title: Stoichiometric expression of mtHsp40 and mtHsp70 modulates mitochondrial morphology and cristae structure via Opa1L cleavage.
abstract: Deregulation of mitochondrial heat-shock protein 40 (mtHsp40) and dysfunction of mtHsp70 are associated with mitochondrial fragmentation, suggesting that mtHsp40 and mtHsp70 may play roles in modulating mitochondrial morphology. However, the mechanism of mitochondrial fragmentation induced by mtHsp40 deregulation and mtHsp70 dysfunction remains unclear. In addition, the functional link between mitochondrial morphology change upon deregulated mtHsp40/mtHsp70 and mitochondrial function has been unexplored. Our coimmunoprecipitation and protein aggregation analysis showed that both overexpression and depletion of mtHsp40 accumulated aggregated proteins in fragmented mitochondria. Moreover, mtHsp70 loss and expression of a mtHsp70 mutant lacking the client-binding domain caused mitochondrial fragmentation. Together the data suggest that the molecular ratio of mtHsp40 to mtHsp70 is important for their chaperone function and mitochondrial morphology. Whereas mitochondrial translocation of Drp1 was not altered, optic atrophy 1 (Opa1) short isoform accumulated in fragmented mitochondria, suggesting that mitochondrial fragmentation in this study results from aberration of mitochondrial inner membrane fusion. Finally, we found that fragmented mitochondria were defective in cristae development, OXPHOS, and ATP production. Taken together, our data suggest that impaired stoichiometry between mtHsp40 and mtHsp70 promotes Opa1L cleavage, leading to cristae opening, decreased OXPHOS, and triggering of mitochondrial fragmentation after reduction in their chaperone function.
authors.affiliation: Southern Alberta Cancer Research Institute, Department of Biochemistry and Molecular Biology, Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Byoungchun
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Pediatrics and Clinical Neurosciences, Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Younghee
authors.initials: Y
authors.lastname: Ahn
authors.affiliation: Southern Alberta Cancer Research Institute, Department of Biochemistry and Molecular Biology, Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Sung-Myung
authors.initials: SM
authors.lastname: Kang
authors.affiliation: College of Medicine, University of Dong-A, Dong-A Medical Center, Busan 602-714, Republic of Korea.
authors.forename: Youngjin
authors.initials: Y
authors.lastname: Park
authors.affiliation: Department of Marine Life Science, Jeju National University, Jeju 690-756, Republic of Korea.
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: Department of Pediatrics and Clinical Neurosciences, Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Jong M
authors.initials: JM
authors.lastname: Rho
authors.affiliation: Department of Pediatrics and Clinical Neurosciences, Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T2N 4N1, Canada swkim@ucalgary.ca.
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Kim
mesh_terms: D020558:GTP Phosphohydrolases / Q000378:metabolism*; D015870:Gene Expression; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure*; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000502:physiology; D024101:Mitochondrial Proteins / Q000235:genetics*; D063306:Mitophagy; D059748:Proteolysis
chemical_list: C120664:DNAJA3 protein, human; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C492001:HSPA9 protein, human; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human