Sirt3-mediated mitophagy protects tumor cells against apoptosis under hypoxia

Abstract

Sirt3, a mitochondrial deacetylase, participates in the regulation of multiple cellular processes through its effect on protein acetylation. The objective of this study was to explore the role of Sirt3 in the mitochondrial autophagy (mitophagy), a process of the specific autophagic elimination of damaged mitochondria. We found that silencing of Sirt3 expression in human glioma cells by RNA interference blunted the hypoxia-induced the localization of LC3 on the mitochondria, and the degradation of mitochondria. These results suggest an important involvement of this protein deacetylase in the induction of mitophagy in cancer cells subjected to hypoxia. Further, we demonstrated that Sirt3 activated the hypoxia-induced mitophagy by increasing the interaction of VDAC1 with Parkin. In the cells subjected to hypoxia, inhibition of Sirt3-mediated mitophagy further decreased the mitochondrial membrane potential, and increased the accumulation of ROS that triggers the degradation of anti-apoptotic proteins Mcl-1 and survivin through the proteasomal pathway. Silencing of Sirt3 expression also promoted apoptosis, and enhanced the sensitivity of cancer cells to hypoxia. The regulatory role of Sirt3 in autophagy and apoptosis was also observed in human breast cancer cells. The results of the current study reveal Sirt3 as a novel regulator coupling mitophagy and apoptosis, two important cellular processes that determine cellular survival and death.

Toxicarioside H induces drug-resistant mitophagy via promoting expression of sirtuin-3 in lung cancer cells

“…VDAC1 can promote hexokinase II binding to mitochondria, which contributes to cancer cell metabolism, and inhibits damage to the mitochondria [40]. In addition, recent studies report that VDAC1 induces mitophagy via recruiting parkin to defective mitochondria to promote their degradation [34,41,42]. Sirt3 expression is increased by ToxH treatment, and the inhibition of Sirt3 with siSirt3 significantly suppressed the induction of mitophagy triggered by ToxH treatment.…”

“…Recent studies have linked parkin, Sirt3, VDAC1, and hexokinase II with drug-resistant mitophagy [34]. Sirt3 is a sirtuin and nicotinamide adenine dinucleotide protein deacetylase that mainly localizes to the mitochondria and controls acetylation of mitochondrial proteins [34,35].…”

“…Sirt3 is a sirtuin and nicotinamide adenine dinucleotide protein deacetylase that mainly localizes to the mitochondria and controls acetylation of mitochondrial proteins [34,35]. Data show that Sirt3 is implicated in the regulation of numerous cellular processes, including the stress response, aging, and energy metabolism, mainly through its effect on protein acetylation [36][37][38].…”

“…Data show that Sirt3 is implicated in the regulation of numerous cellular processes, including the stress response, aging, and energy metabolism, mainly through its effect on protein acetylation [36][37][38]. Sirt3 can protect cells against various types of stress-induced death by maintaining mitochondrial integrity or by mitophagy [34,39]. VDAC1 is an outer mitochondrial membrane protein, and it acts as a mitochondrial binding site for hexokinase II [40].…”

Induction of mitophagy-mediated antitumor activity with folate-appended methyl-β-cyclodextrin

“…12 Qiao et al revealed that Sirt3 activates mitophagy in hypoxic tumor cells. 13 Therefore, the regulation of mitophagy in tumor tissue is a candidate for clinical treatment of cancer.…”