title: MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria.
abstract: Fasting and glucose shortage activate a metabolic switch that shifts more energy production to mitochondria. This metabolic adaptation ensures energy supply, but also elevates the risk of mitochondrial oxidative damage. Here, we present evidence that metabolically challenged mitochondria undergo active fusion to suppress oxidative stress. In response to glucose starvation, mitofusin 1 (MFN1) becomes associated with the protein deacetylase HDAC6. This interaction leads to MFN1 deacetylation and activation, promoting mitochondrial fusion. Deficiency in HDAC6 or MFN1 prevents mitochondrial fusion induced by glucose deprivation. Unexpectedly, failure to undergo fusion does not acutely affect mitochondrial adaptive energy production; instead, it causes excessive production of mitochondrial reactive oxygen species and oxidative damage, a defect suppressed by an acetylation-resistant MFN1 mutant. In mice subjected to fasting, skeletal muscle mitochondria undergo dramatic fusion. Remarkably, fasting-induced mitochondrial fusion is abrogated in HDAC6-knockout mice, resulting in extensive mitochondrial degeneration. These findings show that adaptive mitochondrial fusion protects metabolically challenged mitochondria.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 305-764, Republic of Korea leejooyong@cnu.ac.kr tsopang.yao@duke.edu.
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Kapur
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Moon-Chang
authors.initials: MC
authors.lastname: Choi
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Sujin
authors.initials: S
authors.lastname: Choi
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: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Inhye
authors.initials: I
authors.lastname: Kim
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA leejooyong@cnu.ac.kr tsopang.yao@duke.edu.
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
mesh_terms: D000107:Acetylation; D000818:Animals; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse
keywords: Acetylation; HDAC6; MFN1; Metabolic stress; Mitochondrial fusion; ROS