren CEJ, Rodenburg RJ, et al. High-through-put, pooled sequencing identifies mutations in NUBPL and

FOXRED1 in human complex I deficiency. Nat Genet. 2010;42

(10):851–8. https://doi.org/10.1038/ng.659.

64. Schuelke M, Smeitink J, Mariman E, Loeffen J, Plecko B,Trijbels F, Stöckler-Ipsiroglu S, Van den Heuvel L. Mutant

NDUFV1 subunit of mitochondrial complex I causes leukodys-

trophy and myoclonic epilepsy. Nat Genet. 1999;21(3):260–1.

https://doi.org/10.1038/6772.65. Bugiani M, Invernizzi F, Alberio S, et al. Clinical and molecular

findings in children with complex I deficiency. Biochim Biophys

Acta - Bioenerg. 2004;1659(2):136–47. https://doi.org/10.1016/j.bbabio.2004.09.006.

66. Potluri P, Davila A, Ruiz-Pesini E, et al. A novel NDUFA1

mutation leads to a progressive mitochondrial complex I-

specific neurodegenerative disease. Mol Genet Metab. 2009;96(4):189–95. https://doi.org/10.1016/j.ymgme.2008.12.004.

67. Mayr JA, Bodamer O, Haack TB, et al. Heterozygous mutation

in the X chromosomal NDUFA1 gene in a girl with complex I

deficiency. Mol Genet Metab. 2011;103(4):358–61. https://doi.org/10.1016/j.ymgme.2011.04.010.

68. Calvo SE, Tucker EJ, Compton AG, et al. High-throughput,

pooled sequencing identifies mutations in NUBPL and FOXRED1

in human complex I deficiency. Nat Genet. 2010;42(10):851–8.https://doi.org/10.1038/ng.659.

69. Haack TB, Danhauser K, Haberberger B, et al. Exome

sequencing identifies ACAD9 mutations as a cause of complexI deficiency. Nat Genet. 2010;42(12):1131–4. https://doi.org/

10.1038/ng.706.

70. Bénit P, Beugnot R, Chretien D, et al. Mutant NDUFV2 subunit

of mitochondrial complex I causes early onset hypertrophiccardiomyopathy and encephalopathy. Hum Mutat. 2003;21(6):

582–6. https://doi.org/10.1002/humu.10225.

71. Ogilvie I, Kennaway NG, Shoubridge EA. A molecular chaper-

one for mitochondrial complex I assembly is mutated in aprogressive encephalopathy. J Clin Invest. 2005;115(10):2784–

92. https://doi.org/10.1172/JCI26020.

72. Berger I, Hershkovitz E, Shaag A, Edvardson S, Saada A, ElpelegO. Mitochondrial complex I deficiency caused by a deleterious

NDUFA11 mutation. Ann Neurol. 2008;63(3):405–8. https://

doi.org/10.1002/ana.21332.

73. Filosto M, Scarpelli M, Cotelli MS, et al. The role ofmitochondria in neurodegenerative diseases. J Neurol. 2011;258

(10):1763–74. https://doi.org/10.1007/s00415-011-6104-z.

74. Wu Y, Chen M, Jiang J. Mitochondrial dysfunction in neurode-

generative diseases and drug targets via apoptotic signaling.Mitochondrion. 2019;49:35–45. https://doi.org/10.1016/j.

mito.2019.07.003.

75. Pollard AK, Craig EL, Chakrabarti L. Mitochondrial complex 1activity measured by spectrophotometry is reduced across all

brain regions in ageing and more specifically in neurodegen-

eration. PLoS One. 2016;11(6):e0157405. https://doi.org/10.

1371/journal.pone.0157405.76. Lenaz G, Bovina C, D'Aurelio M, et al. Role of mitochondria in

oxidative stress and aging. Ann N Y Acad Sci. 2002;959(1):199–

213. https://doi.org/10.1111/j.1749-6632.2002.tb02094.x.77. Schapira AHV, Cooper JM, Dexter D, Clark JB, Jenner P,

Marsden C. Mitochondrial complex I deficiency in Parkinson's

disease. J Neurochem. 1990;54(3):823–7. https://doi.org/10.

