{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:03:20Z","timestamp":1790676200071,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T00:00:00Z","timestamp":1573516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The history of \u201cmitochondrial pathologies\u201d, namely genetic pathologies affecting mitochondrial metabolism because of mutations in nuclear DNA-encoded genes for proteins active inside mitochondria or mutations in mitochondrial DNA-encoded genes, began in 1988. In that year, two different groups of researchers discovered, respectively, large-scale single deletions of mitochondrial DNA (mtDNA) in muscle biopsies from patients with \u201cmitochondrial myopathies\u201d and a point mutation in the mtDNA gene for subunit 4 of NADH dehydrogenase (MTND4), associated with maternally inherited Leber\u2019s hereditary optic neuropathy (LHON). Henceforth, a novel conceptual \u201cmitochondrial genetics\u201d, separate from mendelian genetics, arose, based on three features of mtDNA: (1) polyplasmy; (2) maternal inheritance; and (3) mitotic segregation. Diagnosis of mtDNA-related diseases became possible through genetic analysis and experimental approaches involving histochemical staining of muscle or brain sections, single-fiber polymerase chain reaction (PCR) of mtDNA, and the creation of patient-derived \u201ccybrid\u201d (cytoplasmic hybrid) immortal fibroblast cell lines. The availability of the above-mentioned techniques along with the novel sensitivity of clinicians to such disorders led to the characterization of a constantly growing number of pathologies. Here is traced a brief historical perspective on the discovery of autonomous pathogenic mtDNA mutations and on the related mendelian pathology altering mtDNA integrity.<\/jats:p>","DOI":"10.3390\/ijms20225643","type":"journal-article","created":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T04:07:07Z","timestamp":1573531627000},"page":"5643","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["A Brief History of Mitochondrial Pathologies"],"prefix":"10.3390","volume":"20","author":[{"given":"Salvatore","family":"DiMauro","sequence":"first","affiliation":[{"name":"Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/331717a0","article-title":"Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies","volume":"331","author":"Holt","year":"1988","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1126\/science.3201231","article-title":"Mitochondrial DNA mutation associated with Leber\u2019s hereditary optic neuropathy","volume":"242","author":"Wallace","year":"1988","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1212\/WNL.38.8.1339","article-title":"Deletions of mitochondrial DNA in Kearns-Sayre syndrome","volume":"38","author":"Zeviani","year":"1988","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1056\/NEJMra022567","article-title":"Mitochondrial respiratory-chain diseases (Mechanisms of Disease)","volume":"348","author":"DiMauro","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nrneurol.2013.126","article-title":"The clinical maze of mitochondrial neurology","volume":"9","author":"DiMauro","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1056\/NEJM199909303411404","article-title":"Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA","volume":"341","author":"Andreu","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6715","DOI":"10.1073\/pnas.77.11.6715","article-title":"Maternal inheritance of human mitochondrial DNA","volume":"77","author":"Giles","year":"1980","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/S0140-6736(04)16851-7","article-title":"Risk of developing a mitochondrial DNA deletion disorder","volume":"364","author":"Chinnery","year":"2004","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13039","DOI":"10.1073\/pnas.1810946115","article-title":"Biparental Inheritance of Mitochondrial DNA in Humans","volume":"115","author":"Luo","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0091-679X(06)80006-3","article-title":"Optical imaging techniques (histochemical, immunohistochemical, and in situ hybridization staining methods) to visualize mitochondria","volume":"80","author":"Tanji","year":"2007","journal-title":"Methods Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1002\/ana.20758","article-title":"Motor neuron disease in a patient with a mitochondrial tRNAIle mutation","volume":"59","author":"Borthwick","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1172\/JCI116913","article-title":"Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. Is the tRNA (Leu(UUR)) gene an etiologic hot spot?","volume":"92","author":"Moraes","year":"1993","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1212\/WNL.55.5.644","article-title":"Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA","volume":"55","author":"Karadimas","year":"2000","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1126\/science.2814477","article-title":"Human cells lacking mtDNA: Repopulation with exogenous mitochondria by complementation","volume":"246","author":"King","year":"1989","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/339309a0","article-title":"An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region","volume":"339","author":"Zeviani","year":"1989","journal-title":"Nature"},{"key":"ref_16","first-page":"492","article-title":"mtDNA depletion with variable tissue expression: A novel genetic abnormality in mitochondrial diseases","volume":"48","author":"Moraes","year":"1991","journal-title":"Am. J. Hum. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1212\/WNL.42.1.209","article-title":"Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA","volume":"42","author":"Tritschler","year":"1992","journal-title":"Neurology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/ng746","article-title":"The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA","volume":"29","author":"Mandel","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1136\/jmedgenet-2017-105012","article-title":"Retrospective natural history of thymidine kinase 2 deficiency","volume":"55","author":"Garone","year":"2018","journal-title":"J. Med. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ymgme.2018.04.012","article-title":"Clinical and molecular spectrum of thymidine kinase 2-related mtDNA maintenance defect","volume":"124","author":"Wang","year":"2018","journal-title":"Mol. Genet. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1002\/ana.24922","article-title":"Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency","volume":"81","author":"Levy","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1042\/EBC20170114","article-title":"Emerging therapies for mitochondrial diseases","volume":"62","author":"Hirano","year":"2018","journal-title":"Essays Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1086\/430843","article-title":"Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion","volume":"76","author":"Elpeleg","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1177\/0883073816666221","article-title":"A Novel SUCLA2 Mutation Presenting as a Complex Childhood Movement Disorder","volume":"32","author":"Garone","year":"2017","journal-title":"J. Child. