4.6 Article

SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy

Journal

AGING-US
Volume 9, Issue 10, Pages 2160-+

Publisher

IMPACT JOURNALS LLC
DOI: 10.18632/aging.101307

Keywords

Sirtuin-4/SIRT4; mitochondrial quality control; mitochondrial fusion/fission; mitophagy; OPA1; reactive oxygen species/ROS; senescence; fibroblast; aging

Funding

  1. Strategischer Forschungsfond of the Heinrich-Heine-University [701.301.987]
  2. research commission of the Medical Faculty of the Heinrich-Heine-University [9772643]
  3. Deutsche Forschungsgemeinschaft project A05 [SFB728]
  4. Deutsche Forschungsgemeinschaft project B09 [SFB594]
  5. research commission grant by the Medical Faculty of the Heinrich-Heine-University Dusseldorf [2/2015]

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The stress-responsive mitochondrial sirtuin SIRT4 controls cellular energy metabolism in a NAD+-dependent manner and is implicated in cellular senescence and aging. Here we reveal a novel function of SIRT4 in mitochondrial morphology/quality control and regulation of mitophagy. We report that moderate overexpression of SIRT4, but not its enzymatically inactive mutant H161Y, sensitized cells to mitochondrial stress. CCCP-triggered dissipation of the mitochondrial membrane potential resulted in increased mitochondrial ROS levels and autophagic flux, but surprisingly led to increased mitochondrial mass and decreased Parkin-regulated mitophagy. The anti-respiratory effect of elevated SIRT4 was accompanied by increased levels of the inner-membrane bound long form of the GTPase OPA1 (L-OPA1) that promotes mitochondrial fusion and thereby counteracts fission and mitophagy. Consistent with this, upregulation of endogenous SIRT4 expression in fibroblast models of senescence either by transfection with miR-15b inhibitors or by ionizing radiation increased L-OPA1 levels and mitochondrial fusion in a SIRT4-dependent manner. We further demonstrate that SIRT4 interacts physically with OPA1 in co-immunoprecipitation experiments. Overall, we propose that the SIRT4-OPA1 axis is causally linked to mitochondrial dysfunction and altered mitochondrial dynamics that translates into aging-associated decreased mitophagy based on an unbalanced mitochondrial fusion/fission cycle.

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