1111/j.1471-4159.1990.tb02325.x.78. Schapira AH. Neurobiology and treatment of Parkinson's

disease. Trends Pharmacol Sci. 2009;30(1):41–7.

79. Tretter L, Sipos I, Adam-Vizi V. Initiation of neuronal damage

by complex I deficiency and oxidative stress in Parkinson'sdisease. Neurochem Res. 2004;29(3):569–77. https://doi.org/

10.1023/B:NERE.0000014827.94562.4b.

80. Höglinger GU, Carrard G, Michel PP, et al. Dysfunction ofmitochondrial complex I and the proteasome: interactions

between two biochemical deficits in a cellular model of

Parkinson's disease. J Neurochem. 2003;86(5):1297–307.

https://doi.org/10.1046/j.1471-4159.2003.01952.x.81. Höglinger GU, Lannuzel A, Khondiker ME, et al. The mitochon-

drial complex I inhibitor rotenone triggers a cerebral

tauopathy. J Neurochem. 2005;95(4):930–9. https://doi.org/

10.1111/j.1471-4159.2005.03493.x.82. Golpich M, Amini E, Mohamed Z, Azman Ali R, Mohamed

Ibrahim N, Ahmadiani A. Mitochondrial dysfunction and

biogenesis in neurodegenerative diseases: pathogenesis andtreatment. CNS Neurosci Ther. 2017;23(1):5–22. https://doi.

org/10.1111/cns.12655.

83. Hashimoto M, Rockenstein E, Crews LME. Role of protein

aggregation in mitochondrial dysfunction and neurodegenera-tion in Alzheimer's and Parkinson's diseases. Neuromolecular

Med. 2003;4(1–2):21–36.

84. Manczak M, Park BS, Jung Y, Reddy PH. Differential expression

of oxidative phosphorylation genes in patients with Alzheimer'sdisease. Neuromolecular Med. 2004;5(2):147–62. https://doi.

org/10.1385/NMM:5:2:147.

85. Chandrasekaran K, Hatanpää K, Brady DR, Rapoport SI.

Evidence for physiological down-regulation of brain oxidativephosphorylation in Alzheimer's disease. Exp Neurol. 1996;142

(1):80–8.

86. Fukuyama R, Hatanpää K, Rapoport SI, Chandrasekaran K.Gene expression of ND4, a subunit of complex I of oxidative

phosphorylation in mitochondria, is decreased in temporal

cortex of brains of Alzheimer's disease patients. Brain Res.

1996;713(1):290–3. https://doi.org/10.1016/0006-8993(95)01517-5.

87. Melov S, Adlard PA, Morten K, et al. Mitochondrial oxidative

stress causes hyperphosphorylation of tau. PLoS One. 2007;2(6):

e536. https://doi.org/10.1371/journal.pone.0000536.88. Andreazza AC, Shao L, Wang J-F, Young LT. Mitochondrial

complex I activity and oxidative damage to mitochondrial

proteins in the prefrontal cortex of patients with bipolardisorder. Arch Gen Psychiatry. 2010;67(4):360–8. https://doi.

org/10.1001/archgenpsychiatry.2010.22.

89. Schrier SA, Falk MJ. Mitochondrial disorders and the eye. Curr

Opin Ophthalmol. 2011;22(5):325–31. https://doi.org/10.1097/ICU.0b013e328349419d.

90. Madsen-Bouterse SA, Mohammad G, Kanwar M, Kowluru RA.

Role of mitochondrial DNA damage in the development of

diabetic retinopathy, and the metabolic memory phenomenonassociated with its progression. Antioxid Redox Signal. 2010;13

(6):797–805. https://doi.org/10.1089/ars.2009.2932.

S. Mohana Devi, Aswathy P Nair, I. Mahalaxmi, et al.

230

91. Guy J, Feuer WJ, Davis JL, et al. Gene therapy for Leberhereditary optic neuropathy: low- and medium-dose visual

results. Ophthalmology. 2017;124(11):1621–34. https://doi.

org/10.1016/j.ophtha.2017.05.016.

