Parkin and Mitofusins Reciprocally Regulate Mitophagy and Mitochondrial Spheroid Formation

• Published in: The Journal of biological chemistry Vol. 287; no. 50; pp. 42379 - 42388
• Main Authors: Ding, Wen-Xing, Guo, Fengli, Ni, Hong-Min, Bockus, Abigail, Manley, Sharon, Stolz, Donna B., Eskelinen, Eeva-Liisa, Jaeschke, Hartmut, Yin, Xiao-Ming
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.12.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Acetaminophen - adverse effects; Acetaminophen - pharmacology; Analgesics, Non-Narcotic - adverse effects; Analgesics, Non-Narcotic - pharmacology; Animals; Autophagy; Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology; Cell Biology; Cells, Cultured; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Liver - metabolism; Liver - ultrastructure; Mice; Mice, Knockout; Mitochondria; Mitochondria, Liver - metabolism; Mitochondria, Liver - ultrastructure; Mitochondrial Dynamics - drug effects; Mitochondrial Dynamics - physiology; Mitophagy - drug effects; Mitophagy - physiology; Oxidative Stress; Parkin; Proteolysis - drug effects; Proton Ionophores - pharmacology; Reactive Oxygen Species - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Mitochondria; Oxidative Stress; Autophagy; Cell Biology; Parkin
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.413682

Mitochondrial homeostasis via mitochondrial dynamics and quality control is crucial to normal cellular functions. Mitophagy (mitochondria removed by autophagy) stimulated by a mitochondrial uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), requires Parkin, but it is not clear why Parkin is crucial to this process. We found that in the absence of Parkin, carbonyl cyanide m-chlorophenylhydrazone induced the formation of mitochondrial spheroids. Mitochondrial spheroid formation is also induced in vivo in the liver by acetaminophen overdose, a condition causing severe oxidative mitochondrial damages and liver injury. Mitochondrial spheroids could undergo a maturation process by interactions with acidic compartments. The formation of this new structure required reactive oxygen species and mitofusins. Parkin suppressed these mitochondrial dynamics by promoting mitofusin degradation. Consistently, genetic deletion of mitofusins without concomitant expression of Parkin was sufficient to prevent mitochondrial spheroid formation and resumed mitophagy. Mitochondrial spheroid formation and mitophagy could represent different strategies of mitochondrial homeostatic response to oxidative stress and are reciprocally regulated by mitofusins and Parkin. Background: The mechanistic relationship of Parkin and mitofusins in mitochondria quality control is not known. Results: CCCP-induced mitophagy and mitochondrial spheroid formation differentially require Parkin and mitofusins. Conclusion: Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation. Significance: This study revealed a default response of mitochondria to oxidative stress and a molecular mechanism by which Parkin primes the mitochondria for mitophagy.