{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:36:30Z","timestamp":1790890590491,"version":"4.1.0"},"reference-count":80,"publisher":"Oxford University Press (OUP)","issue":"R2","license":[{"start":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T00:00:00Z","timestamp":1624579200000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["CL-2016-01-003"],"award-info":[{"award-number":["CL-2016-01-003"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["204709\/Z\/16\/Z"],"award-info":[{"award-number":["204709\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["215888\/Z\/19\/Z"],"award-info":[{"award-number":["215888\/Z\/19\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["203105\/Z\/16\/Z"],"award-info":[{"award-number":["203105\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Newcastle University Centre for Ageing and Vitality"},{"name":"Biotechnology and Biological Sciences Research Council and Medical Research Council","award":["G016354\/1"],"award-info":[{"award-number":["G016354\/1"]}]},{"name":"United Kingdom National Institute for Health Research Biomedical Research Centre for Ageing and Age-Related Disease"},{"name":"Newcastle upon Tyne Hospitals National Health Service Foundation Trust"},{"name":"Lily Foundation"},{"name":"United Kingdom National Health Service Specialist Commissioners"},{"name":"Rare Mitochondrial Disorders of Adults and Children Diagnostic Service in Newcastle upon Tyne"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mitochondrial DNA (mtDNA) disorders are recognized as one of the most common causes of inherited metabolic disorders. The mitochondrial genome occurs in multiple copies resulting in both homoplasmic and heteroplasmic pathogenic mtDNA variants. A biochemical defect arises when the pathogenic variant level reaches a threshold, which differs between variants. Moreover, variants can segregate, clonally expand, or be lost from cellular populations resulting in a dynamic and tissue-specific mosaic pattern of oxidative deficiency. MtDNA is maternally inherited but transmission patterns of heteroplasmic pathogenic variants are complex. During oogenesis, a mitochondrial bottleneck results in offspring with widely differing variant levels to their mother, whilst highly deleterious variants, such as deletions, are not transmitted. Complemented by a complex interplay between mitochondrial and nuclear genomes, these peculiar genetics produce marked phenotypic variation, posing challenges to the diagnosis and clinical management of patients. Novel therapeutic compounds and several genetic therapies are currently under investigation, but proven disease-modifying therapies remain elusive. Women who carry pathogenic mtDNA variants require bespoke genetic counselling to determine their reproductive options. Recent advances in in vitro fertilization techniques, have greatly improved reproductive choices, but are not without their challenges. Since the first pathogenic mtDNA variants were identified over 30 years ago, there has been remarkable progress in our understanding of these diseases. However, many questions remain unanswered and future studies are required to investigate the mechanisms of disease progression and to identify new disease-specific therapeutic targets.<\/jats:p>","DOI":"10.1093\/hmg\/ddab156","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T23:12:05Z","timestamp":1623885125000},"page":"R245-R253","source":"Crossref","is-referenced-by-count":38,"title":["Mitochondrial DNA disorders: from pathogenic variants to preventing transmission"],"prefix":"10.1093","volume":"30","author":[{"given":"Tiago M","family":"Bernardino Gomes","sequence":"first","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Shiau","family":"Ng","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J","family":"Pickett","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doug M","family":"Turnbull","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E","family":"Vincent","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,24]]},"reference":[{"key":"2021100513221726900_ref1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/13779","article-title":"Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA","volume":"23","author":"Andrews","year":"1999","journal-title":"Nat. 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