Sirtuins in mitophagy: key gatekeepers of mitochondrial quality

Abstract

Mitochondria are highly dynamic organelles essential for cellular energy production. However, they are also a primary source of reactive oxygen species, making them particularly vulnerable to oxidative damage. To preserve mitochondrial integrity, cells employ quality control mechanisms such as mitophagy, a selective form of autophagy that targets damaged or dysfunctional mitochondria for degradation. Among the key regulators of mitophagy are the sirtuins, a family of NAD⁺-dependent deacetylases. SIRT1, SIRT3, and SIRT6 generally promote mitophagy, whereas SIRT2, SIRT4, SIRT5, and SIRT7 often act as negative regulators. Sirtuin-mediated regulation of mitophagy is critical for maintaining cellular homeostasis and is implicated in a variety of physiological and pathological conditions. The aim of this review is to provide an overview focused on describing how sirtuins influence the mitophagy process. It highlights the different molecular mechanisms by which individual members of the sirtuin family modulate mitophagy, either by promoting or suppressing it, depending on the context. In addition, the review explores the relevance of sirtuin-regulated mitophagy in health and disease, emphasizing some conditions under which altered sirtuin activity could be harnessed for therapeutic benefit.

Keywords: FOXO transcription factors; Mitochondria; PINK1-PARKIN pathway; Receptor-mediated mitophagy; Ubiquitin-mediated mitophagy.

Fig. 1

Mitophagy mechanisms. Mitophagy can proceed through both ubiquitin-dependent and receptor-mediated pathways. In ubiquitin-mediated mitophagy, mitochondrial damage and loss of membrane potential (ΔΨm) stabilize PINK1 on the outer mitochondrial membrane (OMM), where it recruits and activates PARKIN. PARKIN ubiquitinates multiple OMM proteins, forming polyubiquitin (poly-Ub) chains that are phosphorylated by PINK1, serving as “eat me” signals for the autophagy machinery. Adaptor proteins such as OPTN, SQSTM1/p62, CALCOCO2/NDP52, NBR1, and TAX1BP1 recognize these phosphorylated poly-Ub chains and link damaged mitochondria to autophagosomes via interaction with LC3. TBK1 further enhances this process by phosphorylating adaptor proteins, increasing their affinity for ubiquitinated substrates. In receptor-mediated mitophagy, proteins such as BNIP3, NIX, and FUNDC1 are embedded in the OMM and directly interact with LC3 to drive mitophagosome formation. PHB2, normally located in the inner mitochondrial membrane, is exposed to the OMM upon mitochondrial damage and also binds LC3. The expression and activation of specific receptors vary across tissues and stimuli, adding specificity to the process. Phosphorylation of BNIP3 and NIX enhances their LC3-binding ability, and these receptors also contribute to mitochondrial fission by promoting OPA1 disassembly and recruiting DRP1. Notably, PARKIN-mediated ubiquitination of NIX and BNIP3 illustrates the functional crosstalk between receptor-driven and ubiquitin-mediated mitophagy pathways

Fig. 2

Sirtuins that positively regulate mitophagy. SIRT1 promotes mitophagy by activating the transcription factors FOXO1 and FOXO3, which induce the expression of genes involved in mitochondrial degradation. SIRT3 also enhances mitophagy through activation of FOXO3 and further contributes by deacetylating TFAM which interacts with LC3 to facilitate mitophagosome formation. Additionally, SIRT3 supports PARKIN recruitment by promoting HK2 dissociation from VDAC1 and deacetylating ATP5IF1. SIRT6 contributes indirectly by activating AMPK, which in turn stimulates FOXO3 activity

Fig. 3

Sirtuins that negatively regulate mitophagy. SIRT2 impairs mitophagy by destabilizing microtubules through the deacetylation of tubulin and by deacetylating ATG5, which hinders the conjugation of LC3B to phosphatidylethanolamine, a key step in autophagosome formation. SIRT4 inhibits mitophagy by binding to and stabilizing the long form of OPA1. SIRT5 exerts multiple inhibitory effects: it deacetylates and activates CPS1 for ammonia detoxification via the urea cycle, and desuccinylates GLS, enhancing the conversion of glutamine (Gln) to glutamate (Glu). It also inhibits ULK1 activity through suppression of the PI3K/AKT signaling pathway. Additionally, SIRT5 desuccinylates and inhibits PDK1, which enhances PDH activity and reduces the cellular reliance on mitophagy. Like SIRT2, SIRT5 also regulates cytoskeletal dynamics by deacetylating β-tubulin. Finally, SIRT7 suppresses mitophagy by maintaining PARKIN in a deacetylated state, thereby preventing its activation and mitochondrial recruitment

Fig. 4

Differential roles of sirtuins in mitophagy. This figure illustrates the distinct roles of sirtuin family members in the regulation of mitophagy. SIRT1, SIRT3, and SIRT6 generally act as positive regulators, promoting mitophagy, while SIRT2, SIRT4, SIRT5, and SIRT7 are more commonly associated with inhibitory or limiting effects on the process. The subcellular localization of each sirtuin is also depicted, highlighting their compartment-specific functions