SIRT3: A Central Regulator of Mitochondrial Adaptation in Health and Disease

Abstract

SIRT3 is a NAD(+)-dependent deacetylase that regulates the function of numerous mitochondrial proteins with roles in metabolism, oxidative stress, and cell survival. It is emerging as an instrumental regulator of the mitochondrial adaptive responses to stress, including metabolic reprogramming and enhancing antioxidant defense mechanisms. Here, we discuss the role that SIRT3 plays at both a cellular and physiological level and consider its involvement in disease. Mitochondrial dysfunction is a key contributing factor in many diseases; however, the mechanisms involved are often not well understood, and few targeted therapies exist. If manipulation of SIRT3 proves to be beneficial in disease states, then it could be a promising target for novel therapies.

Keywords: cell protection; mitochondria; sirtuins; stress.

Figure 1.

SIRT3 is required to mount adaptive mitochondrial responses to stress. SIRT3-deficient mice are less able to mount adaptive responses to external stresses such as aging and altered nutrient availability. Hyperacetylation of SIRT3 substrates results in increased oxidative stress and opening of the mPTP and decreased ATP levels, leading to genomic instability and cell death. A failure to trigger cell-protective mechanisms to counteract the stress may contribute to the development of cancer, neurodegenerative diseases, and metabolic disorders.

Figure 2.

Speculative strategies to harness the cell-protective effects of SIRT3. If modulation of SIRT3 function proves beneficial, manipulating its expression and function could be targets for therapeutic intervention. It may be possible to increase SIRT3 expression by targeting the PGC-1α/ERRα axis or other as yet unidentified transcriptional regulators of SIRT3. Enhancing SIRT3 activity could be achieved via direct activation or by increasing mitochondrial NAD⁺ levels.