Advancement in the diagnosis of mitochondrial diseases

Abstract

Mitochondrial diseases are multi-systemic, heterogeneous groups of diseases that are associated with various neuromuscular problems, cardiovascular disorders, metabolic syndrome, cancer, and obesity. Mitochondrial diseases are due to mutations in mitochondrial DNA or nuclear DNA that can affect the assembly of the mitochondrial components and mitochondrial function. Typically, mitochondrial diseases can be inherited through an autosomal dominant, autosomal recessive or X-linked pattern of inheritance. To date, there are more than 100 mitochondrial diseases identified. However, clinical phenotype heterogeneity is a huge problem for the diagnosis of mitochondrial diseases, as patients with the same mutations exhibit different clinical symptoms. Also, the heteroplasmy/homoplasmy conditions complicate the diagnosis process. Here, in this review, we discuss these challenges and problems in mitochondrial disease diagnosis, focusing on the mutational profile of both primary and secondary mitochondrial diseases. We also review the utilization of next-generation technology and multi-omics strategy to improve the diagnosis. The discussion addresses the current evidence of those applications and the challenges that need some improvement for better diagnosis yield.

Keywords

Genomics / next-generation sequencing / mtDNA / mitochondrial diseases

References

[1] Gorman GS,DiMauro S,Koga Y.Mitochondrial diseases..Nat Rev Dis Primers2016;2:16080

[2] DiMauro S,Carelli V.The clinical maze of mitochondrial neurology..Nat Rev Neurol2013;9:429-44 PMCID:PMC3959773

[3] Duran J,Adler E.Cardiovascular manifestations of mitochondrial disease..Biology2019;8:34 PMCID:PMC6628328

[4] Zong WX,White E.Mitochondria and Cancer..Mol Cell2016;61:667-76 PMCID:PMC4779192

[5] McCormick EM,Falk MJ.Mitochondrial Genomics: a complex field now coming of age..Curr Genet Med Rep2018;6:52-61 PMCID:PMC6205240

[6] Osellame LD,Duchen MR.Cellular and molecular mechanisms of mitochondrial function..Best Pract Res Clin Endocrinol Metab2012;26:711-23 PMCID:PMC3513836

[7] Tuppen HAL,Turnbull DM.Mitochondrial DNA mutations and human disease..Biochim Biophys Acta Bioenerg2010;1797:113-28

[8] Greaves LC,Elson JL,Taylor GA.Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing..PLoS Genet2014;10:e1004620 PMCID:PMC4169240

[9] Castellanos E.Phosphorylation of OXPHOS machinery subunits: functional implications in cell biology and disease..Yale J Biol Med2019;92:523-31 PMCID:PMC6747953

[10] Natarajan V,Mah T,Tan SY.Mitochondrial dysfunction in age-related metabolic disorders..Proteomics2020;1800404:

[11] Nass S.Intramitochondrial fibers with DNA characteristics. II. enzymatic and other hydrolytic treatments..J Cell Biology1963;19:613-29 PMCID:PMC2106332

[12] Anderson S,Barrell BG,Coulson AR.Sequence and organization of the human mitochondrial genome..Nature1981;290:457-65

[13] Andrews RM,Chinnery PF,Turnbull DM.Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA..Nat Genet1999;23:147

[14] D’Souza AR.Mitochondrial transcription and translation: overview..Essays Biochem2018;62:309-20 PMCID:PMC6056719

[15] Russell O.Mitochondrial DNA disease-molecular insights and potential routes to a cure..Exp Cell Res2014;325:38-43 PMCID:PMC4058519

[16] Bayir H.Bench-to-bedside review: mitochondrial injury, oxidative stress and apoptosis--there is nothing more practical than a good theory..Critical Care (London, England)2008;12:206 PMCID:PMC2374589

[17] Wallace DC,Lott MT.Mitochondrial DNA variation in human evolution and disease..Gene1999;238:211-30

[18] Gorman GS,Ng Y,Blakely EL.Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease..Ann Neurol2015;77:753-9 PMCID:PMC4737121

[19] Skladal D,Thorburn DR.Minimum birth prevalence of mitochondrial respiratory chain disorders in children..Brain2003;126:1905-12

[20] DiMauro S.Mitochondrial encephalomyopathies--fifty years on: the Robert Wartenberg Lecture..Neurology2013;81:281-91 PMCID:PMC3959764

[21] Frazier AE,Compton AG.Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology..J Biol Chem2019;294:5386-95 PMCID:PMC6462508

[22] Lebon S,Benit P,Chretien D.Recurrent de novo mitochondrial DNA mutations in respiratory chain deficiency..J Med Genet2003;40:896-9 PMCID:PMC1735336

[23] Chinnery PF,Mitalipov S,Herbert M.The challenges of mitochondrial replacement..PLoS genet2014;10:e1004315 PMCID:PMC3998882

[24] Schon EA.Neuronal degeneration and mitochondrial dysfunction..J Clin Invest2003;111:303-12 PMCID:PMC151870

[25] Pek NMQ,Ho BX,Hor JH.Mitochondrial 3243A > G mutation confers pro-atherogenic and pro-inflammatory properties in MELAS iPS derived endothelial cells..Cell Death Dis2019;10:802 PMCID:PMC6805858

[26] Kucharczyk R,Gombeau K,Tribouillard-Tanvier D.The pathogenic MT-ATP6 m.8851T>C mutation prevents proton movements within the n-side hydrophilic cleft of the membrane domain of ATP synthase..Biochim Biophys Acta Bioenerg2019;1860:562-72

[27] Blanco-Grau A,Coll-Cantí J,Martinez R.Identification and biochemical characterization of the novel mutation m.8839G>C in the mitochondrial ATP6 gene associated with NARP syndrome..Genes Brain Behav2013;12:812-20

