SIRT2-mediated deacetylation of ANT3 at Lys96 promotes cell death

Abstract ANT3 is a key molecule that constitutes the mitochondrial permeability transition pore (mPTP) and mediates cell death. Disruption or conformational changes in ANT3 protein homeostasis can trigger cell death. However, the molecular mechanism of ANT3 protein homeostasis regulation remains unclear. We found that prolonged starvation induces cell death by mediating ANT3 deacetylation-dependent pathways through the mitochondrial translocation of SIRT2, which in turn regulates ANT3 protein levels and conformational changes. Specifically, we demonstrated that prolonged starvation promotes the mitochondrial translocation of SIRT2, thereby enhancing its binding to ANT3. This interaction leads to the deacetylation of ANT3 at K96 by SIRT2. Deacetylation of K96 by SIRT2 simultaneously promotes ANT3 conformational changes and the formation of the ANT3-VDAC1 complex. Concurrently, ANT3 also binds more strongly to USP15, leading to enhanced ANT3 deubiquitination and protein stability, which further increases the formation of the ANT3-VDAC1 complex and accelerates the process of cell death. In summary, this study reveals a rarely reported molecular mechanism of SIRT2-mediated acetylation-dependent regulation of programmed cell death.