SIRT3 protects from hypoxia and staurosporine-mediated cell death by maintaining mitochondrial membrane potential and intracellular pH

Abstract

Mitochondrial sirtuin 3 (SIRT3) mediates cellular resistance toward various forms of stress. Here, we show that in mammalian cells subjected to hypoxia and staurosporine treatment SIRT3 prevents loss of mitochondrial membrane potential (DW mt ), intracellular acidification and reactive oxygen species accumulation. Our results indicate that: (i) SIRT3 inhibits mitochondrial permeability transition and loss of membrane potential by preventing HKII binding to the mitochondria, (ii) SIRT3 increases catalytic activity of the mitochondrial carbonic anhydrase VB, thereby preventing intracellular acidification, Bax activation and apoptotic cell death. In conclusion we propose that, in mammalian cells, SIRT3 has a central role in connecting changes in DW mt , intracellular pH and mitochondrial-regulated apoptotic pathways. Cell Death and Differentiation (2012) 19, 1815-1825 doi:10.1038/cdd.2012 published online 18 May 2012 Sirtuins are a family of protein highly conserved in both prokaryotes and eukaryotes. 1 The name derives from the Saccharomyces cerevisiae gene silent information regulator 2 (Sir2), the first known sirtuin, that, by silencing chromatin via deacetylation of histones, regulates both replicative and overall life span. 2 In mammals, seven Sir2 homologs, designated SIRT1 through SIRT7 have been identified, that regulate a wide range of intracellular processes including metabolism, longevity, aging, cancer and response to stress. 3-5 These proteins are characterized by an evolutionarily conserved sirtuin core domain 6 that contains the catalytic and nicotinamide adenine dinucleotide (NAD þ )-binding domain. Each sirtuin catalyzes protein deacetylation or adenosine diphosphate (ADP) ribosylation in vitro, requires NAD þ for enzymatic activity and generates nicotinamide, which then acts as a negative feedback inhibitor. 7 Because of the NAD þ requirement, sirtuins are categorized as class III histone deacetylases. 8 Mammalian sirtuins show distinct acetylated protein substrates and are localized in distinct subcellular compartments. Sirtuin 1 (SIRT1), SIRT6 and SIRT7 are in the nucleus, SIRT2 is primarily cytosolic and SIRT3, SIRT4 and SIRT5 are in the mitochondria. 9 Mitochondrial sirtuins participate in the regulation of ATP production, metabolism, apoptosis and cell signaling. 10 Among the three mitochondrial sirtuins, SIRT3 controls the global lysine acetylation of these organelles. 11 SIRT3 mediates cellular resistance toward various forms of stress by maintaining genomic stability and mitochondrial integrity. For example, SIRT3 influences cell survival by regulating the state of the mitochondrial permeability transition (MPT). However, the precise effects of SIRT3 on MPT are still not clear. In fact, some reports have shown that SIRT3 would deacetylate and inhibit the enzymatic activity of cyclophilin D 12 with the following dissociation from adenine nucleotide translocator, which, in turn, promotes detachment of hexokinase II (HKII) from voltage-dependent anion channel. Inhibition of cyclophilin D i...

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Sirtuin-3 modulates Bak- and Bax-dependent apoptosis

“…Sirt-3 also activates mitochondrial manganese superoxide dismutase, another key element of the mitochondrial ROS detoxification pathway (Tao et al, 2010). Importantly, sirt-3 has been demonstrated to exert a protective effect against hypoxia and staurosporine induced cell death by inhibiting the mitochondrial permeability transition and dampening intracellular acidification (Pellegrini et al, 2012;Zamzami et al, 1997). Carbonic anhydrase helps to regulate intracellular pH by catalyzing the conversion of carbon dioxide to bicarbonate.…”

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