Loss of NAD-Dependent Protein Deacetylase Sirtuin-2 Alters Mitochondrial Protein Acetylation and Dysregulates Mitophagy

Guoxiang Liu, Seong Hoon Park, Marta Imbesi, William Joseph Nathan, Xianghui Zou, Yueming Zhu, Haiyan Jiang, Loukia Parisiadou, David Gius*

*Corresponding author for this work

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Aims: Sirtuins connect energy generation and metabolic stress to the cellular acetylome. Currently, only the mitochondrial sirtuins (SIRT3-5) and SIRT1 have been shown to direct mitochondrial function; however, Aims: NAD-dependent protein deacetylase sirtuin-2 (SIRT2), the primary cytoplasmic sirtuin, is not yet reported to associate with mitochondria. Results: This study revealed a novel physiological function of SIRT2: The regulation of mitochondrial function. First, the acetylation of several metabolic mitochondrial proteins was found to be altered in Sirt2-deficient mice, which was, subsequently, validated by immunoprecipitation experiments in which the acetylated mitochondrial proteins directly interacted with SIRT2. Moreover, immuno-gold electron microscopic images of mouse brains showed that SIRT2 associates with the inner mitochondrial membrane in central nervous system cells. The loss of Sirt2 increased oxidative stress, decreased adenosine triphosphate levels, and altered mitochondrial morphology at the cellular and tissue (i.e., brain) level. Furthermore, the autophagic/mitophagic processes were dysregulated in Sirt2-deficient neurons and mouse embryonic fibroblasts. Innovation: For the first time it is shown that SIRT2 directs mitochondrial metabolism. Conclusion: Together, these findings support that SIRT2 functions as a mitochondrial sirtuin, as well as a regulator of autophagy/mitophagy to maintain mitochondrial biology, thus facilitating cell survival. Antioxid. Redox Signal. 26, 849-863.

Original languageEnglish (US)
Pages (from-to)846-863
Number of pages18
JournalAntioxidants and Redox Signaling
Volume26
Issue number15
DOIs
StatePublished - May 20 2017

Keywords

  • ROS
  • SIRT2
  • Sirtuins
  • autophagy
  • metabolism
  • mitochondria
  • mitophagy

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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