The Roles of Mitochondrial SIRT4 in Cellular Metabolism

Abstract

Sirtuins comprise a family of nicotinamide adenine dinucleotide (NAD⁺)-dependent lysine deacylases that regulate the life span, aging, and metabolism. Seven sirtuin family members (SIRT1-7) have been identified in mammals, including humans. Despite the indispensable role of mitochondrial sirtuin 4 (SIRT4) in metabolic regulation, the primary enzymatic activity of SIRT4 remains enigmatic. SIRT4 possesses ADP-ribosyltransferase, lipoamidase and deacylase activities. Interestingly, the enzymatic activities and substrates of SIRT4 vary in different tissues and cells. SIRT4 inhibits insulin secretion in pancreatic β cells and regulates insulin sensitivity as a deacylase in the pancreas. SIRT4 represses fatty acid oxidation (FAO) in muscle and liver cells differently. SIRT4 has also been identified as a mitochondrial-localized tumor suppressor. A comprehensive understanding of the enzymology of SIRT4 in metabolism is essential for developing novel therapeutic agents for human metabolic diseases. This review will update the roles of SIRT4 in cellular and organismal metabolic homeostasis.

Keywords: SIRT4; enzymatic activities; fatty acid metabolism; insulin secretion; mitochondrial; tumor suppressor.

Figure 1

The characteristics of mitochondrial SIRT4 (A). Sequence analyses show the amino acid sequence of the mitochondrial localization, NAD⁺-binding, substrate specificity, catalytic and Zn²⁺-binding domains (B). SIRT4 is localized in the mitochondrion (C). SIRT4 is belong to a class II human sirtuins (D). Structure of groups catalyzed by SIRT4.

Figure 2

SIRT4 regulates insulin secretion in pancreatic β cells. GDH is ADP-ribosylated and inhibited by SIRT4, repressing insulin secretion.

Figure 3

SIRT4 mediates fatty acid oxidation in muscle and adipose cells. In fed state, SIRT4 decreases the activity of the mitochondrial malonyl-CoA decarboxylase (MCD), which can increase malonyl-CoA levels, thus inhibiting FAO. In fasted state, the level malonyl-CoA of is decreased conversely.

Figure 4

SIRT4 mediates fatty acid oxidation in liver cells. The interaction of SIRT1 and PPARα is blocked by SIRT4, leading to a decrease in FAO.

Figure 5

SIRT4 plays a role in tumor suppression. SIRT4 suppresses tumor proliferation by inhibiting glutamine metabolism and DNA damage repair.

Figure 6

The metabolic roles of SIRT4 in various organs. SIRT4 is mainly involved in the metabolism of muscle, liver, fat, pancreatic, and cancer cells. The up arrows indicate the increased regulation pathways and the down arrows indicate the decreased regulation pathways induced by SIRT4.