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Published in final edited form as: Cell Calcium. 2012 Mar 28;52(1):44–51. doi: 10.1016/j.ceca.2012.03.001

Fig. 2 — Suppression of InsP₃R Ca²⁺ transfer to mitochondria induces mTOR-independent autophagy. A. In resting cells, low-level InsP₃ production is maintained by circulating ligands for receptors that couple to phospholipases C (PLC) beta and gamma. In addition, InsP₃R-mediated Ca²⁺ release and/or extracellular influx the Ca²⁺ can activate calpain, which cleaves and activates the heterotrimeric G-protein alpha subunit G_s, increasing the levels of cAMP, activating Epac to stimulate the small G protein Rap2B that activates PLCε. Phosphatidylinositol 4–5-biphosphate (PIP₂) levels are maintained by a constant supply of inositol (Ins) by the inositol monophosphatase (IMPase). Low-level stochastic Ca²⁺ release from the endoplasmic reticulum by InsP₃R, enhanced by Bcl-2 and Bcl-x_L bound to the channel, provides Ca²⁺ to mitochondria in close proximity, mediated by the outer membrane VDAC and MCU at the inner mitochondrial membrane. Matrix Ca²⁺ activates pathways, including dehydrogenases and the F₁-F₀-ATPase, that fuel the electron transport chain and O₂ consumption by providing reducing equivalents in the form of NADH. ATP production maintains a low cytoplasmic AMP:ATP ratio. This mechanism provides the cell with bioenergetic fitness that suppresses autophagy. B. The absence of constitutive delivery of Ca²⁺ from ER to mitochondria, due either to inhibition of InsP₃R-mediated Ca²⁺ release (by genetic deletion of InsP₃R (DT40-KO), inhibition of InsP₃R activity (by xestospongin B (XeB), molecular ablation of the InsP₃R (by RNAi), inhibition of InsP₃ production by blocking the IMPase (by lithium (Li⁺) or L-690,330), blocking PLC (not shown; [37]), or inhibiting the calpain cascade that impinges on PLCε)); or by inhibition of mitochondrial Ca²⁺ uptake (Ru360 or MCU RNAi), results in diminished pyruvate dehydrogenase (PDH) activity (as well as the activities possibly other Ca²⁺-sensitive dehydrogenases and the ATP-synthase) that results in insufficient production of NADH, limiting the activity of the electron transport chain, diminishing O₂ consumption and reducing ATP production. The consequent rise of the AMP:ATP ratio activates AMPK, which induces pro-survival, mTOR-independent autophagy, possibly involving ULK1/2 and/or sirtuin1.

Fig. 2 — Suppression of InsP₃R Ca²⁺ transfer to mitochondria induces mTOR-independent autophagy. A. In resting cells, low-level InsP₃ production is maintained by circulating ligands for receptors that couple to phospholipases C (PLC) beta and gamma. In addition, InsP₃R-mediated Ca²⁺ release and/or extracellular influx the Ca²⁺ can activate calpain, which cleaves and activates the heterotrimeric G-protein alpha subunit G_s, increasing the levels of cAMP, activating Epac to stimulate the small G protein Rap2B that activates PLCε. Phosphatidylinositol 4–5-biphosphate (PIP₂) levels are maintained by a constant supply of inositol (Ins) by the inositol monophosphatase (IMPase). Low-level stochastic Ca²⁺ release from the endoplasmic reticulum by InsP₃R, enhanced by Bcl-2 and Bcl-x_L bound to the channel, provides Ca²⁺ to mitochondria in close proximity, mediated by the outer membrane VDAC and MCU at the inner mitochondrial membrane. Matrix Ca²⁺ activates pathways, including dehydrogenases and the F₁-F₀-ATPase, that fuel the electron transport chain and O₂ consumption by providing reducing equivalents in the form of NADH. ATP production maintains a low cytoplasmic AMP:ATP ratio. This mechanism provides the cell with bioenergetic fitness that suppresses autophagy. B. The absence of constitutive delivery of Ca²⁺ from ER to mitochondria, due either to inhibition of InsP₃R-mediated Ca²⁺ release (by genetic deletion of InsP₃R (DT40-KO), inhibition of InsP₃R activity (by xestospongin B (XeB), molecular ablation of the InsP₃R (by RNAi), inhibition of InsP₃ production by blocking the IMPase (by lithium (Li⁺) or L-690,330), blocking PLC (not shown; [37]), or inhibiting the calpain cascade that impinges on PLCε)); or by inhibition of mitochondrial Ca²⁺ uptake (Ru360 or MCU RNAi), results in diminished pyruvate dehydrogenase (PDH) activity (as well as the activities possibly other Ca²⁺-sensitive dehydrogenases and the ATP-synthase) that results in insufficient production of NADH, limiting the activity of the electron transport chain, diminishing O₂ consumption and reducing ATP production. The consequent rise of the AMP:ATP ratio activates AMPK, which induces pro-survival, mTOR-independent autophagy, possibly involving ULK1/2 and/or sirtuin1.