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Review
. 2022 Mar 16;23(6):3212.
doi: 10.3390/ijms23063212.

Mitochondrial Sirtuins in Chronic Degenerative Diseases: New Metabolic Targets in Colorectal Cancer

Antonino Colloca  1 , Anna Balestrieri  2 , Camilla Anastasio  1 , Maria Luisa Balestrieri  1 , Nunzia D'Onofrio  1
Affiliations
Review

Mitochondrial Sirtuins in Chronic Degenerative Diseases: New Metabolic Targets in Colorectal Cancer

Antonino Colloca et al. Int J Mol Sci. .

Abstract

Sirtuins (SIRTs) are a family of class III histone deacetylases (HDACs) consisting of seven members, widely expressed in mammals. SIRTs mainly participate in metabolic homeostasis, DNA damage repair, cell survival, and differentiation, as well as other cancer-related biological processes. Growing evidence shows that SIRTs have pivotal roles in chronic degenerative diseases, including colorectal cancer (CRC), the third most frequent malignant disease worldwide. Metabolic alterations are gaining attention in the context of CRC development and progression, with mitochondrion representing a crucial point of complex and intricate molecular mechanisms. Mitochondrial SIRTs, SIRT2, SIRT3, SIRT4 and SIRT5, control mitochondrial homeostasis and dynamics. Here, we provide a comprehensive review on the latest advances on the role of mitochondrial SIRTs in the initiation, promotion and progression of CRC. A deeper understanding of the pathways by which mitochondrial SIRTs control CRC metabolism may provide new molecular targets for future innovative strategies for CRC prevention and therapy.

Keywords: SIRT2; SIRT3; SIRT4; SIRT5; chronic degenerative diseases; colorectal cancer; metabolism; mitochondria.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
SIRT2 acts both as tumor suppressor and tumor promoter, inhibiting tumor proliferation but also promoting tumor survival and the angiogenetic process. HIF1α, Hypoxia inducible factor 1α; IDH1, Isocitrate dehydrogenase 1; STAT3, signal transducer and activator of transcription 3; VEGFA, vascular endothelial growth factor A; ENO1, α-enolase.
Figure 2
Figure 2
SIRT3 pathways in CRC. SIRT3 activation regulates mitochondrial homeostasis and promotes metabolic alterations deeply influencing CRC cells phenotype. PGC1α, peroxisome proliferator-activated receptor alpha; NRF1, nuclear respiratory factor 1; TFAM, Transcription factor A, mitochondrial; UCP2, Mitochondrial uncoupling protein 2; UCP5, Mitochondrial uncoupling protein 5; COX IV, Cytochrome c oxidase (complex IV); MUTYH, mutY DNA glycosylase; LIG3, DNA Ligase 3; APE1, Human apurinic/apyrimidinic endonuclease; OGG1, 8-Oxoguanine DNA Glycosylase; NEIL1/2, Nei Like DNA Glycosylase 1/2; MLKL, Mixed Lineage Kinase Domain Like Pseudokinase; PINK1, PTEN-induced kinase 1; LC3B, microtubule-associated proteins 1A/1B light chain 3B; MnSOD, Manganese superoxide dismutase; SOD2, superoxide dismutase 2; NOS1, nitric oxide synthase 1; SHMT2, Serine Hydroxy methyltransferase 2; MTHFD2, Methylenetetra-hydrofolate Dehydrogenase 2.
Figure 3
Figure 3
Role of SIRT4 in CRC. SIRT4 is mainly suppressive and counteract the activation of proliferation and the accumulation of important metabolites originated from glutamine metabolism. Akt, Protein kinase B; Gsk3β, Glycogen synthase kinase 3β; CycD1, CyclinD1; GDH, Glutamate dehydrogenase; Glu, glutamate; αKG, α-ketoglutarate; E-Cad, E-Cadherin; GLS, glutaminase; Gln, glutamine.
Figure 4
Figure 4
SIRT5 activity confers proliferative advantages to CRC cells enhancing energetic metabolism, cell renewal and chemoresistance. TCA, tricarboxylic acid cycle; GDH1, glutamate dehydrogenase 1; CS, citrate synthase; TrX2, thioredoxin 2; SDHA, succinate dehydrogenase complex subunit A; SHMT2, serine hydroxy methyltransferase 2; LDHB, lactate dehydrogenase B.
Figure 5
Figure 5
Mitochondrial SIRTs, SIRT2, SIRT3, SIRT4 and SIRT5, exert different effects on CRC initiation, promotion and progression. The blue arrows stand for an oncogenic activity, while the red ones indicate a tumor suppressive role. SIRT2 and SIRT3 exert a multifaceted activity on CRC, SIRT4 is mainly a tumor suppressor while SIRT5 is mainly a tumor promoter.
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