Parkin and Mitofusins Reciprocally Regulate Mitophagy and Mitochondrial Spheroid Formation*
- Wen-Xing Ding‡,1,
- Fengli Guo§,
- Hong-Min Ni‡,
- Abigail Bockus‡,
- Sharon Manley‡,
- Donna B. Stolz¶,
- Eeva-Liisa Eskelinen‖,
- Hartmut Jaeschke‡ and
- Xiao-Ming Yin**,2
- From the ‡Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160,
- the §Stowers Institute for Medical Research, Kansas City, Missouri 64110,
- the ¶Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261,
- the ‖Department of Biosciences, Division of Biochemistry and Biotechnology, University of Helsinki, 00014 Helsinki, Finland, and
- the **Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202
- ↵1 To whom correspondence may be addressed: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, MS 1018, 3901 Rainbow Blvd., Kansas City, KS 66160. Tel.: 913-588-9813; Fax: 913-588-7501; E-mail: wxding{at}kumc.edu.
- ↵2 To whom correspondence may be addressed: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, W. 350 11th St., Indianapolis, IN 46202. Tel.: 317-491-6096; Fax: 317-274-1782, E-mail: xmyin{at}iupui.edu.
Abstract
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.
Footnotes
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↵* This work was supported, in whole or in part, by National Institutes of Health Grants R01 AA020518-01, R21AA017421, P20 RR021940, and P20 RR016475 (to W. X. D.) and R01CA111456 and R01CA 83817 (to X. M. Y.).
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This article contains supplemental Figs. S1–S6.
- Received August 25, 2012.
- Revision received October 23, 2012.
- © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
