A Calcium Guard in the Outer Membrane: Is VDAC a Regulated Gatekeeper of Mitochondrial Calcium Uptake?

Already in the early 1960s, researchers noted the potential of mitochondria to take up large amounts of Ca2+. However, the physiological role and the molecular identity of the mitochondrial Ca2+ uptake mechanisms remained elusive for a long time. The identification of the individual components of the mitochondrial calcium uniporter complex (MCUC) in the inner mitochondrial membrane in 2011 started a new era of research on mitochondrial Ca2+ uptake. Today, many studies investigate mitochondrial Ca2+ uptake with a strong focus on function, regulation, and localization of the MCUC. However, on its way into mitochondria Ca2+ has to pass two membranes, and the first barrier before even reaching the MCUC is the outer mitochondrial membrane (OMM). The common opinion is that the OMM is freely permeable to Ca2+. This idea is supported by the presence of a high density of voltage-dependent anion channels (VDACs) in the OMM, forming large Ca2+ permeable pores. However, several reports challenge this idea and describe VDAC as a regulated Ca2+ channel. In line with this idea is the notion that its Ca2+ selectivity depends on the open state of the channel, and its gating behavior can be modified by interaction with partner proteins, metabolites, or small synthetic molecules. Furthermore, mitochondrial Ca2+ uptake is controlled by the localization of VDAC through scaffolding proteins, which anchor VDAC to ER/SR calcium release channels. This review will discuss the possibility that VDAC serves as a physiological regulator of mitochondrial Ca2+ uptake in the OMM.