title: Phosphorylation-dependent mitochondrial translocation of MAP4 is an early step in hypoxia-induced apoptosis in cardiomyocytes.
abstract: Hypoxic or ischemic apoptosis is often tightly associated with the opening of mitochondrial permeability transition pore (mPTP); however, the molecular mechanisms regulating mPTP and thus mitochondrial-dependent apoptosis remain elusive. Emerging evidence indicates that the movement of key proteins in or out of mitochondria play a critical regulatory role in apoptosis. Here, we reported that, unexpectedly, the microtubule-associated protein 4 (MAP4) translocated from cytosol to mitochondria upon phosphorylation after hypoxia treatment in neonatal cardiomyocytes. When targeted to mitochondria, MAP4 was found to lead to mPTP opening and induce apoptosis. Mitochondrial accumulation and pro-apoptotic function of MAP4 could be reversed through the genetic inhibition of MAP4 phosphorylation. The MAP4(Ala) mutant, which mimicked the dephosphorylated form, suppressed mitochondrial translocation and apoptosis. Our data reveal a novel role of MAP4 in cardiac apoptosis and suggest a potential therapeutic strategy targeting mitochondrial translocation of MAP4 against apoptotic heart diseases.
authors.affiliation: Endocrinology Department, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China.
authors.forename: J
authors.initials: J
authors.lastname: Hu
authors.affiliation: Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Chu
authors.affiliation: Department of Gynecology and Obstetrics, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: J
authors.initials: J
authors.lastname: Han
authors.affiliation: Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Dang
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ren
authors.affiliation: Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of Ministry of Education of China (Jinan University-Chinese University of Hong Kong), School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: H C
authors.initials: HC
authors.lastname: Chan
authors.affiliation: Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore