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Review
. 2024 Feb;47(2):100029.
doi: 10.1016/j.mocell.2024.100029. Epub 2024 Feb 6.

Mitochondrial sirtuins: Energy dynamics and cancer metabolism

Hojun Lee  1 , Haejin Yoon  2
Affiliations
Review

Mitochondrial sirtuins: Energy dynamics and cancer metabolism

Hojun Lee et al. Mol Cells. 2024 Feb.

Abstract

Mitochondria are pivotal for energy regulation and are linked to cancer. Mitochondrial sirtuins, (Sirtuin) SIRT3, SIRT4, and SIRT5, play crucial roles in cancer metabolism. This review explores their impact on cellular processes, with a focus on the NAD+ interplay and the modulation of their enzymatic activities. The varied roles of SIRT3, SIRT4, and SIRT5 in metabolic adaptation and cancer are outlined, emphasizing their tumor suppressor or oncogenic nature. We propose new insights into sirtuin biology, and cancer therapeutics, suggesting an integrated proteomics and metabolomics approach for a comprehensive understanding of mitochondrial sirtuins in cancer.

Keywords: Cancer metabolism; Mitochondria metabolism; Mitochondrial sirtuins; NAD+; SIRT3.

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Conflict of interest statement

Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Structural insights and functional domains of mitochondrial sirtuin proteins. (A) Schematic representation of the structural domains of sirtuin proteins. Each sirtuin protein possesses distinct functional domains: Mitochondrial targeting sequence (green), NAD+ binding site (blue), deacetylase sirtuin-type domain (dark gray), and zinc ion binding zone (pink). (B) Molecular structures of key sirtuin proteins—SIRT3 (PDB: 4BV3), SIRT4 (PDB: 5OJN), and SIRT5 (PDB: 6LJK). The structures highlight the intricate arrangement of functional domains crucial for their respective biological activities. aa, amino acid.
Fig. 2
Fig. 2
Tumorigenic and tumor suppressor roles of mitochondrial sirtuins across diverse cancer types. The schematic illustrates the potential role of SIRT3 (yellow box), SIRT4 (purple box), and SIRT5 (green box) in various human cancer types. These sirtuins function as either tumorigenic (red edge) or tumor suppressor (blue edge) across a range of human cancers, including prostate cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, gastric cancer, pancreatic cancer, and ovarian cancer. AIF, apoptosis-inducing factor; SUN2, Sad1 and UNC84 domain containing 2; PI3K/AKT, phosphatidylinositol-3-kinase/protein kinase B (Akt); GSK-3β, glycogen synthase kinase 3 beta; SET8, methyltransferase activity (SET) domain-containing protein 8; ACOX, acyl-CoA oxidase; GOT, glutamic-oxaloacetic transaminase; MDH2, malate dehydrogenase 2; UHRF1, ubiquitin-like with plant homeodomain and ring finger domains 1; FOXO3A, Forkhead Box O3A; PAK6, p21-activated kinase 6; ANT1, adenine nucleotide translocase 1; ACAT1, acetyl-CoA acetyltransferase 1; MAPK, mitogen-activated protein kinase; MnSOD, manganese superoxide dismutase; LDHA, lactate dehydrogenase A; NRF2, nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase 1; SHMT, serine hydroxymethyltransferase.
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