title: Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation.
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.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA. wxding@kumc.edu
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Ding
authors.forename: Fengli
authors.initials: F
authors.lastname: Guo
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Ni
authors.forename: Abigail
authors.initials: A
authors.lastname: Bockus
authors.forename: Sharon
authors.initials: S
authors.lastname: Manley
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.forename: Eeva-Liisa
authors.initials: EL
authors.lastname: Eskelinen
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Yin
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000502:physiology*; D063306:Mitophagy / Q000187:drug effects / Q000502:physiology*; D059748:Proteolysis / Q000187:drug effects; D061209:Proton Ionophores / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018712:Analgesics, Non-Narcotic; D061209:Proton Ionophores; D017382:Reactive Oxygen Species; D000082:Acetaminophen; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D020558:GTP Phosphohydrolases