92. Dimitriadis K, Leonhardt M, Yu-Wai-Man P, et al. Leber'shereditary optic neuropathy with late disease onset: clinical

and molecular characteristics of 20 patients. Orphanet J Rare

Dis. 2014;9:158. https://doi.org/10.1186/s13023-014-0158-9.93. Yu-Wai-Man P, Votruba M, Moore AT, Chinnery PF. Treatment

strategies for inherited optic neuropathies: past, present and

future. Eye (Lond). 2014;28(5):521–37. https://doi.org/10.

1038/eye.2014.37.94. Chang M. Leber's hereditary optic neuropathy misdiagnosed as

optic neuritis and Lyme disease in a patient with multiple

sclerosis. BMJ Case Rep. 2018;11(1), e227109. https://doi.

org/10.1136/bcr-2018-227109.95. Lee C, Park K-A, Lee G-I, Oh SY, Min J-H, Kim BJ. Leber's

hereditary optic neuropathy following unilateral painful optic

neuritis: a case report. BMC Ophthalmol. 2020;20(1):195.https://doi.org/10.1186/s12886-020-01461-6.

96. Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al. A randomized

placebo-controlled trial of idebenone in Leber's hereditary

optic neuropathy. Brain. 2011;134(Pt 9):2677–86. https://doi.org/10.1093/brain/awr170.

97. Shrader WD, Amagata A, Barnes A, et al. α-Tocotrienol

quinone modulates oxidative stress response and the biochem-

istry of aging. Bioorg Med Chem Lett. 2011;21(12):3693–8.https://doi.org/10.1016/j.bmcl.2011.04.085.

98. Zhao X, Zhang Y, Lu L, Yang H. Therapeutic effects of

idebenone on Leber hereditary optic neuropathy. Curr EyeRes. 2020;45(10):1315–23. https://doi.org/10.1080/02713683.

2020.1736307.

99. Cullom ME, Heher KL, Miller NR, Savino PJ, Johns DR. Leber's

hereditary optic neuropathy masquerading as tobacco-alcoholamblyopia. Arch Ophthalmol. 1993;111(11):1482–5. https://

doi.org/10.1001/archopht.1993.01090110048021.

100. Golnik KC, Schaible ER. Folate-responsive optic neuropathy. J

Neuroophthalmol. 1994;14(3):163–9. http://europepmc.org/abstract/MED/7804421.

101. Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa

J, Harding AE. The clinical features of Leber's hereditary optic

neuropathy defined by the presence of a pathogenic mito-chondrial DNA mutation. Brain. 1995;118(2):319–37. https://

doi.org/10.1093/brain/118.2.319.

102. Chalmers RM, Harding AE. A case-control study of Leber'shereditary optic neuropathy. Brain. 1996;119(5):1481–6.

https://doi.org/10.1093/brain/119.5.1481.

103. Sadun AA, Carelli V, Salomao SR, Berezovsky A, Quiros PA,

Sadun F, DeNegri AM, Andrade R, Moraes M, Passos A, Kjaer P,Pereira J, Valentino ML, Schein SBR. Extensive investigation of a

large Brazilian pedigree of 11778/haplogroup J Leber hereditary

optic neuropathy. Am J Ophthalmol. 2003;136(2):231–8.

104. Kirkman MA, Korsten A, Leonhardt M, Dimitriadis K, De Coo IF,Klopstock T, Griffiths PG, Hudson G, Chinnery PF, PY-W-M.

Quality of life in patients with Leber hereditary optic

neuropathy. Invest Ophthalmol Vis Sci. 2009;50(7):3112–5.https://doi.org/10.1167/iovs.08-3166.

105. Johns DR, Smith KH, Miller NR, Sulewski ME, Bias WB. Identical

twins who are discordant for Leber's hereditary optic neurop-

athy. Arch Ophthalmol. 1993;111(11):1491–4. https://doi.org/10.1001/archopht.1993.01090110057023.

106. Tsao K, Aitken PA, Johns D. Smoking as an aetiological factor in

a pedigree with Leber's hereditary optic neuropathy. Br J

Ophthalmol. 1999;83:577–81. https://doi.org/10.1136/bjo.83.5.577.

