Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1

• 成果类型: Article
• 署名作者: Yamada, Tatsuya; Ikeda, Arisa; Murata, Daisuke; Wang, Hu; Zhang, Cissy; Khare, Pratik; Adachi, Yoshihiro; Ito, Fumiya; Quiros, Pedro M.; Blackshaw, Seth; Lopez-Otin, Carlos; Langer, Thomas; Chan, David C.; Le, Anne; Dawson, Valina L.; Dawson, Ted M.; Iijima, Miho; Sesaki, Hiromi
• 署名单位: Johns Hopkins University; University of Nebraska System; University of Nebraska Lincoln; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; University of Oviedo; Instituto Universitario de Oncologia de Asturias; Johns Hopkins University; Max Planck Society; California Institute of Technology; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Sorbonne Universite; Universidad Antonio de Nebrija
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2573
• DOI: 10.1038/s41586-025-08590-2
• 发表日期: 2025-03-20
• 关键词: gtpase opa1; protease; mitofusins; mutations; ubiquitin; division; release; disease; anchors; pink1

摘要

Mitochondrial stress pathways protect mitochondrial health from cellular insults1, 2, 3, 4, 5, 6, 7-8. However, their role under physiological conditions is largely unknown. Here, using 18 single, double and triple whole-body and tissue-specific knockout and mutant mice, along with systematic mitochondrial morphology analysis, untargeted metabolomics and RNA sequencing, we discovered that the synergy between two stress-responsive systems-the ubiquitin E3 ligase Parkin and the metalloprotease OMA1-safeguards mitochondrial structure and genome by mitochondrial fusion, mediated by the outer membrane GTPase MFN1 and the inner membrane GTPase OPA1. Whereas the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses. Thus, our data show that Parkin and OMA1 maintain a dual regulatory mechanism that controls mitochondrial fusion at the two membranes, even in the absence of extrinsic stress.