[28] Mordel P,Dupas Q,Gérard M.A 2 bp deletion in the mitochondrial ATP 6 gene responsible for the NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome..Biochem Biophys Res Commun2017;494:133-7

[29] Rahman S,Dahl HHM,Kirby DM.Leigh syndrome: clinical features and biochemical and DNA abnormalities..Ann Neurol1996;39:343-51

[30] Alston CL,Heidler J,Alaimo JT.Pathogenic Bi-allelic Mutations in NDUFAF8 cause leigh syndrome with an isolated complex I deficiency..Am J Hum Genet2020;106:92-101 PMCID:PMC7042492

[31] Park SY,Lee YM.Molecular diagnosis of myoclonus epilepsy associated with ragged-red fibers syndrome in the absence of ragged red fibers..Front Neurol2017;8:520 PMCID:PMC5626808

[32] Mackey DA,Rosenberg T,Bronte-Stewart J.Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy..Am J Hum Genet1996;59:481-5 PMCID:PMC1914749

[33] Manickam AH,Ramasamy S.Mitochondrial genetics and therapeutic overview of Leber’s hereditary optic neuropathy..Indian J Ophthalmol2017;65:1087-92 PMCID:PMC5700573

[34] Emperador S,Hernández-Ainsa C,Montoya J.Ketogenic treatment reduces the percentage of a LHON heteroplasmic mutation and increases mtDNA amount of a LHON homoplasmic mutation..Orphanet J Rare dis2019;14:150

[35] Remes AM,Herva R,Hassinen IE.Kearns-Sayre syndrome case presenting a mitochondrial DNA deletion with unusual direct repeats and a rudimentary RNAase mitochondrial ribonucleotide processing target sequence..Genomics1993;16:256-8

[36] Poulton J,Mark Gardiner R.Duplications of mitochondrial dna in mitochondrial myopathy..Lancet1989;333:236-40

[37] Shoubridge EA,Karpati G.Complete restoration of a wild-type mtDNA genotype in regenerating muscle fibres in a patient with a tRNA point mutation and mitochondrial encephalomyopathy..Hum Mol Genet1997;6:2239-42

[38] Pineda M,López-Gallardo E,Solano A.Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion..Ann Neurol2006;59:394-8

[39] Patel R,Rimmer J,Chinnery PF.Mitochondrial neurogastrointestinal encephalopathy: a clinicopathological mimic of Crohn’s disease..BMC Gastroenterol2019;19:11 PMCID:PMC6334462

[40] Nishino I,Hirano M.Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder..Science1999;283:689-92

[41] González-Vioque E,Andreu AL.Limited dCTP availability accounts for mitochondrial DNA depletion in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)..PLoS genet2011;7:e1002035 PMCID:PMC3069123

[42] Shaibani A,Zhang S,Lichtarge O.Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B..Arch Neurol2009;66:1028-32 PMCID:PMC2747647

[43] Tang S,Milone M.Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations..J Neurol2012;259:862-8

[44] Saneto RP,Copeland WC.Alpers-Huttenlocher syndrome..Pediatr Neurol2013;48:167-78 PMCID:PMC3578656

[45] El-Hattab AW.Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options..Neurotherapeutics2013;10:186-98 PMCID:PMC3625391

[46] Suomalainen A.Mitochondrial DNA depletion syndromes--many genes, common mechanisms..Neuromuscul Disord2010;20:429-37

[47] Rahman S.POLG-related disorders and their neurological manifestations..Nat Rev Neurol2019;15:40-52

[48] de Vries DD,Gabreëls FJM,van Oost BA.A second missense mutation in the mitochondrial ATPase 6 gene in Leigh’s syndrome..Ann Neurol1993;34:410-2

[49] Harding AE,Sweeney MG,Davis MB.Prenatal diagnosis of mitochondrial DNA8993 T----G disease..Am J Hum Genet1992;50:629-33 PMCID:PMC1684296

[50] Holt IJ,Petty RK.A new mitochondrial disease associated with mitochondrial DNA heteroplasmy..Am J Hum Genet1990;46:428-33 PMCID:PMC1683641

[51] Carrozzo R,Santorelli FM.The T9176G mutation of human mtDNA gives a fully assembled but inactive ATP synthase when modeled in Escherichia coli..FEBS Letters2000;486:297-9

[52] Verny C,Desquiret V,Prundean A.Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation..Mitochondrion2011;11:70-5

[53] Thyagarajan D,Vazquez-Memije M,Dimauro S.A novel mitochondrial ATPase 6 point mutation in familial bilateral striatal necrosis..Ann Neurol1995;38:468-72

[54] Moslemi AR,Tulinius M,Holme E.Two new mutations in the MTATP6 gene associated with Leigh syndrome..Neuropediatrics2005;36:314-8

[55] Tiranti V,Greco M,Carrara F.A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome..Hum Mol Genet2000;9:2733-42

[56] Crimi M,Galbiati S,Fortunato F.A new mitochondrial DNA mutation in ND3 gene causing severe Leigh syndrome with early lethality..Pediatr Res2004;55:842-6

[57] McFarland R,Fowler KJ,Ryan MT.De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency..Ann Neurol2004;55:58-64

[58] Taylor RW,Hayes CM,Turnbull DM.Progressive mitochondrial disease resulting from a novel missense mutation in the mitochondrial DNA ND3 gene..Ann Neurol2001;50:104-7

[59] Sarzi E,Lebon S,Munnich A.A novel recurrent mitochondrial DNA mutation in ND3 gene is associated with isolated complex I deficiency causing Leigh syndrome and dystonia..Am J Med Genet A2007;143a:33-41