107. Kerrison JB, Miller NR, Hsu F, et al. A case-control study of

tobacco and alcohol consumption in Leber hereditary optic

neuropathy. Am J Ophthalmol. 2000;130(6):803–12. https://doi.org/10.1016/s0002-9394(00)00603-6.

108. Brinkman K, ter Hofstede HJM, Burger DM, Smeitink JAM,

Koopmans PP. Adverse effects of reverse transcriptase

inhibitors: mitochondrial toxicity as common pathway. AIDS.1998;12(14). https://journals.lww.com/aidsonline/Fulltext/

1998/14000/Adverse_effects_of_reverse_transcriptase.4.aspx.

109. Lüke C, Cornely OA, Fricke J, Lehrer E, Bartz-Schmidt KU. Lateonset of Leber's hereditary optic neuropathy in HIV infection.

Br J Ophthalmol. 1999;83(10):1204–5. https://doi.org/10.

1136/bjo.83.10.1194k.

110. Shaikh S, Ta C, Basham AAMS. Leber hereditary opticneuropathy associated with antiretroviral therapy for

human immunodeficiency virus infection. Am J Ophthalmol.

2001;131(1):143–5.

111. JEA Warner, Ries KM. Optic Neuropathy in a Patient With AIDS.J Neuro-Ophthalmol. 2001;21(2). https://journals.lww.com/

jneuro-ophthalmology/Fulltext/2001/06000/Optic_Neuropa-

thy_in_a_Patient_With_AIDS.6.aspx.112. Mackey DA, Fingert JH, Luzhansky JZ, et al. Leber's hereditary

optic neuropathy triggered by antiretroviral therapy for

human immunodeficiency virus. Eye. 2003;17(3):312–7.

https://doi.org/10.1038/sj.eye.6700362.113. Seo JH, Hwang J-M, Park SS. Antituberculosis medication as a

possible epigenetic factor of Leber's hereditary optic neurop-

athy. Clin Experiment Ophthalmol. 2010;38(4):363–6.

https://doi.org/10.1111/j.1442-9071.2010.02240.x.114. Hwang JM, Park HW. Carbon monoxide poisoning as an

epigenetic factor for Leber's hereditary optic neuropathy.

Korean J Ophthalmol. 1996;10(2):122–3. https://doi.org/10.3341/kjo.1996.10.2.122.

115. Carelli V, Franceschini F, Venturi S, et al. Grand rounds: could

occupational exposure to n-hexane and other solvents precip-

itate visual failure in leber hereditary optic neuropathy?Environ Health Perspect. 2007;115(1):113–5. https://doi.

org/10.1289/ehp.9245.

116. Rufa A, Dotti MT, Cardaioli E, Da Pozzo P, Federico A. Leber

hereditary optic neuropathy in 2 of 4 siblings with 11778mtDNA mutation: clinical variability or effect of toxic

environmental exposure? Eur Neurol. 2005;53(1):32–4.

https://doi.org/10.1159/000083927.

117. Sanchez RN, Smith AJ, Carelli V, Sadun AA, Keltner JL. Leberhereditary optic neuropathy possibly triggered by exposure to

tire fire. J Neuro-Ophthalmol. 2006;26(4). https://journals.

lww.com/jneuro-ophthalmology/Fulltext/2006/12000/Leber_Hereditary_Optic_Neuropathy_Possibly.8.aspx.

118. Pagliarini DJ, Calvo SE, Chang B, et al. A mitochondrial protein

compendium elucidates complex I disease biology. Cell.

2008;134(1):112–23. https://doi.org/10.1016/j.cell.2008.06.016.

119. Huang Y, Peng J, Oberley LW, Domann FE. Transcriptional

inhibition of manganese superoxide dismutase (SOD2) gene

expression by DNA methylation of the 5′ CpG Island. Free RadicBiol Med. 1997;23(2):314–20. https://doi.org/10.1016/S0891-

5849(97)00095-6.

120. Hitchler MJ, Oberley LW, Domann FE. Epigenetic silencing ofSOD2 by histone modifications in human breast cancer cells.

Free Radic Biol Med. 2008;45(11):1573–80. https://doi.org/

10.1016/j.freeradbiomed.2008.09.005.

