IP3 receptor-binding partners in cell-death mechanisms

Abstract

A multiprotein complex, which involves the inositol 1,4,5-trisphosphate receptor (IP3R) on the endoplasmic reticulum (ER) and the voltage-dependent anion channel (VDAC) on the outer mitochondrial membrane (OMM) along with multiple other IP3R-binding partners, is responsible for a privileged and tightly controlled transfer of Ca2+ from the ER to the mitochondria. To stimulate cell metabolism and survival, the mitochondrial Ca2+ level [Ca2+]mit has to be kept within a small physiological range. Decreased or increased Ca2+ fluxes result in an adaptive cellular response involving, respectively, autophagy to meet cellular energy demands or mitophagy to remove damaged mitochondria. Failure of these autophagic responses eventually leads to initiation of cell death. Malfunction of the interaction between the IP3R and its binding partners may have pathological consequences. In cancer cells, such malfunctions lead to an inability to generate large proapoptotic mitochondrial Ca2+ signals. In familial Alzheimer's disease (FAD) and Huntington's disease (HD) on the other hand, exaggerated Ca2+ signals may result in neuronal damage and cell death. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.