[60] Kirby DM,Ohtake A,Ryan MT.Mutations of the mitochondrial ND1 gene as a cause of MELAS..J Med Genet2004;41:784-9 PMCID:PMC1735602

[61] Deschauer M,Claus D,Turnbull DM.Late-onset encephalopathy associated with a C11777A mutation of mitochondrial DNA..Neurology2003;60:1357-9

[62] Komaki H,Iwata H,Mashima Y.A novel mtDNA C11777A mutation in Leigh syndrome..Mitochondrion2003;2:293-304

[63] Taylor RW,Hutchinson M.Leigh disease associated with a novel mitochondrial DNA ND5 mutation..Eur J Hum Genet2002;10:141-4

[64] Simon DK,Breakefield XO,Brin MF.A heteroplasmic mitochondrial complex I gene mutation in adult-onset dystonia..Neurogenetics2003;4:199-205

[65] Kirby DM,Freckmann ML,Thorburn DR.Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated families..Ann Neurol2000;48:102-4

[66] Jun AS,Wallace DC.A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia..Proc Natl Acad Sci U S A1994;91:6206-10 PMCID:PMC44167

[67] Solano A,Vives-Bauza C,Garcia-Arumi E.Bilateral striatal necrosis associated with a novel mutation in the mitochondrial ND6 gene..Ann Neurol2003;54:527-30

[68] Ugalde C,Coenen MJ,Smeets R.Impaired complex I assembly in a Leigh syndrome patient with a novel missense mutation in the ND6 gene..Ann Neurol2003;54:665-9

[69] Howell N,McCullough DA,Poulton J.Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees..Am J Hum Genet1991;49:939-50 PMCID:PMC1683233

[70] Huoponen K,Aula P,Savontaus ML.A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy..Am J Hum Genet1991;48:1147-53 PMCID:PMC1683111

[71] Wallace D,Lott M,Schurr T.Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy..Science1988;242:1427-30

[72] Brown MD,Lott MT,Wallace DC.Leber’s hereditary optic neuropathy: a model for mitochondrial neurodegenerative diseases..Faseb J1992;6:2791-9

[73] Johns DR,Park RD.An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy..Biochem Biophys Res Commun1992;187:1551-7

[74] Tawata M,Iwase E,Aida K.New mitochondrial DNA homoplasmic mutations associated with Japanese patients with type 2 diabetes..Diabetes1998;47:276-7

[75] Blakely EL,King A,Harrower T.LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation..Eur J Hum Genet2005;13:623-7

[76] Sakuta R,Nonaka I.An A-to-G transition at nucleotide pair 11084 in the ND4 gene may be an mtDNA polymorphism..Am J Hum Genet1993;53:964-5 PMCID:PMC1682373

[77] Lertrit P,Jean-Francois MJ,Dennett X.A new disease-related mutation for mitochondrial encephalopathy lactic acidosis and strokelike episodes (MELAS) syndrome affects the ND4 subunit of the respiratory complex I..Am J Hum Genet1992;51:457-68 PMCID:PMC1682709

[78] Liolitsa D,Benton S,Hanna MG.Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations?.Ann Neurol2003;53:128-32

[79] Crimi M,Moroni I,Perini MP.A missense mutation in the mitochondrial ND5 gene associated with a Leigh-MELAS overlap syndrome..Neurology2003;60:1857-61

[80] Santorelli FM,Kulikova R,Vilarinho L.Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS..Biochem Biophys Res Commun1997;238:326-8

[81] Corona P,Carrara F,Lamantea E.A novel mtDNA mutation in the ND5 subunit of complex I in two MELAS patients..Ann Neurol2001;49:106-10

[82] Ravn K,Hansen FJ,Rosenberg T.An mtDNA mutation, 14453G-->A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome..Eur J Hum Genet2001;9:805-9

[83] De Coo IF,Ruitenbeek W,Bakker M.A 4-base pair deletion in the mitochondrial cytochrome b gene associated with parkinsonism/MELAS overlap syndrome..Ann Neurol1999;45:130-3

[84] Goto Y,Horai S.A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies..Nature1990;348:651-3

[85] Varlamov DA,Vielhaber S,Sassen R.Metabolic consequences of a novel missense mutation of the mtDNA CO I gene..Hum Mol Genet2002;11:1797-805

[86] Andreu AL,Reichmann H,Penn AS.Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA..N Engl J Med1999;341:1037-44

[87] Comi GP,Salani S,Sciacco M.Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease..Ann Neurol1998;43:110-6

[88] Clark KM,Johnson MA,Chrzanowska-Lightowlers ZM.An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy..Am J Hum Genet1999;64:1330-9 PMCID:PMC1377869

[89] Campos Y,Fernandez-Moreno MA,Goda G.Early-onset multisystem mitochondrial disorder caused by a nonsense mutation in the mitochondrial DNA cytochrome C oxidase II gene..Ann Neurol2001;50:409-13

[90] Wong LJ,Tan D,Grix A.Severe lactic acidosis caused by a novel frame-shift mutation in mitochondrial-encoded cytochrome c oxidase subunit II..Am J Med Genet2001;102:95-9

[91] Hanna MG,Rahman S,Land J.Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA..Am J Hum Genet1998;63:29-36 PMCID:PMC1377234

[92] Manfredi G,Moraes CT,Berry GT.A new mutation associated with MELAS is located in a mitochondrial DNA polypeptide-coding gene..Neuromuscul Disord1995;5:391-8

[93] Temperley RJ,Tonska K,Bindoff LA.Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria..Hum Mol Genet2003;12:2341-8

[94] Wibrand F,Schwartz M,Horn N.Multisystem disorder associated with a missense mutation in the mitochondrial cytochrome b gene..Ann Neurol2001;50:540-3

