MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Lee, J-Y; Kapur, M; Li, M; Choi, M-C; Choi, S; Kim, H-J; Kim, I; Lee, E; Taylor, JP; Yao, T-P

Published Date

  • November 15, 2014

Published In

Volume / Issue

  • 127 / Pt 22

Start / End Page

  • 4954 - 4963

PubMed ID

  • 25271058

Pubmed Central ID

  • PMC4231308

Electronic International Standard Serial Number (EISSN)

  • 1477-9137

Digital Object Identifier (DOI)

  • 10.1242/jcs.157321


  • eng

Conference Location

  • England