Lang 2017 Aging (Albany NY)
|Lang A, Anand R, Altinoluk-Hambüchen S, Ezzahoini H, Stefanski A, Iram A, Bergmann L, Urbach J, Böhler P, Hänsel J, Franke M, Stühler K, Krutmann J, Scheller J, Stork B, Reichert AS, Piekorz RP (2017) SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy. Aging (Albany NY) 9:2163-89.|
Lang A, Anand R, Altinoluk-Hambuechen S, Ezzahoini H, Stefanski A, Iram A, Bergmann L, Urbach J, Boehler P, Haensel J, Franke M, Stuehler K, Krutmann J, Scheller J, Stork B, Reichert AS, Piekorz RP (2017) Aging (Albany NY)
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.
• Keywords: OPA1, Sirtuin-4/SIRT4, Aging, Fibroblast, Mitochondrial fusion/fission, Mitochondrial quality control, Mitophagy, Reactive oxygen species/ROS, Senescence • Bioblast editor: Kandolf G
Labels: MiParea: Respiration, mt-Structure;fission;fusion, Genetic knockout;overexpression Pathology: Aging;senescence
Organism: Human Tissue;cell: Kidney, HEK Preparation: Intact cells
Coupling state: LEAK, ROUTINE, ET Pathway: ROX HRR: Oxygraph-2k