[95] Schuelke M,Finckh B,Janssen A.Septo-optic dysplasia associated with a new mitochondrial cytochrome b mutation..Ann Neurol2002;51:388-92

[96] Andreu AL,Dunne TC,Shanske S.A nonsense mutation (G15059A) in the cytochrome b gene in a patient with exercise intolerance and myoglobinuria..Ann Neurol1999;45:127-30

[97] Legros F,Frachon P,Laforet P.Functional characterization of novel mutations in the human cytochrome b gene..Eur J Hum Genet2001;9:510-8

[98] Keightley JA,Burton MD,Buist NR.Mitochondrial encephalomyopathy and complex III deficiency associated with a stop-codon mutation in the cytochrome b gene..Am J Hum Genet2000;67:1400-10 PMCID:PMC1287917

[99] Tarnopolsky MA,Roy BD,Lowther SA.Attenuation of free radical production and paracrystalline inclusions by creatine supplementation in a patient with a novel cytochrome b mutation..Muscle Nerve2004;29:537-47

[100] Dumoulin R,Ferlin T,Stepien G.A novel gly290asp mitochondrial cytochrome b mutation linked to a complex III deficiency in progressive exercise intolerance..Mol Cell Probes1996;10:389-91

[101] Andreu AL,Shanske S,Hirano M.Missense mutation in the mtDNA cytochrome b gene in a patient with myopathy..Neurology1998;51:1444-7

[102] Pulkes T,Nelson IP.Classical mitochondrial phenotypes without mtDNA mutations: the possible role of nuclear genes..Neurology2003;61:1144-7

[103] Karadimas CL,Sue CM,Tanji K.Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA..Neurology2000;55:644-9

[104] Kollberg G,Lindberg C,Oldfors A.Mitochondrial myopathy and rhabdomyolysis associated with a novel nonsense mutation in the gene encoding cytochrome c oxidase subunit I..J Neuropathol Exp Neurol2005;64:123-8

[105] Rahman S,Cooper JM,Hargreaves I.A missense mutation of cytochrome oxidase subunit II causes defective assembly and myopathy..Am J Hum Genet1999;65:1030-9 PMCID:PMC1288235

[106] McFarland R,Chinnery PF,Turnbull DM.A novel sporadic mutation in cytochrome c oxidase subunit II as a cause of rhabdomyolysis..Neuromuscul Disord2004;14:162-6

[107] Kennaway NG,Hall RE,Keightley JA.Mitochondrial myopathy and cytochrome c oxidase (COX) deficiency associated with a 15 bp deletion in the gene for COX subunit III..(Abstract 827)” Neurology1994;44:A335

[108] Musumeci O,Shanske S,Comi GP.Intragenic inversion of mtDNA: a new type of pathogenic mutation in a patient with mitochondrial myopathy..Am J hum genet2000;66:1900-4 PMCID:PMC1378040

[109] Valnot I,Chretien D,Parfait B.A mitochondrial cytochrome b mutation but no mutations of nuclearly encoded subunits in ubiquinol cytochrome c reductase (complex III) deficiency..Human genetics1999;104:460-6

[110] Andreu AL,Iwata S,DiMauro S.A missense mutation in the mitochondrial cytochrome b gene in a revisited case with histiocytoid cardiomyopathy..Pediatr Res2000;48:311-4

[111] Gattermann N,Wang YL,Heinisch J.Heteroplasmic point mutations of mitochondrial DNA affecting subunit I of cytochrome c oxidase in two patients with acquired idiopathic sideroblastic anemia..Blood1997;90:4961-72

[112] Pandya A,Erdenetungalag R,Landa B.Heterogenous point mutations in the mitochondrial tRNA Ser(UCN) precursor coexisting with the A1555G mutation in deaf students from Mongolia..Am J Hum Genet1999;65:1803-6 PMCID:PMC1288397

[113] Wang Q,Zhao H,Liu Q.Clinical and molecular characterization of a Chinese patient with auditory neuropathy associated with mitochondrial 12S rRNA T1095C mutation..Am J Med Genet A2005;133A:27-30 PMCID:PMC1371058

[114] Shoffner JM,Torroni A,Cabell MF.Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients..Genomics1993;17:171-84

[115] Kosel S,Mehraein P.No association of mutations at nucleotide 5460 of mitochondrial NADH dehydrogenase with Alzheimer’s disease..Biochem Biophys Res Commun1994;203:745-9

[116] Lin FH,Wisniewski HM,Grundke-Iqbal I.Detection of point mutations in codon 331 of mitochondrial NADH dehydrogenase subunit 2 in Alzheimer’s brains..Biochem Biophys Res Commun1992;182:238-46

[117] Petruzzella V,Schon EA.Is a point mutation in the mitochondrial ND2 gene associated with Alzheimer’s disease..Biochem Biophys Res Commun1992;186:491-7

[118] Online Mendelian Inheritance in Man O. Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine.2019;Baltimore, MDJohns Hopkins University

[119] Westermann B.Mitochondrial fusion and fission in cell life and death..Nat Rev Mol Cell Biol2010;11:872-84

[120] Geto Z,Challa F,Getahun T.Mitochondrial dynamic dysfunction as a main triggering factor for inflammation associated chronic non-communicable diseases..J Inflamm Res2020;13:97-107 PMCID:PMC7034420

[121] Niyazov DM,Frye RE.Primary mitochondrial disease and secondary mitochondrial dysfunction: importance of distinction for diagnosis and treatment..Mol Syndromol2016;7:122-37 PMCID:PMC4988248

[122] Morava E,Hol F,Hogeveen M.Mitochondrial disease criteria: Diagnostic applications in children..Neurology2006;67:1823-6

