{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:29:13Z","timestamp":1790832553117,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T00:00:00Z","timestamp":1671580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC-109-2314-B-195-015-MY3"],"award-info":[{"award-number":["NSTC-109-2314-B-195-015-MY3"]}]},{"name":"National Science and Technology Council","award":["NSTC-109-2314-B-195-014-MY2"],"award-info":[{"award-number":["NSTC-109-2314-B-195-014-MY2"]}]},{"name":"National Science and Technology Council","award":["MMH-E-110-02"],"award-info":[{"award-number":["MMH-E-110-02"]}]},{"name":"National Science and Technology Council","award":["MMH-E-111-02"],"award-info":[{"award-number":["MMH-E-111-02"]}]},{"name":"Mackay Memorial Hospital","award":["NSTC-109-2314-B-195-015-MY3"],"award-info":[{"award-number":["NSTC-109-2314-B-195-015-MY3"]}]},{"name":"Mackay Memorial Hospital","award":["NSTC-109-2314-B-195-014-MY2"],"award-info":[{"award-number":["NSTC-109-2314-B-195-014-MY2"]}]},{"name":"Mackay Memorial Hospital","award":["MMH-E-110-02"],"award-info":[{"award-number":["MMH-E-110-02"]}]},{"name":"Mackay Memorial Hospital","award":["MMH-E-111-02"],"award-info":[{"award-number":["MMH-E-111-02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The MELAS syndrome primarily affecting the CNS is mainly caused by the m.A3243G mutation. The heteroplasmy in different tissues affects the phenotypic spectrum, yet the impact of various levels of m.A3243G heteroplasmy on CNS remains elusive due to the lack of a proper neuronal model harboring m.A3243G mutation. We generated induced neurons (iNs) through the direct reprogramming of MELAS patients, with derived fibroblasts harboring high (&gt;95%), intermediate (68%), and low (20%) m.A3243G mutation. iNs demonstrated neuronal morphology with neurite outgrowth, branching, and dendritic spines. The heteroplasmy and deficiency of respiratory chain complexes were retained in MELAS iNs. High heteroplasmy elicited the elevation in ROS levels and the disruption of mitochondrial membrane potential. Furthermore, high and intermediate heteroplasmy led to the impairment of mitochondrial bioenergetics and a change in mitochondrial dynamics toward the fission and fragmentation of mitochondria, with a reduction in mitochondrial networks. Moreover, iNs derived from aged individuals manifested with mitochondrial fission. These results help us in understanding the impact of various heteroplasmic levels on mitochondrial bioenergetics and mitochondrial dynamics in neurons as the underlying pathomechanism of neurological manifestations of MELAS syndrome. Furthermore, these findings provide targets for further pharmacological approaches of mitochondrial diseases and validate iNs as a reliable platform for studies in neuronal aspects of aging, neurodegenerative disorders, and mitochondrial diseases.<\/jats:p>","DOI":"10.3390\/cells12010015","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T03:59:26Z","timestamp":1671595166000},"page":"15","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Impact of Mitochondrial A3243G Heteroplasmy on Mitochondrial Bioenergetics and Dynamics of Directly Reprogrammed MELAS Neurons"],"prefix":"10.3390","volume":"12","author":[{"given":"Dar-Shong","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Mackay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"Department of Medicine, Mackay Medical College, New Taipei 25245, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Wen","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Mackay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Che-Sheng","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mackay Medical College, New Taipei 25245, Taiwan"},{"name":"Department of Neurology, Mackay Children\u2019s Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tung-Sun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Mackay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsung-Han","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Mackay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsu-Yen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Mackay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zon-Darr","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Mackay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuan-Jen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Mackay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"D611","DOI":"10.1093\/nar\/gki079","article-title":"MITOMAP: A human mitochondrial genome database\u20142004 update","volume":"33","author":"Brandon","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1056\/NEJMra022567","article-title":"Mitochondrial respiratory-chain diseases","volume":"348","author":"DiMauro","year":"2003","journal-title":"N. 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