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1203\/PDR.0b013e3181e5c3a4","article-title":"Succinyl-CoA ligase deficiency: A mitochondrial hepatoencephalomyopathy","volume":"68","author":"Saenz","year":"2010","journal-title":"Pediatr. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.nmd.2008.04.006","article-title":"Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene","volume":"18","author":"Bornstein","year":"2008","journal-title":"Neuromuscul. Disord."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"R92","DOI":"10.1186\/gb-2011-12-9-r92","article-title":"Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia","volume":"12","author":"Takata","year":"2011","journal-title":"Genome Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1136\/jmg.2010.088328","article-title":"Kearns-Sayre syndrome caused by defective R1\/p53R2 assembly","volume":"48","author":"Pitceathly","year":"2011","journal-title":"J. Med. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1001\/archneurol.2009.139","article-title":"Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B","volume":"66","author":"Shaibani","year":"2009","journal-title":"Arch. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1126\/science.283.5402.689","article-title":"Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder","volume":"283","author":"Nishino","year":"1999","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1093\/hmg\/ddh010","article-title":"ND5 is a hot-spot for multiple atypical mitochondrial DNA deletions in mitochondrial neurogastrointestinal encephalomyopathy","volume":"13","author":"Nishigaki","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1093\/brain\/awv226","article-title":"Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy","volume":"138","author":"Halter","year":"2015","journal-title":"Brain"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/ng1765","article-title":"MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion","volume":"38","author":"Spinazzola","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1086\/506913","article-title":"Navajo neurohepatopathy is caused by a mutation in the MPV17 gene","volume":"79","author":"Karadimas","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1212\/01.wnl.0000182814.55361.70","article-title":"POLG mutations in Alpers syndrome","volume":"65","author":"Nguyen","year":"2005","journal-title":"Neurology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E150","DOI":"10.1002\/humu.20824","article-title":"Molecular and clinical genetics of mitochondrial diseases due to POLG mutations","volume":"29","author":"Wong","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1172\/JCI115856","article-title":"Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia","volume":"90","author":"Suomalainen","year":"1992","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1126\/science.289.5480.782","article-title":"Role of adenine nucleotide translocator 1 in mtDNA maintenance","volume":"289","author":"Kaukonen","year":"2000","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s10545-014-9708-5","article-title":"Mitochondrial transporters of the SLC25 family and associated diseases: A review","volume":"37","author":"Palmieri","year":"2014","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1001\/jamaneurol.2013.3185","article-title":"Longitudinal clinical follow-up of a large family with the R357P Twinkle mutation","volume":"70","author":"Paradas","year":"2013","journal-title":"JAMA Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1002\/mus.21439","article-title":"Clinical phenotype of autosomal dominant progressive external ophthalmoplegia in a family with a novel mutation in the C10orf2 gene","volume":"41","author":"Hong","year":"2010","journal-title":"Muscle Nerve"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1093\/hmg\/ddi328","article-title":"Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky","volume":"14","author":"Nikali","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3822","DOI":"10.1093\/hmg\/ddn280","article-title":"Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion","volume":"17","author":"Hakonen","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1212\/WNL.0b013e31827f0ff7","article-title":"TK2 mutation presenting as indolent myopathy","volume":"80","author":"Paradas","year":"2013","journal-title":"Neurology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/0887-8994(96)00118-X","article-title":"Mitochondrial myopathy simulating spinal muscular atrophy","volume":"15","author":"Pons","year":"1996","journal-title":"Pediatr. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1001\/archneurol.2012.405","article-title":"MPV17 Mutations Causing Adult-Onset Multisystemic Disorder with Multiple Mitochondrial DNA Deletions","volume":"69","author":"Garone","year":"2012","journal-title":"Arch. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.1093\/brain\/aws258","article-title":"Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions","volume":"135","author":"Ronchi","year":"2012","journal-title":"Brain"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1086\/504303","article-title":"Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia","volume":"78","author":"Longley","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.ejmg.2016.08.012","article-title":"Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion","volume":"59","author":"Varma","year":"2016","journal-title":"Eur. J. Med. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.freeradbiomed.2016.06.011","article-title":"The role of mitochondrial DNA damage in the development of atherosclerosis","volume":"100","author":"Yu","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1146\/annurev-physiol-021115-105127","article-title":"DNA Damage and Repair in Vascular Disease","volume":"78","author":"Uryga","year":"2016","journal-title":"Annu. Rev. Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6934394","DOI":"10.1155\/2017\/6934394","article-title":"Role of Mitochondrial Genome Mutations in Pathogenesis of Carotid Atherosclerosis","volume":"2017","author":"Sazonova","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Volobueva, A., Grechko, A., Yet, S.F., Sobenin, I., and Orekhov, A. (2019). Changes in Mitochondrial Genome Associated with Predisposition to Atherosclerosis and Related Disease. Biomolecules, 9.","DOI":"10.3390\/biom9080377"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Sazonova, M.A., Sinyov, V.V., Ryzhkova, A.I., Sazonova, M.D., Khasanova, Z.B., Shkurat, T.P., Karagodin, V.P., Orekhov, A.N., and Sobenin, I.A. (2019). Creation of Cybrid Cultures Containing mtDNA Mutations m.12315G>A and m.1555G>A, Associated with Atherosclerosis. Biomolecules, 9.","DOI":"10.3390\/biom9090499"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/22\/5643\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:33:40Z","timestamp":1760189620000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/22\/5643"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,12]]},"references-count":54,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["ijms20225643"],"URL":"https:\/\/doi.org\/10.3390\/ijms20225643","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,12]]}}}