Suppression of Apoptosis by Cyclophilin D via Stabilization of Hexokinase II Mitochondrial Binding in Cancer Cells

Abstract

The permeability transition pore is involved in the mitochondrial pathway of apoptosis. Cyclophilin D, a pore component, has catalytic activity as a peptidyl prolyl cis, trans-isomerase (PPIase), which is essential to the pore opening. It has been reported that cyclophilin D overexpression suppresses apoptosis in cancer cells. To clarify the mechanism of this effect, we generated glioma cells overexpressing wild-type or a PPIase-deficient mutant of cyclophilin D. Interestingly, we found that the PPIase-dependent apoptosis suppression by cyclophilin D correlated with the amounts of mitochondrialbound hexokinase II, which has anti-apoptotic activity. Inactivation of endogenous cyclophilin D by small interference RNA or a cyclophilin inhibitor was found to release hexokinase II from mitochondria and to enhance Bax-mediated apoptosis. The anti-apoptotic effects of cyclophilin D were canceled out by the detachment of hexokinase II from mitochondria, demonstrating that mitochondrial binding of hexokinase II is essential to the apoptosis suppression by cyclophilin D. Furthermore, cyclophilin D dysfunction appears to abrogate hexokinase II-mediated apoptosis suppression, indicating that cyclophilin D is required for the anti-apoptotic activity of hexokinase II. Based on the above, we propose here that cyclophilin D suppresses apoptotic cell death via a mitochondrial hexokinase II-dependent mechanism in cancer cells.

Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II

“…18 Interestingly, Cyp D, which genetic evidence shows to be critical for PT-pore induction, 19,20 was recently reported to suppress apoptosis via stabilization of HK-II binding to mitochondria. 26 While our data demonstrate that mitochondrial HK-II is a key inhibitor of PT-pore (Ca 2 þ -mediated and Cs-A sensitive) induced cytochrome c release, and previous papers show that overexpression of HK is protective against stress. 37,38 Much additional study will be required to elucidate the mechanisms by which HK-II keeps PT pore opening in check.…”

“…13,22 A role for hexokinase in mitochondrial protection was recently reported. [22][23][24][25][26] Interestingly the ability of Akt to protect against cytochrome c release and apoptosis in fibroblasts was shown to be decreased by HK-II dissociation from mitochondria. 27 The question of whether hexokinase is a mediator of cell survival in the heart has not been examined, although HK-II is abundantly expressed in cardiomyocytes.…”

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

“…100,101 Interestingly, CyPD activity stabilizes mitoHK-II binding and forced dissociation of mitoHK-II leads to disruption of CyPD binding to ANT, suggesting a functional link between a stimulatory (CyPD) and an inhibitory (HK-II) molecule of the mPTP. 96,[102][103][104][105] It seems likely that the interaction between HK-II and CyPD is mediated by the previously mentioned VDAC/ANT interaction. 106,107 However, genetic evidence revealed that neither VDAC nor ANT is the main pore-forming component [108][109][110][111] and thus it is still not clear whether the indirect interaction of HK-II with CyPD plays a direct role in regulation of the mPTP.…”

Methyl jasmonate binds to and detaches mitochondria-bound hexokinase

“…Fast and massive ATP depletion by jasmonate-induced hexokinase detachment fits with the fact that other agents known to detach mitochondrial hexokinase also induce ATP depletion preceding the decrease in cell viability (Miccoli et al, 1998;Machida et al, 2006).…”