MTOR-independent autophagy induced by interrupted endoplasmic reticulum-mitochondrial Ca2+ communication: a dead end in cancer cells.
The interruption of endoplasmic reticulum (ER)-mitochondrial Ca2+ communication induces a bioenergetic crisis characterized by an increase of MTOR-independent AMPK-dependent macroautophagic/autophagic flux, which is not sufficient to reestablish the metabolic and energetic homeostasis in cancer cells. Here, we propose that upon ER-mitochondrial Ca2+ transfer inhibition, AMPK present at the mitochondria-associated membranes (MAMs) activate localized autophagy via BECN1 (beclin 1). This local response could prevent the proper interorganelle communication that would allow the autophagy-derived metabolites to reach the necessary anabolic pathways to maintain mitochondrial function and cellular homeostasis. Abbreviations: 3MA: 3-methyladenine; ADP: adenosine diphosphate; AMP: adenosine monophosphate; ATG13: autophagy related 13; ATG14: autophagy related 14; ATP: adenosine triphosphate; BECN1: beclin 1; Ca2+: calcium; DNA: deoxyribonucleic acid; ER: endoplasmic reticulum; GEF: guanine nucleotide exchange factor; ITPR: inositol 1,4,5-trisphosphate receptor; MAMs: mitochondria-associated membranes; MCU: mitochondrial calcium uniporter; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OCR: oxygen consumption rate; PtdIns3K: class III phosphatidylinositol 3-kinase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RPTOR: regulatory associated protein of MTOR complex 1; RYRs: ryanodine receptors; STK11/LKB1: serine/threonine kinase 11; TCA: tricarboxylic acid; TSC2: TSC complex subunit 2; ULK1: unc-51 like autophagy activating kinase 1; V-ATPase: vacuolar-type H+-ATPase; VDAC: voltage dependent anion channel; XeB: xestospongin B.
['Ahumada-Castro|Ulises|U|', 'Silva-Pavez|Eduardo|E|', 'Lovy|Alenka|A|', 'Pardo|Evelyn|E|0000-0002-2516-5632', 'Molgό|Jordi|J|', 'Cárdenas|César|C|']
D001343:Autophagy D002118:Calcium D019069:Cell Respiration D004721:Endoplasmic Reticulum D006367:HeLa Cells D006801:Humans D008928:Mitochondria D009369:Neoplasms D058570:TOR Serine-Threonine Kinases
AMPK MCU 4 5-triphosphate receptors ITPRs/inositol 1 mitochondria associated membranes