Mitochondrial Ca2+ channels: Great unknowns with important functions

Abstract

Mitochondria process local and global Ca(2+) signals. Thereby the spatiotemporal patterns of mitochondrial Ca(2+) signals determine whether the metabolism of these organelles is adjusted or cell death is executed. Mitochondrial Ca(2+) channels of the inner mitochondrial membrane (IMM) actually implement mitochondrial uptake from cytosolic Ca(2+) rises. Despite great efforts in the past, the identity of mitochondrial Ca(2+) channels is still elusive. Numerous studies aimed to characterize mitochondrial Ca(2+) uniport channels and provided a detailed profile of these great unknowns with important functions. This mini-review revisits previous research on the mechanisms of mitochondrial Ca(2+) uptake and aligns them with most recent findings.

Fig. 1. Schematic illustration of mitochondrial Ca²⁺ uptake channels/carrier in the IMM, potential protagonists and the complexity if the mitochondrial environment.

(A) The complex environmental aspects of mitochondria in intact cells are illustrated. Local Ca²⁺ transfer from the ER via IP₃ mediated Ca²⁺ release. VDAC as porines in the OMM deliver Ca²⁺ ions to the MCU or Ca²⁺ exchanger at the IMM. (B) Electrophysiological characterizations revealed distinct mitochondrial Ca²⁺ channels: the MiCa in COS-7 cells and mCa1 as well as mCa2 in human ventricular myocytes. (C) Overexpression and siRNA mediated knock-down of UCP2/3 suggest a fundamental importance of these proteins for mitochondrial Ca²⁺ uniport. A genome-wide RNAi screen identified Letm1 as a mitochondrial Ca²⁺/H⁺ antiporter that significantly contributes to mitochondrial Ca²⁺ uptake in the physiological range of cytosolic Ca²⁺ elevation. (D) ER-mitochondria contact sites are stabilized by mitofusin 2 and probably other, so far unknown, proteins. The chaperon grp75 was shown to link the IP₃R to the VDAC in the OMM. Although proteins/factors that might link the VDAC to mitochondrial Ca²⁺ channels of the IMM have not been identified so far it is tempting to speculate that Ca²⁺ enters mitochondria via a Ca²⁺ tunnel spanning the OMM and IMM. (E) Evidence accumulated that kinases as well as Ca²⁺ and Ca²⁺-calmodulin differentially modulate the activities of mitochondrial Ca²⁺ channels.