{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:20:05Z","timestamp":1787026805603,"version":"build-2736575974"},"reference-count":123,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>Mitochondrial bioenergetic competence critically depends on cristae architecture, which is organized and stabilized by the mitochondrial contact site and cristae organizing system (MICOS) complex. As a core MICOS subunit, CHCHD3 (also known as MIC19) contributes to assembly of the mitochondrial intermembrane space bridging (MIB) supercomplex and regulates cristae morphology, endoplasmic reticulum\u2013mitochondria contact sites, and cellular metabolic homeostasis. Aberrant CHCHD3 expression or functional deficiency is implicated in the pathogenesis of neurodegenerative disorders, cardiovascular diseases, metabolic syndromes, and cancers. Notably, CHCHD3 function is governed by a dose-dependent \u201cGoldilocks\u201d principle, wherein both insufficient and excessive expression\u2014as well as preserved abundance with impaired functional integrity\u2014can compromise mitochondrial homeostasis, underscoring the need for context-specific therapeutic modulation. Here, we systematically summarize CHCHD3 molecular characteristics and post-translational modification networks, with emphasis on its roles in energy metabolism, organelle crosstalk, and apoptosis. We further examine the mechanistic links between CHCHD3 dysregulation and disease pathogenesis, evaluate current targeting strategies and their pharmacological limitations, and identify remaining controversies and knowledge gaps to guide future research toward clinical translation.<\/jats:p>","DOI":"10.3389\/fmolb.2026.1861303","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T04:37:28Z","timestamp":1781152648000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["CHCHD3(MIC19): mitochondrial cristae structure regulation and disease associations"],"prefix":"10.3389","volume":"13","author":[{"given":"Zheng Tai","family":"Kuai","sequence":"first","affiliation":[{"name":"Wuxi Maternity and Child Health Care Hospital, Affiliated Women\u2019s Hospital of Jiangnan University","place":["Wuxi, China"]},{"name":"Department of Clinical Medicine, Wuxi School of Medicine, Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao Min","family":"Zheng","sequence":"additional","affiliation":[{"name":"Wuxi Maternity and Child Health Care Hospital, Affiliated Women\u2019s Hospital of Jiangnan University","place":["Wuxi, China"]},{"name":"Department of Clinical Medicine, Wuxi School of Medicine, Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue Yue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Wuxi School of Medicine, Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Wuxi School of Medicine, Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"C583","DOI":"10.1152\/ajpcell.00523.2018","article-title":"Posttranslational modifications of mitochondrial fission and fusion proteins in cardiac physiology and pathophysiology","volume":"316","author":"Adaniya","year":"2019","journal-title":"Am. 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