[123] Bris C,Desquiret-Dumas V,Colin E.Bioinformatics Tools and Databases to Assess the Pathogenicity of Mitochondrial DNA Variants in the Field of Next Generation Sequencing..Front Genet2018;9:632 PMCID:PMC6297213

[124] Xu J,Koya D.The impact of mitochondrial quality control by Sirtuins on the treatment of type 2 diabetes and diabetic kidney disease..Biochim Biophys Acta Mol Basis Dis2020;1866:165756

[125] Li K,Liu J,Qi Q.Maternally inherited diabetes mellitus associated with a Novel m.15897G>A mutation in mitochondrial tRNA(Thr) gene..J Diabetes Res2020;2020:2057187 PMCID:PMC7011485

[126] Sangwung P,Shulman GI.Mitochondrial dysfunction, insulin resistance and potential genetic implications..Endocrinology2020;

[127] Pereira CA,Ferreira NS,Zanotto CZ.Mitochondrial DNA promotes NLRP3 inflammasome activation and contributes to endothelial dysfunction and inflammation in Type 1 diabetes..Front Physiol2020;10:1557 PMCID:PMC6978691

[128] Docrat TF,Naicker N,Singh S.The protective effect of metformin on mitochondrial dysfunction and endoplasmic reticulum stress in diabetic mice brain..Eur J Pharmacol2020;875:173059

[129] Umbria M,Aluja MP.The role of control region mitochondrial DNA mutations in cardiovascular disease: stroke and myocardial infarction..Sci Rep2020;10:2766 PMCID:PMC7026394

[130] Hirata Y,Suzuki S,Matsui R.Trans-Fatty acids facilitate DNA damage-induced apoptosis through the mitochondrial JNK-Sab-ROS positive feedback loop..Sci Rep2020;10:2743 PMCID:PMC7026443

[131] Aguilar-López BA,Dockrell HM,Sánchez-García FJ.Mitochondria: an integrative Hub coordinating circadian rhythms, metabolism, the microbiome, and immunity..Front Cell Dev Biol2020;8:51 PMCID:PMC7025554

[132] Yang S,Guo Y,Qi F.Circadian gene clock participates in mitochondrial apoptosis pathways by regulating mitochondrial membrane potential, mitochondria out membrane permeablization and apoptosis factors in AML12 hepatocytes..Mol Cell Biochem2020;

[133] Sardon Puig L,Cantó C.Circadian rhythms and mitochondria: connecting the dots..Front genet2018;9:452 PMCID:PMC6187225

[134] Rahman A,Nishiyama A.Altered circadian timing system-mediated non-dipping pattern of blood pressure and associated cardiovascular disorders in metabolic and kidney diseases..Int J Mol Sci2018;19:400 PMCID:PMC5855622

[135] Gombert M,Pin-Arboledas G.The connection of circadian rhythm to inflammatory bowel disease..Trans Res2019;206:107-18

[136] Maiese K.Moving to the rhythm with clock (Circadian) genes, autophagy, mTOR, and SIRT1 in degenerative disease and cancer..Curr Neurovasc Res2017;14:299-304 PMCID:PMC5600856

[137] Leng Y,Hu K,Yaffe K.Association between circadian rhythms and neurodegenerative diseases..Lancet Neurol2019;18:307-18 PMCID:PMC6426656

[138] Takaguri A,Akihiro O.The role of circadian clock gene BMAL1 in vascular proliferation..Eur J Pharmacol2020;872:172924

[139] Škrlec I,Steiner R.The impact of the circadian genes CLOCK and ARNTL on myocardial infarction..J Clin Med2020;9:484 PMCID:PMC7074039

[140] Zhang ZQ,Wang XA,Yu B.Abnormal circadian rhythms are associated with plaque instability in acute coronary syndrome patients..Int J Clin Exp Pathol2019;12:3761-71 PMCID:PMC6949736

[141] Wang XB,Liu Xn.Mitochondrial 8-hydroxy-2’-deoxyguanosine and coronary artery disease in patients with type 2 diabetes mellitus..Cardiovasc Diabetol2020;19:22 PMCID:PMC7029479

[142] Ward PS.Metabolic reprogramming: a cancer hallmark even warburg did not anticipate..Cancer Cell2012;21:297-308 PMCID:PMC3311998

[143] Ganapathy-Kanniappan S.Molecular intricacies of aerobic glycolysis in cancer: current insights into the classic metabolic phenotype..Crit Rev Biochem Mol Biol2018;53:667-82

[144] Feng Z,de Stanchina E,Jin S.The regulation of AMPK β1, TSC2, and PTEN Expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways..Cancer Res2007;67:3043-53

[145] Levine AJ.The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes..Science2010;330:1340-4

[146] Elstrom RL,Buzzai M,Harris MH.Akt stimulates aerobic glycolysis in cancer cells..Cancer Res2004;64:3892-9

[147] Gray LR,Taylor EB.Regulation of pyruvate metabolism and human disease..Cell Mol Life Sci2014;71:2577-604 PMCID:PMC4059968

[148] Bauer DE,Zhao F,Thompson CB.ATP citrate lyase is an important component of cell growth and transformation..Oncogene2005;24:6314-22

[149] Hatzivassiliou G,Bauer DE,Shaw AN.ATP citrate lyase inhibition can suppress tumor cell growth..Cancer Cell2005;8:311-21

[150] Land SC.Hypoxia-inducible factor 1α is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif..J Biolog Chem2007;282:20534-43

[151] Sakamoto T,Hara T,Kozuka-Hata H.Hypoxia-inducible factor 1 regulation through cross talk between mTOR and MT1-MMP..Mol Cell Biol2014;34:30-42 PMCID:PMC3911284

