title: HDAC6 maintains mitochondrial connectivity under hypoxic stress by suppressing MARCH5/MITOL dependent MFN2 degradation.
abstract: Mitochondria undergo fusion and fission in response to various metabolic stresses. Growing evidences have suggested that the morphological change of mitochondria by fusion and fission plays a critical role in protecting mitochondria from metabolic stresses. Here, we showed that hypoxia treatment could induce interaction between HDAC6 and MFN2, thus protecting mitochondrial connectivity. Mechanistically, we demonstrated that a mitochondrial ubiquitin ligase MARCH5/MITOL was responsible for hypoxia-induced MFN2 degradation in HDAC6 deficient cells. Notably, genetic abolition of HDAC6 in amyotrophic lateral sclerosis model mice showed MFN2 degradation with MARCH5 induction. Our results indicate that HDAC6 is a critical regulator of MFN2 degradation by MARCH5, thus protecting mitochondrial connectivity from hypoxic stress.
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764, Republic of Korea.
authors.forename: Hak-June
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8551, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Nagano
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764, Republic of Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Choi
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764, Republic of Korea.
authors.forename: Song Yi
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University (SKKU), Suwon, 440-746, Republic of Korea.
authors.forename: Hongtae
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. Electronic address: tsopang.yao@duke.edu.
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764, Republic of Korea. Electronic address: leejooyong@cnu.ac.kr.
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D015536:Down-Regulation; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C515578:MARCHF5 protein, human; C581898:Marchf5 protein, mouse; D044767:Ubiquitin-Protein Ligases; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; D010100:Oxygen
keywords: HDAC6; Hypoxia; MARCH5; MFN2; Mitochondrial connectivity