SIRT3 Deacetylates FOXO3 to Protect Mitochondria Against Oxidative Damage

Free Radic Biol Med. 2013 Oct;63:222-34. doi: 10.1016/j.freeradbiomed.2013.05.002. Epub 2013 May 7.

Abstract

Progressive accumulation of defective mitochondria is a common feature of aged cells. SIRT3 is a NAD(+)-dependent protein deacetylase that regulates mitochondrial function and metabolism in response to caloric restriction and stress. FOXO3 is a direct target of SIRT3 and functions as a forkhead transcription factor to govern diverse cellular responses to stress. Here we show that hydrogen peroxide induces SIRT3 to deacetylate FOXO3 at K271 and K290, followed by the upregulation of a set of genes that are essential for mitochondrial homeostasis (mitochondrial biogenesis, fission/fusion, and mitophagy). Consequently, SIRT3-mediated deacetylation of FOXO3 modulates mitochondrial mass, ATP production, and clearance of defective mitochondria. Thus, mitochondrial quantity and quality are ensured to maintain mitochondrial reserve capacity in response to oxidative damage. Maladaptation to oxidative stress is a major risk factor underlying aging and many aging-related diseases. Hence, our finding that SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative stress provides a possible direction for aging-delaying therapies and disease intervention.

Keywords: Aging; BAEC; CR; EC; FOXO3; Free radicals; HUVEC; Mitochondrial biogenesis; Mitochondrial fission/fusion; Mitochondrial homeostasis; Mitophagy; OCR; Oxidative stress; ROS; SIRT3; bovine aortic endothelial cell; caloric restriction; endothelial cell; human umbilical vein endothelial cell; oxygen consumption rate; reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation*
  • Aging / metabolism
  • Aging / pathology
  • Animals
  • Aorta / cytology
  • Aorta / metabolism
  • Caloric Restriction
  • Cattle
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Oxidation-Reduction
  • Oxidative Stress*
  • Protein Interaction Maps
  • Reactive Oxygen Species / metabolism
  • Sirtuin 3 / metabolism*

Substances

  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Reactive Oxygen Species
  • SIRT3 protein, human
  • Sirtuin 3