title: Mitochondrial dysfunction induced by knockdown of mortalin is rescued by Parkin.
abstract: Mutations in the parkin gene are the most common cause of autosomal recessive Parkinson's disease (PD). As an E3-ubiquitin ligase, Parkin is associated with mitochondrial dynamics and mitophagy. Mortalin, a molecular chaperone, is located primarily in mitochondria, where it functions to maintain mitochondrial homeostasis and antagonize oxidative stress injury. A reduced expression level of mortalin has been observed in the affected brain regions of PD patients. Mortalin also interacts with a variety of PD-related proteins and plays an indispensible role in helping native protein refolding and importing proteins into the mitochondrial matrix. Thus, the main aims of the present study were to investigate mitochondrial dysfunction induced by knockdown of mortalin and to test whether Parkin overexpression could rescue this effect. We found that lentivirus-mediated knockdown of mortalin in HeLa cells resulted in a collapse of mitochondrial membrane potential, an abnormal accumulation of reactive oxygen species and apparent alterations in mitochondrial morphology under H(2)O(2)-induced stress conditions. Remarkably, Parkin overexpression rescued these mitochondrial abnormalities. In HeLa cells expressing Parkin, co-immunoprecipitation of endogenous mortalin and wild-type Parkin was detected when they were treated with carbonyl cyanide 3-chlorophenylhydrazone (CCCP). In conclusion, we indicate that the relatively decreased mortalin expression level and its impaired interaction with Parkin could affect its roles in mitochondrial function.
authors.affiliation: Department of Cellular and Genetic Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhou
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Dongliang
authors.initials: D
authors.lastname: Zhao
authors.forename: Ji
authors.initials: J
authors.lastname: Zuo
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
mesh_terms: D017209:Apoptosis; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; C080352:mortalin; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein