Mitochondrial diseases caused by mtDNA mutations: a mini-review

Figures & data

Table 1 mtDNA mutations associated with mitochondrial cytopathies

Syndrome/disease	Gene/complex	Mutation	Position of mutant nucleotide/amino acid	Cited article
MELAS	MT-TL1	m.3243A>G	DHU Nucleotide 14, localized in the mTERF binding site	^Citation3, ^Citation16, ^Citation18, ^Citation37^–^Citation44
		m.3256C>T	Nucleotide 25, localized in the region of transcription termination of the stem of DHU loop	^Citation43, ^Citation44
		m.3271T>C	Nucleotide 40, localized in the stem of anticodon loop	^Citation18, ^Citation29, ^Citation41^–^Citation44
	MT-ND3, complex 1	m.10197G>A	Amino acid 47: a substitution of A>T*	^Citation45
	MT-ND5, complex 1	m.13042A>T	Amino acid 236: a substitution of A>T*	^Citation43, ^Citation46, ^Citation47
	MT-CYTB, complex 3	m.15533A>G	Amino acid 263: a substitution of N>D*	^Citation48
CPEO/PEO	MT-TV	m.1658T>C	Nucleotide 61, localized in the stem of T-loop	^Citation49, ^Citation50
	MT-TL2	m.12315G>A	Nucleotide 52, localized in the stem of T-loop	^Citation51^–^Citation53
KSS	Duplication of nucleotides (CCCCCTCCCC-tandem repeats at positions 305–314 and 956–965, which allows doubling a region in 652 bp)			^Citation54
	A large deletion of mitochondrial genome at positions from 8,469 to 13,447			^Citation3, ^Citation29, ^Citation38
MIDD	A large deletion of mitochondrial genome at positions from 4,308 to 14,874			^Citation55
	A large deletion of mitochondrial genome at positions from 4,398 to 14,822			^Citation56
	MT-TL1	m.3243A>G	Nucleotide 14, localized in the mTERF binding site	^Citation18, ^Citation40, ^Citation57, ^Citation58
	MT-ND1, complex 1	m.3421A>G	Amino acid 39: a substitution of V>I*	^Citation59
MERRF	MT-TK	m.8344A>G	Nucleotide 55, localized in the T-loop	^Citation3, ^Citation16, ^Citation18, ^Citation27, ^Citation29, ^Citation37, ^Citation42, ^Citation45, ^Citation54
		m.8356T>C	Nucleotide 65, localized in the stem of T-loop	^Citation16, ^Citation18, ^Citation27, ^Citation38, ^Citation46
		m.8363G>A	Nucleotide 72, localized in the stem of acceptor	^Citation16, ^Citation27, ^Citation38, ^Citation46
	MT-ND5, complex 1	m.13042A>T	Amino acid 236: a substitution of A>T*	^Citation46, ^Citation47
NIDDM	MT-RNR2	m.3200T>C	Nucleotide 1529	^Citation57
	MT-TL1	m.3242G>A	Nucleotide 13, localized in the region of transcription termination of DHU loop	^Citation60
		m.3252A>G	Nucleotide 23, localized in the region of transcription termination of DHU loop	^Citation61, ^Citation62
		m.3264T>C	Nucleotide 33, localized in the anticodon loop	^Citation57, ^Citation63
	MT-ND1, complex 1	m.3316G>A	Amino acid 4: a substitution of A>T*	^Citation57, ^Citation64
		m.3394T>C	Amino acid 30: a substitution of Y>H*	^Citation57, ^Citation65
	MT-ND6, complex 1	m.14577T>C	Reverse direction of synthesis: a substitution of I>V*	^Citation57, ^Citation66
	MT-ND2, complex 1	m.4833A>G	Amino acid 122: a substitution of A>T*	^Citation67
LHON	MT-ND1, complex 1	m.3460G>A	Amino acid 52: a substitution of A>T*	^Citation3, ^Citation16, ^Citation18, ^Citation27, ^Citation42, ^Citation68
	MT-CO3, complex 4	m.9804G>A	Amino acid 200: a substitution of A>T*	^Citation69
	MT-ND4, complex 1	m.11778G>A	Amino acid 340: a substitution of R>H*	^Citation3, ^Citation16, ^Citation27, ^Citation37, ^Citation42, ^Citation68, ^Citation70
	MT-ND6, complex 1	m.14459G>A	Reverse direction of synthesis. Amino acid 72: a substitution of A>V*	^Citation42
		m.14484A>G	Reverse direction of synthesis. Amino acid 64: a substitution of M>V*	^Citation3, ^Citation16, ^Citation27, ^Citation42, ^Citation68
	MT-CYTB, complex 3	m.15257G>A	Amino acid 171: a substitution of D>N*	^Citation71
LS	MT-ATP6, complex 5	m.8993T>C	Amino acid 156: a substitution of L>P*	^Citation16, ^Citation23, ^Citation27, ^Citation29, ^Citation42, ^Citation70, ^Citation72
	MT-ATP6, complex 5	m.8993T>G	Amino acid 156: a substitution of L>R*	^Citation3, ^Citation16, ^Citation25, ^Citation27, ^Citation42, ^Citation70, ^Citation72^–^Citation74
	MT-ND3, complex 1	m.10197G>A	Amino acid 47: a substitution of A>T*	^Citation45, ^Citation75
	MT-ND5, complex 1	m.13513G>A	Amino acid 393: a substitution of D>N*	^Citation76, ^Citation77
Aminoglycoside induced hearing disorders	MT-RNR1	m.1095T>C	Nucleotide 448	^Citation78
		m.1494C>T	Nucleotide 847	^Citation78, ^Citation79
		m.1555A>G Nucleotide 908 16, 79
		m.961ins/delC	Nucleotide 314, duplication/deletion C	^Citation78
NARP	MT-ATP6, complex 5	m.8993T>G	Amino acid 156: a substitution of L>R*	1^Citation6, ^Citation18, ^Citation23, ^Citation27, ^Citation29, ^Citation42
	MT-ATP6, complex 5	m.8993T>C	Amino acid 156: a substitution of L>P*	^Citation16, ^Citation23, ^Citation29, ^Citation42
Cardiomyopathy and encephalomyopathy	MT-RNR1	m.1541G>A	Nucleotide 894	^Citation80, ^Citation81
	MT-TV	m.1634C>T	Nucleotide 35, localized in anticodon	^Citation80
	MT-TL1	m.3243A>G	DHU nucleotide 14, localized in the mTERF binding site	^Citation16, ^Citation40, ^Citation71
		m.3260A>G	Nucleotide 29, localized in the stem of anticodon loop	^Citation40, ^Citation71, ^Citation82
	MT-TI	m.4269A>G	Nucleotide 7, localized in the stem of acceptor	^Citation40, ^Citation71
	MT-CO2, complex 4	m.7587T>C	Amino acid 1: a substitution of M>T*	^Citation83
	MT-TK	m.8296A>G	Nucleotide 2, localized in the stem of acceptor	^Citation71, ^Citation82
		m.8348A>G	Nucleotide 59, localized in the stem of T-loop	^Citation84
		m.8363G>A	Nucleotide 72, localized in the stem of acceptor	^Citation40, ^Citation71
	MT-CO3, complex 4	m.9957T>C	Amino acid 1: a substitution of F>L*	^Citation26
	MT-TG	m.9997T>C	Nucleotide 7, localized in the stem of acceptor	^Citation71
	MT-TH	m.12192G>A	Nucleotide 59, localized in the stem of T-loop	^Citation85
	MT-TL2	m.12297C>T	Nucleotide 33, localized in the anticodon loop	^Citation40
	MT-ND6, complex 1	m.14484A>G	Reverse direction of synthesis. Amino acid 64: a substitution of M>V*	^Citation86
	MT-CYTB, complex 3	m.15059G>A	Amino acid 105: a substitution of G>R*	^Citation87, ^Citation88

