title: Essential control of mitochondrial morphology and function by chaperone-mediated autophagy through degradation of PARK7.
abstract: As a selective degradation system, chaperone-mediated autophagy (CMA) is essential for maintaining cellular homeostasis and survival under stress conditions. Increasing evidence points to an important role for the dysfunction of CMA in the pathogenesis of Parkinson disease (PD). However, the mechanisms by which CMA regulates neuronal survival under stress and its role in neurodegenerative diseases are not fully understood. PARK7/DJ-1 is an autosomal recessive familial PD gene. PARK7 plays a critical role in antioxidative response and its dysfunction leads to mitochondrial defects. In the current study, we showed that CMA mediated the lysosome-dependent degradation of PARK7. Importantly, CMA preferentially removed the oxidatively damaged nonfunctional PARK7 protein. Furthermore, CMA protected cells from mitochondrial toxin MPP(+)-induced changes in mitochondrial morphology and function, and increased cell viability. These protective effects were lost under PARK7-deficiency conditions. Conversely, overexpression of PARK7 significantly attenuated the mitochondrial dysfunction and cell death exacerbated by blocking CMA under oxidative stress. Thus, our findings reveal a mechanism by which CMA protects mitochondrial function by degrading nonfunctional PARK7 and maintaining its homeostasis, and dysregulation of this pathway may contribute to the neuronal stress and death in PD pathogenesis.
authors.affiliation: a Department of Neurosurgery , Tangdu Hospital, The Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Bao
authors.initials: B
authors.lastname: Wang
authors.affiliation: a Department of Neurosurgery , Tangdu Hospital, The Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Zhibiao
authors.initials: Z
authors.lastname: Cai
authors.affiliation: a Department of Neurosurgery , Tangdu Hospital, The Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Kai
authors.initials: K
authors.lastname: Tao
authors.affiliation: a Department of Neurosurgery , Tangdu Hospital, The Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Zeng
authors.affiliation: a Department of Neurosurgery , Tangdu Hospital, The Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Lu
authors.affiliation: a Department of Neurosurgery , Tangdu Hospital, The Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Ruixin
authors.initials: R
authors.lastname: Yang
authors.affiliation: a Department of Neurosurgery , Tangdu Hospital, The Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Dayun
authors.initials: D
authors.lastname: Feng
authors.affiliation: a Department of Neurosurgery , Tangdu Hospital, The Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Gao
authors.affiliation: a Department of Neurosurgery , Tangdu Hospital, The Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001343:Autophagy; D016923:Cell Death; D002470:Cell Survival; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism; D000071617:Protein Deglycase DJ-1 / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
chemical_list: D000975:Antioxidants; D018832:Molecular Chaperones; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse; C404267:PARK7 protein, rat; D000071617:Protein Deglycase DJ-1
keywords: CMA; DJ-1; PARK7; Parkinson disease; mitochondria; neuronal death