SIRT3: as simple as it seems?

Abstract

Identification of conserved pathways regulating longevity holds out the eventual possibility of pharmacologic health- and lifespan extension in humans. Members of the sirtuin deacetylase/ADP-ribosyltransferase/deacylase family extend longevity in invertebrates and promote various aspects of mammalian healthspan. The mitochondrial sirtuin SIRT3 deacetylates numerous proteins in this organelle, regulating mitochondrial functions and suppressing diverse age-associated pathologies. However, recent findings raise the possibility that SIRT3 may regulate some mitochondrial functions indirectly, rather than by direct deacetylation of specific mitochondrial substrates. Specifically, it has been found that SIRT3 promotes activities of the upstream mitochondrial regulators adenosine monophosphate-activated protein kinase and PGC1α. In addition, studies of tissue-specific SIRT3 knockouts suggest non-tissue-autonomous roles for SIRT3. Thus, mitochondrial regulation by SIRT3 is likely much more complex than initially appreciated, potentially involving both direct and indirect mechanisms. Unraveling these may reveal novel aspects of how the functional status of the mitochondria is communicated to the rest of the cell, and to the organism overall.

Figure 1. Schematic overview of SIRT3 targets and biological functions

Through its deacetylase activity, SIRT3 activates multiple protein targets (blue circles) modulating key cellular and physiological processes (black boxes) leading to improved healthspan. Many of these processes are mediated by decreased reactive oxygen species (ROS) production through deacetylated SOD2 and IDH2.

Figure 2. Promotion of AMPK-PGC1α signaling by SIRT3: hypothetical mechanisms

AMPK is phosphorylated by LKB1 and CaMKKβ, and in turn activates PGC1α. Four possible mechanisms through which SIRT3 might impact this pathway are depicted here: (1) by deacetylating and activating LKB1, (2) by deacetylating and activating FOXO3A, a transcriptional activator of PGC1α, (3) by increasing the NAD⁺/NADH ratio, allowing for increased sirtuin activity which could function to activate AMPK and/or PGC1α through deacetylation, or (4) by promoting increased cytosolic calcium levels, thus promoting AMPK activity through CaMKKβ and PGC1α expression through CaMKIV.