Notes:

* One letter amino acids designation: A, alanine; D, aspartic acid; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; L, leucine; M, methionine; N, asparagine; P, proline; R, arginine; T, threonine; V, valine; Y, tyrosine.

Abbreviations: CPEO/PEO, chronic progressive external ophthalmoplegia syndrome/progressive external ophthalmoplegia; KSS, Kearns–Sayre syndrome; LHON, Leber hereditary optic neuropathy; LS, Leigh syndrome; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MERRF, myoclonic epilepsy associated with ragged red fibers; MIDD, maternally inherited diabetes and deafness; NARP, neuropathy, ataxia and pigmentary retinopathy; NIDDM, noninsulin-dependent diabetes mellitus.

ZapicoSCUbelakerDHmtDNA Mutations and Their Role in Aging, Diseases and Forensic SciencesAging Dis20134636438024307969

 PubMed Web of Science ®Google Scholar

SchmiedelJJacksonSSchaferJReichmannHMitochondrial cytopathiesJ Neurol2003250326727712638015

 PubMed Web of Science ®Google Scholar

GreavesLCReeveAKTaylorRWTurnbullDMMitochondrial DNA and diseaseJ Pathol2012226227428621989606

 PubMed Web of Science ®Google Scholar

WallaceDCA mitochondrial bioenergetic etiology of diseaseJ Clin Invest201312341405141223543062

 PubMed Web of Science ®Google Scholar

WangYXWdLProgress in Diagnosing Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like EpisodesChin Med J2015128131820182526112726

 PubMed Web of Science ®Google Scholar

LorenzoniPJWerneckLCKayCSSilvadoCEScolaRHWhen should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis?Arq Neuropsiquiatr2015731195996726517220

 PubMed Web of Science ®Google Scholar

BerardoAMusumeciOToscanoACardiological manifestations of mitochondrial respiratory chain disordersActa Myol201130191521842587

 PubMedGoogle Scholar

VydtTCGde CooRFMSolimanOIICardiac involvement in adults with m.3243A>G MELAS gene mutationAm J Cardiol200799226426917223431

 PubMed Web of Science ®Google Scholar

LengYLiuYFangXThe mitochondrial DNA 10197 G > A mutation causes MELAS/Leigh overlap syndrome presenting with acute auditory agnosiaMitochondrial DNA201526220821224708134

 PubMed Web of Science ®Google Scholar

LorenzoniPJScolaRHCskKSilvadoCESWerneckLCWhen should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?Arq Neuropsiquiatr20147280381125337734

 PubMed Web of Science ®Google Scholar

SchinwelskiMKierdaszukBDulskiJChanging phenotypic expression in a patient with a mitochondrial encephalopathy due to 13042G>A de novo mutation – a 5 year follow upMetab Brain Dis20153041083108525550170

 PubMed Web of Science ®Google Scholar

Gil BorladoMCMoreno LastresDGonzalez HoyuelaMImpact of the mitochondrial genetic background in complex III deficiencyPLoS One201059e1280120862300

 PubMed Web of Science ®Google Scholar

ZhouLWangHWeiJWangYWangYNo association between mitochondrial tRNA(Val) T1658C mutation and chronic progressive external ophthalmoplegia (CPEO)Mitochondrial DNA201425538538623815321

 PubMed Web of Science ®Google Scholar

YanNCaiSGuoBA novel mitochondrial tRNA(Val) T1658C mutation identified in a CPEO familyMol Vis2010161736174220806033

 PubMed Web of Science ®Google Scholar

ElsonJLSwalwellHBlakelyELMcfarlandRTaylorRWTurnbullDMPathogenic mitochondrial tRNA mutations-which mutations are inherited and why?Hum Mutat20093011E984E99219718780

 PubMed Web of Science ®Google Scholar

CardaioliEda PozzoPMalfattiEChronic progressive external ophthalmoplegia: A new heteroplasmic tRNA(Leu(CUN)) mutation of mitochondrial DNAJ Neurol Sci2008272110610918603265

 PubMed Web of Science ®Google Scholar

MancusoMPetrozziLFilostoMMERRF syndrome without ragged-red fibers: the need for molecular diagnosisBiochem Biophys Res Commun200735441058106017275787

 PubMed Web of Science ®Google Scholar

KabungaPLauAKPhanKSystematic review of cardiac electrical disease in Kearns-Sayre syndrome and mitochondrial cytopathyInt J Cardiol201518130331025540845

 PubMed Web of Science ®Google Scholar

BallingerSWShoffnerJMHedayaEVMaternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletionNat Genet19921111151301992

 PubMed Web of Science ®Google Scholar

BallingerSWShoffnerJMGebhartSKoontzDAWallaceDCMitochondrial diabetes revisitedNat Genet1994744584597951312

 PubMed Web of Science ®Google Scholar

MohammedSBahithamWChanAChiuBBamforthFSergiCMitochondrial DNA related cardiomyopathiesFront Biosci (Elite Ed)201241706171622201986

 PubMedGoogle Scholar

ZhelankinAVSazonovaMAAssociation of the mutations in the human mitochondrial genome with chronic non-inflammatory diseases: type 2 diabetes, hypertension and different types of cardiomyopathyPatol Fiziol Eksp Ter20123123128

 Google Scholar

MaassenJAvan den OuwelandJMT HartLMLemkesHHMaternally inherited diabetes and deafness: a diabetic subtype associated with a mutation in mitochondrial DNAHorm Metab Res199729250559105898

 PubMed Web of Science ®Google Scholar

ChenFLLiuYSongXYA novel mitochondrial DNA missense mutation at G3421A in a family with maternally inherited diabetes and deafnessMutat Res20066021–2263316949108

 PubMed Web of Science ®Google Scholar

DimauroSMitochondrial diseasesBiochim Biophys Acta200416581–2808815282178

 PubMed Web of Science ®Google Scholar

WallaceDCMitochondrial defects in neurodegenerative diseaseMent Retard Dev Disabil Res Rev20017315816611553931

 PubMedGoogle Scholar

WortmannSBChampionMPvan den HeuvelLMitochondrial DNA m.3242G > A mutation. An under diagnosed cause of hypertrophic cardiomyopathy and renal tubular dysfunction?Eur J Med Genet2012551055255622781753

 PubMed Web of Science ®Google Scholar

IvanovaMMBorodachevENSazonovaMAHuman pathologies associated with mutations of mitochondrial genomePatol Fiziol Eksp Ter20123115122

 Google Scholar

MaLWangHChenJMitochondrial gene variation in type 2 diabetes mellitus: detection of a novel mutation associated with maternally inherited diabetes in a Chinese familyChin Med J2000113211111611775531

 PubMed Web of Science ®Google Scholar

SchaeferAMWalkerMTurnbullDMTaylorRWEndocrine disorders in mitochondrial diseaseMol Cell Endocrinol20133791–221123769710

 PubMed Web of Science ®Google Scholar

TangJLiJTianXKongQZhangYMitochondrial DNA 3243, 3316 point mutations and type 2 diabetes mellitusZhonghua Yi Xue Yi Chuan Xue Za Zhi200522219820015793785

 PubMedGoogle Scholar

HiraiMSuzukiSOnodaMMitochondrial DNA 3394 mutation in the NADH dehydrogenase subunit 1 associated with non-insulin-dependent diabetes mellitusBiochem Biophys Res Commun199621939519558645285

 PubMed Web of Science ®Google Scholar

TawataMHayashiJIIsobeKA new mitochondrial DNA mutation at 14577 T/C is probably a major pathogenic mutation for maternally inherited type 2 diabetesDiabetes20004971269127210909988

 PubMed Web of Science ®Google Scholar

OhkuboEAidaKChenJA patient with type 2 diabetes mellitus associated with mutations in calcium sensing receptor gene and mitochondrial DNABiochem Biophys Res Commun2000278380881311095989

 PubMed Web of Science ®Google Scholar

PatsiJKervinenMFinelMHassinenIELeber hereditary optic neuropathy mutations in the ND6 subunit of mitochondrial complex I affect ubiquinone reduction kinetics in a bacterial model of the enzymeBiochem J2008409112913717894548

 PubMed Web of Science ®Google Scholar

TanselTPacalFUstekDA novel ATP8 gene mutation in an infant with tetralogy of FallotCardiol Young201424353153323735083

 PubMed Web of Science ®Google Scholar

DarinNOldforsAMoslemiA-RHolmeETuliniusMThe incidence of mitochondrial encephalomyopathies in childhood: Clinical features and morphological, biochemical, and DNA abnormalitiesAnn Neurol200149337738311261513

 PubMed Web of Science ®Google Scholar

RossignolRFaustinBRocherCMalgatMMazatJ-PLetellierTMitochondrial threshold effectsBiochem J2003370Pt 375176212467494

 PubMed Web of Science ®Google Scholar

NunnariJSuomalainenAMitochondria: In Sickness and in HealthCell201214861145115922424226