121. Zhong Q, Kowluru RA. Epigenetic changes in mitochondrialsuperoxide dismutase in the retina and the development of

diabetic retinopathy. Diabetes. 2011;60(4):1304–13. https://

doi.org/10.2337/db10-0133.

122. Zhong Q, Kowluru RA. Epigenetic modification of Sod2 in thedevelopment of diabetic retinopathy and in the metabolic

memory: role of histone methylation. Invest Ophthalmol Vis Sci.

2013;54(1):244–50. https://doi.org/10.1167/iovs.12-10854.

Neurology Perspectives 1 (2021) 220–232

231

123. Cervera AM, Bayley J-P, Devilee P, McCreath KJ. Inhibition ofsuccinate dehydrogenase dysregulates histone modification in

mammalian cells. Mol Cancer. 2009;8:89. https://doi.org/10.

1186/1476-4598-8-89.

124. Xu A, Hua Y, Zhang J, et al. Abnormal hypermethylation ofthe VDAC2 promoter is a potential cause of idiopathic

asthenospermia in men. Sci Rep. 2016;6:37836. https://doi.

org/10.1038/srep37836.125. Venugopal A, Iyer M, Balasubramanian V, Vellingiri B.

Mitochondrial calcium uniporter as a potential therapeutic

strategy for Alzheimer's disease. Acta Neuropsychiatr. 2020;32

(2):65–71. https://doi.org/10.1017/neu.2019.39.126. Mohana Devi S, Mahalaxmi I, Aswathy NP, Dhivya V,

Balachandar V. Does retina play a role in Parkinson's disease?

Acta Neurol Belg. 2020;120(2):257–65. https://doi.org/10.

1007/s13760-020-01274-w.127. Venkatesan D, Iyer M, S RW, G L, Vellingiri B. The association

between multiple risk factors, clinical correlations and

molecular insights in Parkinson's disease patients from TamilNadu population, India. Neurosci Lett. 2021;755:135903.

https://doi.org/10.1016/j.neulet.2021.135903.

128. Gomathi M, Padmapriya S, Balachandar V. Drug studies on Rett

syndrome: from bench to bedside. J Autism Dev Disord. 2020;50(8):2740–64. https://doi.org/10.1007/s10803-020-04381-y.

129. Ganesan H, Balasubramanian V, Iyer M, et al. mTOR signalling

pathway - A root cause for idiopathic autism? BMB Rep.

2019;52(7):424–33. https://doi.org/10.5483/BMBRep.2019.52.7.137.

130. Venkatesan D, Iyer M, Narayanasamy A, Siva K, Vellingiri B.

Kynurenine pathway in Parkinson's disease-An update.

eNeurologicalSci. 2020;21:100270. https://doi.org/10.1016/j.ensci.2020.100270.

131. Balachandar V, Rajagopalan K, Jayaramayya K, Jeevanandam

M, Iyer M. Mitochondrial dysfunction: a hidden trigger ofautism? Gen Dis. 2020 https://doi.org/10.1016/j.gendis.2020.

07.002 Published online.

132. Geetha B, Sukumar C, Dhivyadeepa E, Reddy JK, Balachandar

V. Autism in India: a case–control study to understand theassociation between socio-economic and environmental risk

factors. Acta Neurol Belg. 2019;119(3):393–401. https://doi.

org/10.1007/s13760-018-01057-4.

133. Mohana Devi S, Mahalaxmi I, Kaavya J, Chinnkulandhai V,Balachandar V. Does epigenetics have a role in age related

macular degeneration and diabetic retinopathy? Genes Dis.

2021;8(3):279–86. https://doi.org/10.1016/j.gendis.2020.01.003.

134. Mohana Devi S, Mahalaxmi I, Aswathy P, Nair Dhivya V,

Nimmisha E, Soumya K, Manoj Kumar C, Ayan R, Abilash VG,

Balachandar V. Oxidative stress and mitochondrial transfer: anew dimension towards Ocular diseases. Gen Dis. 2020

https://doi.org/10.1016/j.gendis.2020.11.020.

S. Mohana Devi, Aswathy P Nair, I. Mahalaxmi, et al.

232