SIRT3, a pivotal actor in mitochondrial functions: metabolism, cell death and aging

Abstract

SIRT3 is a member of the sirtuin family of protein deacetylases that is preferentially localized to mitochondria. Prominent among the proteins targeted by SIRT3 are enzymes involved in energy metabolism processes, including the respiratory chain, tricarboxylic acid cycle, fatty acid β-oxidation and ketogenesis. Through these actions, SIRT3 controls the flow of mitochondrial oxidative pathways and, consequently, the rate of production of reactive oxygen species. In addition, SIRT3-mediated deacetylation activates enzymes responsible for quenching reactive oxygen species, and thereby exerts a profound protective action against oxidative stress-dependent pathologies, such as cardiac hypertrophy and neural degeneration. SIRT3 also plays a role in multiple additional metabolic processes, from acetate metabolism to brown adipose tissue thermogenesis, often by controlling mitochondrial pathways through the deacetylation of target enzymes. In general, SIRT3 activity and subsequent control of enzymes involved in energy metabolism is consistent with an overall role of protecting against age-related diseases. In fact, experimental and genetic evidence has linked SIRT3 activity with increased lifespan. In the coming years, the identification of drugs and nutrients capable of increasing SIRT3 expression or modulating SIRT3 activity can be expected to provide promising strategies for ameliorating the metabolic syndrome and other oxidative stress-related diseases that appear preferentially with aging, such as cancer, cardiac dysfunction and neural degeneration.

Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle

“…multiple nuclear transcriptional regulators, including PGC-1a, PGC-1b, NRF1, GABP, PPARa, PPARd, and ERRs (13)(14)(15)(53)(54)(55). Perm1 also led to enhanced levels of PGC1a and ERRa, suggesting that the effects of Perm1 on gene expression are at least in part mediated through increases in these transcriptional regulators.…”

“…The increase in mitochondrial content may be driven by the enhanced expression of Tfam, Tfb2m, and Endog, which interact with the mitochondrial genome and control mitochondrial mass (52,53). Enhancements in enzymatic activities may be driven by the increase in mitochondrial Sirt3, which deacetylates and activates SDH and other subunits of oxphos complexes, and fatty acid oxidation enzymes (54,55).…”

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

“…SIRT3 is a key regulator of mitochondrial protein acetylation status [20,37], but the precise regulatory role of this enzyme has not been examined in pancreatic islets or beta cells. We report here that SIRT3 mRNA expression is suppressed in human islets isolated from type 2 diabetes patients (compared with islets from non-diabetic controls), as well as in mouse islets and INS1 cells exposed to chronic inflammatory conditions.…”

Aging and uremia: Is there cellular and molecular crossover?

“…Silent information regulator two protein 1 modulates mitochondrial biogenesis via the transcriptional coactivator PGC1a [116] and the removal of damaged mitochondria by autophagy [117] . SIRT3 targets many enzymes involved in energy metabolism [118] , and may directly control ROS production by deacetylating manganese superoxide dismutase, a mitochondrial antioxidant enzyme [119] . Mutations and deletions in mitochondrial DNA are known to accumulate with aging [3] .…”