Abstract
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.
Highlights
Aging is defined as a time-dependent loss of physiological integrity and organ function and is characterized by key hallmarks, among them genomic instability, stem cell exhaustion, mitochondrial dysfunction, and cellular senescence [1]
We addressed the role of SIRT4, a miR-15b repressed and stress-inducible senescenceassociated mitochondrial sirtuin [35, 45], in the regulation of mitochondrial dynamics and quality control
Expression and subcellular www.aging‐us.com localization of SIRT4-eGFP and its mutants were confirmed by confocal microscopy, immunoblotting, and flow cytometry analysis
Summary
Aging is defined as a time-dependent loss of physiological integrity and organ function and is characterized by key hallmarks, among them genomic instability, stem cell exhaustion, mitochondrial dysfunction, and cellular senescence [1]. Senescent cells occur and accumulate in-vivo, and clearance of senescent cells ameliorates aging-associated pathologies thereby extending healthy lifespan [8, 9]. Upregulation of the cyclin-dependent kinase (CDK) and cell cycle inhibitor p21WAF, a p53 target gene and key effector of stress-induced cellular senescence [10, 11], leads to a reduced capacity of stem cell dependent tissue regeneration [12]. The pro-aging effects of senescence and the SASP (senescence associated secretory phenotype) seem to be at least in part dependent on the presence of mitochondria [14, 15]
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