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Review
. 2024 Jun 25;25(13):6936.
doi: 10.3390/ijms25136936.

The Role of Mitochondrial Sirtuins (SIRT3, SIRT4 and SIRT5) in Renal Cell Metabolism: Implication for Kidney Diseases

Florian Juszczak  1 , Thierry Arnould  2 , Anne-Emilie Declèves  1
Affiliations
Review

The Role of Mitochondrial Sirtuins (SIRT3, SIRT4 and SIRT5) in Renal Cell Metabolism: Implication for Kidney Diseases

Florian Juszczak et al. Int J Mol Sci. .

Abstract

Kidney diseases, including chronic kidney disease (CKD), diabetic nephropathy, and acute kidney injury (AKI), represent a significant global health burden. The kidneys are metabolically very active organs demanding a large amount of ATP. They are composed of highly specialized cell types in the glomerulus and subsequent tubular compartments which fine-tune metabolism to meet their numerous and diverse functions. Defective renal cell metabolism, including altered fatty acid oxidation or glycolysis, has been linked to both AKI and CKD. Mitochondria play a vital role in renal metabolism, and emerging research has identified mitochondrial sirtuins (SIRT3, SIRT4 and SIRT5) as key regulators of renal cell metabolic adaptation, especially SIRT3. Sirtuins belong to an evolutionarily conserved family of mainly NAD+-dependent deacetylases, deacylases, and ADP-ribosyl transferases. Their dependence on NAD+, used as a co-substrate, directly links their enzymatic activity to the metabolic status of the cell. In the kidney, SIRT3 has been described to play crucial roles in the regulation of mitochondrial function, and the antioxidative and antifibrotic response. SIRT3 has been found to be constantly downregulated in renal diseases. Genetic or pharmacologic upregulation of SIRT3 has also been associated with beneficial renal outcomes. Importantly, experimental pieces of evidence suggest that SIRT3 may act as an important energy sensor in renal cells by regulating the activity of key enzymes involved in metabolic adaptation. Activation of SIRT3 may thus represent an interesting strategy to ameliorate renal cell energetics. In this review, we discuss the roles of SIRT3 in lipid and glucose metabolism and in mediating a metabolic switch in a physiological and pathological context. Moreover, we highlight the emerging significance of other mitochondrial sirtuins, SIRT4 and SIRT5, in renal metabolism. Understanding the role of mitochondrial sirtuins in kidney diseases may also open new avenues for innovative and efficient therapeutic interventions and ultimately improve the management of renal injuries.

Keywords: SIRT3; SIRT4; SIRT5; glucose metabolism; kidney disease; lipid metabolism; lipotoxicity; metabolic switch; mitochondrial homeostasis; sirtuins.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
SIRT3-mediated regulation of renal lipid metabolism. SIRT3 directly deacetylates LCAD which promotes FAO and LKB1. LKB1 is an upstream kinase that activates AMPK, leading to the phosphorylation of ACC and suppression of malonyl-CoA production, which leads to the suppression of inhibition of CPT-1 activity and increased FAO. In parallel, AMPK induces the stimulation of PGC1α transcriptional activity via CREB, enhancing SIRT3 expression. AMPK, AMP-activated protein kinase; ACC, Acetyl-CoA carboxylase; LCAD, long-chain acyl-CoA dehydrogenase; CREB, cAMP response element-binding protein; PGC1α, co-activator peroxisome proliferator-activated receptor-γ co-activator-1α; LKB1, serine/threonine liver kinase B1; CPT1, carnitine palmitoyltransferase I; FAO, fatty acid oxidation.
Figure 2
Figure 2
SIRT3 deficiency leads to a metabolic switch from FAO to glycolysis which drives the epithelial–mesenchymal transition (EMT) in renal cells. SIRT3 plays a central role in renal fibrosis through its regulation of cellular metabolism and various signaling pathways. SIRT3 deficiency leads to a metabolic switch from FAO to glycolysis, which drives epithelial–mesenchymal transition (EMT) in renal cells. In the context of acute kidney injury (AKI) and chronic kidney disease (CKD), SIRT3 inhibition (red arrows) exacerbates fibrosis and EMT due to increased glycolysis. This process is mainly mediated by Smad3, HIF-1α, and the dimerization of PKM2. SIRT3 inhibits TGFβ-Smad3 signaling, thus preventing the Smad3-induced fibrotic response. SIRT3 suppresses HIF-1α by inhibiting mitochondrial ROS production. SIRT3 also controls the PKM2 tetramer-to-dimer interconversion, preventing EMT. Additionally, SIRT3 inhibition results in reduced pyruvate dehydrogenase complex (PDC) activity and increased lactate accumulation, further promoting a glycolytic phenotype. These changes contribute to a profibrotic environment, highlighting the critical role of SIRT3 in maintaining metabolic homeostasis and preventing renal fibrosis. TGFβ, transforming growth factor β1; Smad3, SMAD family member 3; PKM2, pyruvate kinase isozymes M2; HIF-1α, Hypoxia-inducible factor 1α; TCA, tricarboxylic cycle; FAO, fatty acid oxidation; PDC, pyruvate dehydrogenase complex.
Figure 3
Figure 3
The pivotal roles of mitochondrial SIRT3, SIRT4, and SIRT5 in renal cell metabolism. Both AKI, CKD, and diabetic nephropathy are linked to decreased NAD+ content and subsequent SIRT activity inhibition. SIRT3 is linked to the inhibition of glycolysis while it activates FAO. SIRT3 is inhibited in renal diseases. Activity of SIRT4 is also decreased in renal diseases and plays a putative role in regulating FAO in renal cells. Activity of SIRT5 expression is increased in renal diseases and plays a role in regulating peroxisomal FAO as well as glycolysis in renal cells. SIRT5 inhibition (in SIRT5−/− kidney) blocks mitochondrial FAO and leads to a compensatory shift to peroxisomal FAO (red arrows). FAO, fatty acid oxidation; NAD, nicotinamide adenine dinucleotide.
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Grants and funding

This work was supported by UMONS and UNamur co-funding (T.A. and A.-E.D. joint PhD supervision fellowship) as well as the UMONS Research Institute for Health Sciences and Technology (Belgium), the NARILIS (NAmur Research Institute for LIfe Sciences, Belgium), the FRMH (Fonds pour la Recherche Médicale dans le Hainaut, Belgium), the French Diabetes Society (France) and the F.R.S-FNRS (Fonds de la Recherche Scientifique; grant number J004620F).