Dual regulation of mitochondrial fusion by Parkin–PINK1 and OMA1

Tatsuya Yamada, Arisa Ikeda, Daisuke Murata, Hu Wang, Cissy Zhang, Pratik Khare, Yoshihiro Adachi, Fumiya Ito, Pedro M. Quirós, Seth Blackshaw, Carlos López-Otín, Thomas Langer, David C. Chan, Anne Le, Valina L. Dawson, Ted M. Dawson, Miho Iijima () and Hiromi Sesaki ()
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Tatsuya Yamada: Johns Hopkins University School of Medicine
Arisa Ikeda: Johns Hopkins University School of Medicine
Daisuke Murata: Johns Hopkins University School of Medicine
Hu Wang: Johns Hopkins University School of Medicine
Cissy Zhang: Johns Hopkins University School of Medicine
Pratik Khare: Johns Hopkins University School of Medicine
Yoshihiro Adachi: Johns Hopkins University School of Medicine
Fumiya Ito: Johns Hopkins University School of Medicine
Pedro M. Quirós: Universidad de Oviedo
Seth Blackshaw: Johns Hopkins University School of Medicine
Carlos López-Otín: Universidad de Oviedo
Thomas Langer: Max Planck Institute for Biology of Ageing
David C. Chan: California Institute of Technology
Anne Le: Johns Hopkins University School of Medicine
Valina L. Dawson: Johns Hopkins University School of Medicine
Ted M. Dawson: Johns Hopkins University School of Medicine
Miho Iijima: Johns Hopkins University School of Medicine
Hiromi Sesaki: Johns Hopkins University School of Medicine

Nature, 2025, vol. 639, issue 8055, 776-783

Abstract: Abstract Mitochondrial stress pathways protect mitochondrial health from cellular insults1–8. 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.

Date: 2025
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DOI: 10.1038/s41586-025-08590-2

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