[152] Kietzmann T,Dimova EY.Hypoxia-inducible factors (HIFs) and Phosphorylation: impact on stability, localization, and transactivity..Front Cell Dev Biol2016;4: PMCID:PMC4763087

[153] Papandreou I,Fontana L,Denko NC.HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption..Cell Metab2006;3:187-97

[154] Kim JW,Semenza GL.HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia..Cell Metab2006;3:177-85

[155] Le A,Hamaker M,Gouw A.Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells..Cell Metab2012;15:110-21 PMCID:PMC3345194

[156] Wang JB,Fuji R,Gao P.Targeting mitochondrial glutaminase activity inhibits oncogenic transformation..Cancer cell2010;18:207-19 PMCID:PMC3078749

[157] Itahana Y.Emerging roles of p53 family members in glucose metabolism..Int J Mol Sci2018;19:776 PMCID:PMC5877637

[158] Schwartzenberg-Bar-Yoseph F,Karnieli E.The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression..Cancer Res2004;64:2627-33

[159] Boidot R,Meulle A,Dessy C.Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors..Cancer Res2012;72:939-48

[160] Bensaad K,Selak MA,Nakano K.TIGAR, a p53-inducible regulator of glycolysis and apoptosis..Cell2006;126:107-20

[161] Kondoh H,Gil J,Degan P.Glycolytic enzymes can modulate cellular life Span..Cancer Res2005;65:177-85

[162] Zhou S,Singh KK.Mitochondrial impairment in p53-deficient human cancer cells..Mutagenesis2003;18:287-92

[163] Lebedeva MA,Shadel GS.Loss of p53 causes mitochondrial DNA depletion and altered mitochondrial reactive oxygen species homeostasis..Biochim Biophys Acta2009;1787:328-34 PMCID:PMC2680458

[164] Kulawiec M,Singh KK.p53 regulates mtDNA copy number and mitocheckpoint pathway..J carcinog2009;8:8 PMCID:PMC2687143

[165] D’Souza AD,Kaech SM.Convergence of multiple signaling pathways is required to coordinately up-regulate mtDNA and mitochondrial biogenesis during T cell activation..Mitochondrion2007;7:374-85 PMCID:PMC2692272

[166] Di Donato S.Disorders related to mitochondrial membranes: pathology of the respiratory chain and neurodegeneration..J Inherit Metab Dis2000;23:247-63

[167] Polster BM.Mitochondrial mechanisms of neural cell apoptosis..J Neurochem2004;90:1281-9

[168] Rehm M,Jänicke RU,Kögel D.Single-cell fluorescence resonance energy transfer analysis demonstrates that caspase activation during apoptosis is a rapid process: role of caspase-3..J Biol Chem2002;277:24506-14

[169] Verhagen AM,Pakusch M,Connolly LM.Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins..Cell2000;102:43-53

[170] Liu X,Yang J,Wang X.Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c..Cell1996;86:147-57

[171] Susin SA,Zamzami N,Snow BE.Molecular characterization of mitochondrial apoptosis-inducing factor..Nature1999;397:441-6

[172] Du C,Li Y,Wang X.Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition..Cell2000;102:33-42

[173] Zou H,Liu X.An APAF-1·Cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9..J Biolog Chem1999;274:11549-56

[174] Trushina E.Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases..Neuroscience2007;145:1233-48

[175] Saccon RA,Fisher EMC.Is SOD1 loss of function involved in amyotrophic lateral sclerosis?.Brain: a journal of neurology2013;136:2342-58 PMCID:PMC3722346

[176] Grünewald A,Sue CM.New insights into the complex role of mitochondria in Parkinson’s disease..Prog Neurobiol2019;177:73-93

[177] Antony PMA,Mommaerts K,Sokolowska K.Fibroblast mitochondria in idiopathic Parkinson’s disease display morphological changes and enhanced resistance to depolarization..Sci Rep2020;10:1569 PMCID:PMC6994699

[178] Sironi L,Tolnay M,Frank S.Dysregulated Interorganellar Crosstalk Of Mitochondria In The Pathogenesis of Parkinson’s disease..Cells2020;9:233 PMCID:PMC7016713

[179] Suomalainen A.Mitochondrial diseases: the contribution of organelle stress responses to pathology..Nat Rev Mol Cell Biol2018;19:77-92

[180] Rahman J.Mitochondrial medicine in the omics era..Lancet2018;391:2560-74

[181] Holt IJ,Morgan-Hughes JA.Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies..Nature1988;331:717-9

[182] Ingman M.mtDB: Human mitochondrial genome database, a resource for population genetics and medical sciences..Nucleic Acids Res2006;34:D749-51 PMCID:PMC1347373

[183] Bourgeron T,Chretien D,Bourgeois M.Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency..Nat Genet1995;11:144-9

[184] Ye F,Clark T.High-throughput sequencing in mitochondrial DNA research..Mitochondrion2014;17:157-63 PMCID:PMC4149223

[185] Liang MH,Wong LJC.Preparation and validation of PCR-generated positive controls for diagnostic dot blotting..Clin Chem1998;44:1578-9

[186] Bai RK.Detection and quantification of heteroplasmic mutant mitochondrial DNA by real-time amplification refractory mutation system quantitative PCR analysis: a single-step approach..Clin Chem2004;50:996-1001

[187] White HE,Seller A,Harvey JF.Accurate detection and quantitation of heteroplasmic mitochondrial point mutations by pyrosequencing..Genet Test2005;9:190-9

[188] Pronicka E,Ciara E,Rokicki D.New perspective in diagnostics of mitochondrial disorders: two years’ experience with whole-exome sequencing at a national paediatric centre..J Transl Med2016;14:174 PMCID:PMC4903158

