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.

Sirt4: A Multifaceted Enzyme at the Crossroads of Mitochondrial Metabolism and Cancer

“…Sirt4 is distributed in both fetal and adult tissues, with higher expression levels in liver, heart, spleen, prostate, testis, kidney, ovary, white adipose tissue, and muscle, and it works as a "bridge protein" between mitochondrial metabolism and tumorigenesis (7). Several pieces of evidence showed that Sirt4 covers a crucial role when cells are subject to toxic stresses able to modulate the mitochondrial levels of the co-substrate NAD + and/or the NAD + /NADH ratio (3)(4)(5)(6). As a mono-ADP-ribosyltransferase, Sirt4 catalyzes the transfer of an ADP-ribosyl moiety from NAD + to glutamate dehydrogenase (GDH), thus inhibiting its activity in mice pancreatic β-cells and (D) Sirt4 effects on mitochondrial oxidative stress.…”

“…Most studies on the involvement of Sirt4 in tumor biology highlight this enzyme as a mitochondrion-localized tumor suppressor due to its crucial regulatory role of mitochondrial metabolism during tumorigenesis (5). Sirt4 mRNA levels are reduced in many human cancers, such as lung, pancreatic, ovarian, gastric, colorectal, prostate, renal, liver, and endometrial cancer as well as hematological tumors (33-45) ( Table 1).…”

“…Sirt4 is one of the three mitochondrial sirtuins and, despite that it was firstly described as a mono-ADP-ribosyltransferase, nowadays it has demonstrated a robust deacylase activity toward 3-hydroxy-3-methyl-glutarylated (HMG) lysine residues (1) as well as substrate-specific lipoamidase and deacetylase properties (2,3). Sirt4 directly or indirectly regulates multiple mitochondrial functions closely connected to the progression of age-related diseases such as type 2 diabetes (T2D), neurodegeneration, and cancer (1)(2)(3)(4)(5)(6).…”

Visualization of Sirtuin 4 Distribution between Mitochondria and the Nucleus, Based on Bimolecular Fluorescence Self-Complementation

“…Several studies, however, have reported that these Sirts can also occur outside of mitochondria [2][3][4], while the molecular mechanisms responsible for the subcellular distribution of Sirts are largely unclear. Sirt4 is an adenosine diphosphate (ADP)-ribosyltransferase enzyme located in the mitochondrial matrix [1,5] that regulates the metabolic activities of the organelle [6][7][8][9], but might also influence a toxic effect of this particular fusion construct. Another strategy to investigate the importation of proteins into the mitochondrial matrix is based on split FP technology [63].…”

Sirtuins, Mitochondria and the Melatonergic Pathway in Alzheimer&rsquo;s Disease<strong> </strong>

“…Although modulating insulin resistance and susceptibility to diabetes, SIRT4 has been relatively little investigated in AD [37]. The effects of SIRT4 are complicated by its apparent diverse effects in different cell types and species [38] and clearly requires further investigation as to how its interactions can be associated with such diverse effects. SIRT5 has been little investigated in AD or AD-associated pathophysiological processes.…”