Figure 1.

Effects of the inhibition of InsP3R-mediated Ca²⁺ transfer to mitochondria on OXPHOS-competent and OXPHOS-defective cancer cell viability. (a) The interruption of the inositol 1,4,5-triphosphate receptors (InsP3R)-mediated calcium (Ca²⁺) transfer to mitochondria in oxidative phosphorylation (OXPHOS)-competent cells decreases the tricarboxylic acid (TCA) cycle activity and OXPHOS, creating a bioenergetic crisis characterized by an increase in the nicotinamide adenine dinucleotide oxidized (NAD⁺)/nicotinamide adenine dinucleotide reduced (NADH) ratio. Consequently, the high NAD⁺/NADH ratio allows the activation of sirtuin 1 (SIRT1) which in turn activates autophagy, providing some protection against cell death. (b) In OXPHOS defective cells, the interruption of the InsP3R-mediated Ca²⁺ transfer to mitochondria reduces the activity of the α-ketoglutarate dehydrogenase (αKGDH) and in turn reduces the levels of NADH necessary to sustain reductive carboxylation. As in OXPHOS-competent cells, the increase in the NAD⁺/NADH ratio activates SIRT1 and autophagy. However, the impaired lysosome function in these cells enhances their death. Abbreviations: ER: endoplasmic reticulum; VDAC: voltage dependent anion channel; MCU: mitochondrial calcium uniporter; XeB: xestospongin B; siRNA: small interfering RNA; OMM: outer mitochondrial membrane; IMM: inner mitochondrial membrane; PDH: pyruvate dehydrogenase; IDH: isocitrate dehydrogenase; ACLY: ATP citrate lyase; Ac-CoA: acetyl-CoA; Glc: glucose; Gln: glutamine; AP: autophagosome; AL: autolysosome; Lys: Lysosome. Created with BioRender.com