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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. - Highlights: • Hypoxic stress induces the interaction between HDAC6 and MFN2. • Hypoxic stress activates MARCH5 in HDAC6 deficient cells to degrade MFN2. • HDAC6 is required to maintain mitochondrial connectivity under hypoxia. • MARCH5 is increased and promotes the degradation of MFN2 in HDAC6 KO ALS mice.

Authors:
 [1];  [2]; ;  [1];  [3];  [4];  [1]
  1. Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764 (Korea, Republic of)
  2. Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8551 (Japan)
  3. Department of Biological Sciences, Sungkyunkwan University (SKKU), Suwon, 440-746 (Korea, Republic of)
  4. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710 (United States)
Publication Date:
OSTI Identifier:
22462243
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 464; Journal Issue: 4; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANOXIA; FISSION; LIGASES; MICE; MITOCHONDRIA; MORPHOLOGICAL CHANGES; STRESSES

Citation Formats

Kim, Hak-June, Nagano, Yoshito, Choi, Su Jin, Park, Song Yi, Kim, Hongtae, Yao, Tso-Pang, and Lee, Joo-Yong. HDAC6 maintains mitochondrial connectivity under hypoxic stress by suppressing MARCH5/MITOL dependent MFN2 degradation. United States: N. p., 2015. Web. doi:10.1016/J.BBRC.2015.07.111.
Kim, Hak-June, Nagano, Yoshito, Choi, Su Jin, Park, Song Yi, Kim, Hongtae, Yao, Tso-Pang, & Lee, Joo-Yong. HDAC6 maintains mitochondrial connectivity under hypoxic stress by suppressing MARCH5/MITOL dependent MFN2 degradation. United States. https://doi.org/10.1016/J.BBRC.2015.07.111
Kim, Hak-June, Nagano, Yoshito, Choi, Su Jin, Park, Song Yi, Kim, Hongtae, Yao, Tso-Pang, and Lee, Joo-Yong. 2015. "HDAC6 maintains mitochondrial connectivity under hypoxic stress by suppressing MARCH5/MITOL dependent MFN2 degradation". United States. https://doi.org/10.1016/J.BBRC.2015.07.111.
@article{osti_22462243,
title = {HDAC6 maintains mitochondrial connectivity under hypoxic stress by suppressing MARCH5/MITOL dependent MFN2 degradation},
author = {Kim, Hak-June and Nagano, Yoshito and Choi, Su Jin and Park, Song Yi and Kim, Hongtae and Yao, Tso-Pang and Lee, Joo-Yong},
abstractNote = {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. - Highlights: • Hypoxic stress induces the interaction between HDAC6 and MFN2. • Hypoxic stress activates MARCH5 in HDAC6 deficient cells to degrade MFN2. • HDAC6 is required to maintain mitochondrial connectivity under hypoxia. • MARCH5 is increased and promotes the degradation of MFN2 in HDAC6 KO ALS mice.},
doi = {10.1016/J.BBRC.2015.07.111},
url = {https://www.osti.gov/biblio/22462243}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 4,
volume = 464,
place = {United States},
year = {Fri Sep 04 00:00:00 EDT 2015},
month = {Fri Sep 04 00:00:00 EDT 2015}
}