[189] Kohda M,Kishita Y,Moriyama Y.A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies..PLoS Genet2016;12:e1005679 PMCID:PMC4704781

[190] Calvo SE,Hershman SG,Lieber DS.Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing..Sci Transl Med2012;4:118ra10 PMCID:PMC3523805

[191] Gould MP,McMahon S,Grimberg BT.PCR-free enrichment of mitochondrial DNA from human blood and cell lines for high quality next-generation DNA sequencing..PLoS One2015;10:e0139253 PMCID:PMC4619561

[192] Vasta V,Turner EH,Hahn SH.Next generation sequence analysis for mitochondrial disorders..Genome Med2009;1:100 PMCID:PMC2784303

[193] Sosa MX,Maragh S,Hariharan R.Next-generation sequencing of human mitochondrial reference genomes uncovers high heteroplasmy frequency..PLoS Comput Biol2012;8:e1002737 PMCID:PMC3486893

[194] Dayama G,Kidd JM.The genomic landscape of polymorphic human nuclear mitochondrial insertions..Nucleic Acids Res2014;42:12640-9 PMCID:PMC4227756

[195] Picardi E.Mitochondrial genomes gleaned from human whole-exome sequencing..Nat Methods2012;9:523-4

[196] Guo Y,Li CI,Samuels DC.MitoSeek: extracting mitochondria information and performing high-throughput mitochondria sequencing analysis..Bioinformatics2013;29:1210-1 PMCID:PMC4492415

[197] Falk MJ,Gonzalez M,Lott MT.Mitochondrial disease sequence data resource (MSeqDR): a global grass-roots consortium to facilitate deposition, curation, annotation, and integrated analysis of genomic data for the mitochondrial disease clinical and research communities..Mol Genet Metabol2015;114:388-96 PMCID:PMC4512182

[198] Kogelnik AM,Brown MD,Wallace DC.MITOMAP: a human mitochondrial genome database..Nucleic acids Res1996;24:177-9 PMCID:PMC145607

[199] Preste R,Clima R,Attimonelli M.HmtVar: a new resource for human mitochondrial variations and pathogenicity data..Nucleic Acids Res2019;47:D1202-10 PMCID:PMC6323908

[200] Clima R,Calabrese C,Santorsola M.HmtDB 2016: data update, a better performing query system and human mitochondrial DNA haplogroup predictor..Nucleic Acids Res2017;45:D698-706 PMCID:PMC5210550

[201] Rahman J,Thiele I.Leigh map: a novel computational diagnostic resource for mitochondrial disease..Ann Neurol2017;81:9-16 PMCID:PMC5347854

[202] Abicht A,Kleinle S,Holinski-Feder E.Mitochondrial and nuclear disease panel (Mito-aND-Panel): combined sequencing of mitochondrial and nuclear DNA by a cost-effective and sensitive NGS-based method..Mol Genet Genomic Med2018;6:1188-98 PMCID:PMC6305657

[203] Dames S,Xiao Y,Stocks J.The development of next-generation sequencing assays for the mitochondrial genome and 108 nuclear genes associated with mitochondrial disorders..J Mol Diagnos2013;15:526-34

[204] Pereira V,Borsting C.Sequencing of mitochondrial genomes using the precision ID mtDNA whole genome panel..Electrophoresis2018;39:2766-75

[205] Marquis J,Kourmpetis YAI,Ronga F.MitoRS, a method for high throughput, sensitive, and accurate detection of mitochondrial DNA heteroplasmy..BMC Genomics2017;18:326 PMCID:PMC5405551

[206] Kremer LS,Mertes C,Pichler G.Genetic diagnosis of Mendelian disorders via RNA sequencing..Nat Commun2017;8:15824 PMCID:PMC5499207

[207] Cummings BB,Tukiainen T,Donkervoort S.Improving genetic diagnosis in Mendelian disease with transcriptome sequencing..Sci Transl Med2017;9:eaal5209 PMCID:PMC5548421

[208] Gómez-Serrano M,Loureiro M.Mitoproteomics: tackling mitochondrial dysfunction in human disease..Oxid Med Cell Longev2018;2018:1435934 PMCID:PMC6250043

[209] Calvo SE,Mootha VK.MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins..Nucleic Acids Res2016;44:D1251-7 PMCID:PMC4702768

[210] Scharfe C,Hoertnagel K,Klopstock T.MITOP: database for mitochondria-related proteins, genes and diseases..Nucleic Acids Res1999;27:153-5 PMCID:PMC148118

[211] Cotter D,Fahy E.MitoProteome: mitochondrial protein sequence database and annotation system..Nucleic Acids Res2004;32:D463-7 PMCID:PMC308782

[212] Elstner M,Ahting U,Klopstock T.MitoP2: an integrative tool for the analysis of the mitochondrial proteome..Mol Biotechnol2008;40:306-15

[213] Smith AC.MitoMiner, an integrated database for the storage and analysis of mitochondrial proteomics data..Mol Cell Proteomics2009;8:1324-37 PMCID:PMC2690483

[214] Floyd BJ,Veling MT,Xia C.Mitochondrial protein interaction mapping identifies regulators of respiratory chain function..Mol Cell2016;63:621-32 PMCID:PMC4992456

[215] Lake NJ,Stroud DA,Ruzzenente B.Biallelic mutations in MRPS34 lead to instability of the small mitoribosomal subunit and leigh syndrome..Am J Hum Genet2017;101:239-54 PMCID:PMC5544391

[216] Debray FG,Allard P,Hanley JA.Diagnostic accuracy of blood lactate-to-pyruvate molar ratio in the differential diagnosis of congenital lactic acidosis..Clin Chem2007;53:916-21

[217] Finsterer J,Jarius C.Lactate-stress testing in 54 patients with mitochondriopathy..Eur Arch Psychiatry Clin Neurosci2000;250:36-9

