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Mitochondrial acetyltransferase 1 (MAT1) and Sirt3 function as a "nutrient sensors" regulating mitophagy

Tuesday, October 25, 2011 — Poster Session II

Noon – 2:00 p.m.

Natcher Conference Center



* FARE Award Winner


  • BR Webster
  • I Scott
  • MV Stevens
  • KY Kim
  • MN Sack


Defective mitophagy plays a role in cancer and diabetes. Fasting induces mitophagy and activates sirtuin deacetylases. Mitochondrial function is modulated by acetylation status, and the only known regulators of mitochondrial acetylation are Sirt3 and Sirt5. We recently described the first mitochondrial acetyltransferase (MAT1) which counters Sirt3’s effects on respiration and ATP generation. Since mitophagy is induced by fasting and the benefits of fasting are dependent on sirtuins, we hypothesized that Sirt3 augments and MAT1 attenuates mitophagy in a nutrient-dependent manner. Fasted wildtype mice have augmented liver mitophagy, increased Sirt3 and lower MAT1 levels. However, fasted Sirt3 knockouts fail to induce mitophagy. Mitochondria from HepG2 cells depleted of MAT1 show increased levels of the mitophagy markers LC3-II, p62 and ubiquitination, while Sirt3 siRNA attenuates levels. MAT1 depletion also increases autophagosome levels. Dual depletion of MAT1/p62 or MAT1/parkin limits mitochondrial LC3-II levels, suggesting p62 and parkin are necessary for MAT1 siRNA induced mitophagy. Disrupted mitophagy increases ROS levels. MAT1 knockdown also limits ROS induction following rotenone treatment. We propose that MAT1 knockdown mimics fasting leading to augmented mitophagy and protection against oxidative stress possibly through enhanced mitochondrial turnover. MAT1 and Sirt3 may offer unique targets for disorders linked to defective mitochondrial homeostasis.

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