The Principles of Mitochondrial Ca2+ Handling

The Ca2+ uptake pathway Ca2+ has to cross two membranes to enter into the mitochondrial matrix. The selective barrier offered by the inner mitochondrial membrane (IMM) has been recognized for many years, but the role of the outer membrane (OMM) as a regulated Ca2+ barrier has only recently been recognized. Overexpression of the voltage-dependent anion channel (VDAC) of the OMM, mainly known for its role in channelling metabolites, was shown to increase Ca2+ accumulation into the mitochondria (88). Furthermore, despite its name, VDAC may function as a Ca2+-activated Ca2+ channel (6, 102), contributing to the long-standing established ruthenium red (RuR) sensitivity of the Ca2+ uptake machinery (116). An outstanding question is whether other pore-forming proteins participate in Ca2+ channelling through the OMM. Studies on VDAC (isoforms 1-3) knockdown cells suggest that other pathways might exist, since the sensitivity of mitochondria to Ca2+ remained unaltered in these cells with respect to their wild-type counterparts (see below; Ref. 3), although this aspect of Ca2+ signaling was not assessed directly. Interestingly, the insertion of truncated Bid, a proapoptotic member of the Bcl-2 family, into the OMM also facilitates mitochondrial Ca2+ uptake, playing a role in the Ca2+-induced alteration of mitochondrial structure and function that accompanies apoptosis (21). It has long been known that Ca2+ is transported through the IMM by a uniporter. Remarkably, the