 PubMed Web of Science ®Google Scholar

MarieSKNOba-ShinjoSMMarques-DiasMJRosembergSKokFReedUCThe prevalence of mitochondrial DNA mutations in Leigh syndrome in a Brazilian seriesMedicalExpress20141239242

 Google Scholar

KauppilaJHKStewartJBMitochondrial DNA: Radically free of free-radical driven mutationsBiochim Biophys Acta20151847111354136126050972

 PubMed Web of Science ®Google Scholar

IidaYFujiiKMizuochiHRostral brain lesions of Leigh syndrome associated with the mitochondrial DNA 8993T>G mutationJ Neurol Sci2016363777927000225

 PubMed Web of Science ®Google Scholar

WangKTakahashiYGaoZLMitochondrial ND3 as the novel causative gene for Leber hereditary optic neuropathy and dystoniaNeurogenetics200910433734519458970

 PubMed Web of Science ®Google Scholar

WangZXkQYaoSPhenotypic patterns of MELAS/LS overlap syndrome associated with m.13513G>A mutation, and neuropathological findings in one autopsy caseNeuropathology201030660661420408961

 PubMed Web of Science ®Google Scholar

ShanskeSCokuJLuJThe G13513A mutation in the ND5 gene of mitochondrial DNA as a common cause of MELAS or Leigh syndrome: evidence from 12 casesArch Neurol200865336837218332249

 PubMedGoogle Scholar

JingWZongjieHDenggangFMitochondrial mutations associated with aminoglycoside ototoxicity and hearing loss susceptibility identified by meta-analysisJ Med Genet20155229510325515069

 PubMed Web of Science ®Google Scholar

HuangSXiangGKangDRapid identification of aminoglycoside-induced deafness gene mutations using multiplex real-time polymerase chain reactionInt J Pediatr Otorhinolaryngol20157971067107225959403

 PubMed Web of Science ®Google Scholar

O’BrienTWEvolution of a protein-rich mitochondrial ribosome: implications for human genetic diseaseGene20022861737911943462

 PubMed Web of Science ®Google Scholar

JakschMOgilvieIYaoJMutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiencyHum Mol Genet20009579580110749987

 PubMed Web of Science ®Google Scholar

JakschMHorvathRHornNHomozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathyNeurology20015781440144611673586

 PubMed Web of Science ®Google Scholar

FosslienEMitochondrial medicine-cardiomyopathy caused by defective oxidative phosphorylationAnn Clin Lab Sci200333437139514584751

 PubMed Web of Science ®Google Scholar

PereiraLSoaresPRadivojacPLiBSamuelsDCComparing phylogeny and the predicted pathogenicity of protein variations reveals equal purifying selection across the global human mtDNA diversityAm J Hum Genet201188443343921457906

 PubMed Web of Science ®Google Scholar

UekiIKogaYPovalkoNMitochondrial tRNA gene mutations in patients having mitochondrial disease with lactic acidosisMitochondrion200661293616337222

 PubMed Web of Science ®Google Scholar

ArbustiniEDiegoliMPilottoAMitochondrial DNA Mutations and CardiomyopathiesMilanoSpringerCameriniFGavazziADeMariaRCardiomyopathies: Advances in1998117127

 Google Scholar

MimakiMIkotaASatoAA double mutation (G11778A and G12192A) in mitochondrial DNA associated with Leber’s hereditary optic neuropathy and cardiomyopathyJ Hum Genet2003481475012560876

 PubMed Web of Science ®Google Scholar

CaoYMaYZhangYDetection of eight frequently encountered point mutations in mitochondria in Chinese patients suggestive of mitochondrial encephalomyopathiesMitochondrion201010433033420123042

 PubMed Web of Science ®Google Scholar

NikitinAGLavrikovaEYChistiakovDAThe heteroplasmic 15059G>A mutation in the mitochondrial cytochrome b gene and essential hypertension in type 2 diabetesDiabetes Metab Syndr20126315015623158979

 PubMedGoogle Scholar

SobeninIAChistiakovDASazonovaMAAssociation of the level of heteroplasmy of the 15059G>A mutation in the MT-CYB mitochondrial gene with essential hypertensionWorld J Cardiol20135513214023710300

 PubMedGoogle Scholar