[218] Finsterer J.Stress lactate in mitochondrial myopathy under constant, unadjusted workload..Eur J Neurol2004;11:811-6

[219] Thompson Legault J,Tardif J,Tremblay-Vaillancourt V.A metabolic signature of mitochondrial dysfunction revealed through a monogenic form of leigh syndrome..Cell Rep2015;13:981-9 PMCID:PMC4644511

[220] Rodenburg RJ.The functional genomics laboratory: functional validation of genetic variants..J Inherit Metab Dis2018;41:297-307 PMCID:PMC5959958

[221] Gasperskaja E.The most common technologies and tools for functional genome analysis..Acta Med Litu2017;24:1-11 PMCID:PMC5467957

[222] Thompson K,Glasgow RIC,Pyle A.Recent advances in understanding the molecular genetic basis of mitochondrial disease..J Inherit Metab Dis2020;43:36-50 PMCID:PMC7041634

[223] Consortium GT.Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans..Science2015;348:648-60 PMCID:PMC4547484

[224] Gropman AL.Neuroimaging in mitochondrial disorders..Neurotherapeutics2013;10:273-85 PMCID:PMC3625392

[225] Lunsing RJ,de Koning TJ.Diagnostic value of MRS-quantified brain tissue lactate level in identifying children with mitochondrial disorders..Eur Radiol2017;27:976-84 PMCID:PMC5306328

[226] Chi CS,Tsai CR,Tung JN.Lactate peak on brain MRS in children with syndromic mitochondrial diseases..J Chin Med Assoc2011;74:305-9

[227] Dinopoulos A,Schapiro MB,Hadjigeorgiou GM.Brain MRI and proton MRS findings in infants and children with respiratory chain defects..Neuropediatrics2005;36:290-301

[228] Matthews PM,Shoubridge EA,Carpenter S.In vivo muscle magnetic resonance spectroscopy in the clinical investigation of mitochondria1 disease..Neurology1991;41:114

[229] Saito S,Ohki A,Higuchi T.Early detection of elevated lactate levels in a mitochondrial disease model using chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) at 7T-MRI..Radiol Phys Technol2019;12:46-54

[230] Farina L,Uziel G,Zeviani M.MR findings in Leigh syndrome with COX deficiency and SURF-1 mutations..Am J neuroradiol2002;23:1095-100

[231] Bluml S,Ross BD.Developmental changes in choline- and ethanolamine-containing compounds measured with proton-decoupled (31)P MRS in in vivo human brain..Magn Reson Med1999;42:643-54

[232] Pouwels PJ,Kruse B,Wick M.Regional age dependence of human brain metabolites from infancy to adulthood as detected by quantitative localized proton MRS..Pediatric Res1999;46:474-85

[233] Thompson K,Dallabona C,King MS.Recurrent de novo dominant mutations in SLC25A4 cause severe early-onset mitochondrial disease and loss of mitochondrial DNA copy number..Am J Hum Genet2016;99:860-76 PMCID:PMC5065686

[234] Deciphering Developmental Disorders StudyLarge-scale discovery of novel genetic causes of developmental disorders..Nature2015;519:223-8 PMCID:PMC5955210

[235] Griffin BH,Bitner-Glindzicz M.The 100 000 genomes project: what it means for paediatrics..Arch Dis Child Educ Pract Ed2017;102:105-7

[236] Stewart JB.The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease..Nat Rev Genet2015;16:530-42

[237] Perales-Clemente E,Evans JM,Secreto F.Natural underlying mtDNA heteroplasmy as a potential source of intra-person hiPSC variability..EMBO J2016;35:1979-90 PMCID:PMC5282833

[238] Hall AM,Garcia-Perez I,Alston CL.The urinary proteome and metabonome differ from normal in adults with mitochondrial disease..Kidney Int2015;87:610-22

[239] Wettmarshausen J.Isolation of functional mitochondria from cultured cells and mouse tissues. Mitochondria: Practical Protocols.2017;New YorkSpringer New York15-32

[240] Frezza C,Scorrano L.Organelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts..Nat Protoc2007;2:287-95

[241] Tang B,Liang R,Wang L.Magnetic nanoparticles: an improved method for mitochondrial isolation..Mol Med Rep2012;5:1271-6

[242] Pagliarini DJ,Chang B,Vafai SB.A mitochondrial protein compendium elucidates complex I disease biology..Cell2008;134:112-23 PMCID:PMC2778844

[243] Mootha VK,Olsen JV,Wisniewski JR.Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria..Cell2003;115:629-40

[244] Foster LJ,Zhang Y,Xie X.A mammalian organelle map by protein correlation profiling..Cell2006;125:187-99

[245] Costain G,Walker S,Snell M.Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing..Eur J Hum Genet2018;26:740-4 PMCID:PMC5945683

[246] Yang Y,Reid JG,Willis A.Clinical whole-exome sequencing for the diagnosis of mendelian disorders..N Engl J Med2013;369:1502-11 PMCID:PMC4211433

[247] Sun Y,Liu Y,Yu J.Increased diagnostic yield by reanalysis of data from a hearing loss gene panel..BMC Med Genom2019;12:76 PMCID:PMC6540452

[248] Salfati EL,Topol SE,Rueda M.Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases..Genome Med2019;11:83 PMCID:PMC6916453

[249] Rehm HL,Brooks LD,Evans JP.ClinGen--the clinical genome resource..N Engl J Med2015;372:2235-42 PMCID:PMC4474187

[250] Landrum MJ,Brown GR,Gu B.ClinVar: improvements to accessing data..Nucleic Acids Res2019;48:D835-44 PMCID:PMC6943040