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Review
. 2024 May 11;14(7):2993-3013.
doi: 10.7150/thno.97320. eCollection 2024.

Mitochondrial Sirtuins in Cancer: A Revisited Review from Molecular Mechanisms to Therapeutic Strategies

Hui Shen  1 , Wei Ma  1 , Yue Hu  1 , Yuan Liu  2 , Yaowen Song  1 , Leilei Fu  2 , Zheng Qin  1
Affiliations
Review

Mitochondrial Sirtuins in Cancer: A Revisited Review from Molecular Mechanisms to Therapeutic Strategies

Hui Shen et al. Theranostics. .

Abstract

The sirtuin (SIRT) family is well-known as a group of deacetylase enzymes that rely on nicotinamide adenine dinucleotide (NAD+). Among them, mitochondrial SIRTs (SIRT3, SIRT4, and SIRT5) are deacetylases located in mitochondria that regulate the acetylation levels of several key proteins to maintain mitochondrial function and redox homeostasis. Mitochondrial SIRTs are reported to have the Janus role in tumorigenesis, either tumor suppressive or oncogenic functions. Although the multi-faceted roles of mitochondrial SIRTs with tumor-type specificity in tumorigenesis, their critical functions have aroused a rising interest in discovering some small-molecule compounds, including inhibitors and activators for cancer therapy. Herein, we describe the molecular structures of mitochondrial SIRTs, focusing on elucidating their regulatory mechanisms in carcinogenesis, and further discuss the recent advances in developing their targeted small-molecule compounds for cancer therapy. Together, these findings provide a comprehensive understanding of the crucial roles of mitochondrial SIRTs in cancer and potential new therapeutic strategies.

Keywords: Cancer therapy; Mitochondrial sirtuin; SIRT3; SIRT4; SIRT5; Small-molecule compound.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Genomic and molecular structures of the mitochondrial sirtuins (SIRT3, SIRT4 and SIRT5). (A) Schematic view of the genomic structure of mitochondrial SIRT genes. The boxes mark the exons. Start and stop codons are indicated. The numbers on the genes refer to exons. The numbers below the genes indicate the sizes of the exons. (B) SIRT3 (PDB ID: 3GLS), (C) SIRT4 (PDB ID: 5OJ7), and (D) SIRT5 (PDB ID: 3RIY), are characterized by the presence of two domains, the Rossmann-folding domain and the zinc-binding domain. The different substrate-binding sites of mitochondrial SIRTs allows them to exhibit distinct substrate preferences and catalytic activities.
Figure 2
Figure 2
Molecular mechanisms of mitochondrial sirtuins (SIRT3, SIRT4 and SIRT5) in cancer. The function of mitochondrial SIRTs in oncogenesis is multifaceted, serving as (A) oncogenes (indicated in red) or (B) tumor suppressors (indicated in blue) contingent upon the genetic background, alongside the tumor type and developmental stage. SIRT3 engages in the deacetylation and activation of various enzymes involving in the tricarboxylic acid (TCA) cycle, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS), thereby manifesting both tumor-promoting and tumor-suppressive capacities under specific circumstances. SIRT4 is endowed with ADP-ribosyltransferase activity and orchestrates the regulation of enzymes critical for amino acid metabolism, lipid metabolism, and the preservation of mitochondrial DNA. The role of SIRT4 in carcinogenesis is primarily viewed as tumor-suppressive; however, similar to SIRT3, effects specific to the context have been documented. SIRT5 modulates the urea cycle and mitochondrial FAO, thereby influencing cellular energy generation and redox equilibrium. This modulation impacts the metabolism and viability of cancer cells, thereby determining its role as either a promoter or suppressor of tumorigenesis.
Figure 3
Figure 3
Small-molecule modulators targeting SIRT3 and SIRT5 for cancer therapy. SIRT3 and SIRT5 play dual roles in cancer. (A) Small-molecule activators of SIRT3 and SIRT5 and their mechanisms in cancer. (B) Small-molecule inhibitors targeting SIRT3 and SIRT5, as well as their mechanisms in cancer. These modulators regulate tumor proliferation and metastasis by modulating glutamine metabolism, mitochondrial oxidative stress, autophagy, or apoptosis-related pathways. SIRT3 and SIRT5 proteins are represented in blue and green, respectively, and the signaling pathways regulated by small-molecule modulators are indicated in pink.
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