structural:summarization, structural:expansion
Calcium signaling

A critical role for the ER in calcium signaling was acknowledged before such a role for the mitochondria was widely accepted, in part because the low affinity of Ca channels localized to the outer mitochondrial membrane seemed to contradict this organelle's purported responsiveness to changes in intracellular Ca flux. But the presence of the MAM resolves this apparent contradiction: the close physical association between the two organelles results in Ca microdomains at contact points that facilitate efficient Ca transmission from the ER to the mitochondria. Transmission occurs in response to so-called "Ca puffs" generated by spontaneous clustering and activation of IP3R, a canonical ER membrane Ca channel.

The fate of these puffs—in particular, whether they remain restricted to isolated locales or integrated into Ca waves for propagation throughout the cell—is determined in large part by MAM dynamics. Although reuptake of Ca by the ER (concomitant with its release) modulates the intensity of the puffs, thus insulating mitochondria to a certain degree from high Ca exposure, the MAM often serves as a firewall that essentially buffers Ca puffs by acting as a sink into which free ions released into the cytosol can be funneled. This Ca tunneling occurs through the low-affinity Ca receptor VDAC1, which recently has been shown to be physically tethered to the IP3R clusters on the ER membrane and enriched at the MAM. The ability of mitochondria to serve as a Ca sink is a result of the electrochemical gradient generated during oxidative phosphorylation, which makes tunneling of the cation an exergonic process. Normal, mild calcium influx from cytosol into the mitochondrial matrix causes transient depolarization that is corrected by pumping out protons.

But transmission of Ca is not unidirectional; rather, it is a two-way street. The properties of the Ca pump SERCA and the channel IP3R present on the ER membrane facilitate feedback regulation coordinated by MAM function. In particular, the clearance of Ca by the MAM allows for spatio-temporal patterning of Ca signaling because Ca alters IP3R activity in a biphasic manner. SERCA is likewise affected by mitochondrial feedback: uptake of Ca by the MAM stimulates ATP production, thus providing energy that enables SERCA to reload the ER with Ca for continued Ca efflux at the MAM. Thus, the MAM is not a passive buffer for Ca puffs; rather it helps modulate further Ca signaling through feedback loops that affect ER dynamics.

Regulating ER release of Ca at the MAM is especially critical because only a certain window of Ca uptake sustains the mitochondria, and consequently the cell, at homeostasis. Sufficient intraorganelle Ca signaling is required to stimulate metabolism by activating dehydrogenase enzymes critical to flux through the citric acid cycle. However, once Ca signaling in the mitochondria passes a certain threshold, it stimulates the intrinsic pathway of apoptosis in part by collapsing the mitochondrial membrane potential required for metabolism. Studies examining the role of pro- and anti-apoptotic factors support this model; for example, the anti-apoptotic factor Bcl-2 has been shown to interact with IP3Rs to reduce Ca filling of the ER, leading to reduced efflux at the MAM and preventing collapse of the mitochondrial membrane potential post-apoptotic stimuli. Given the need for such fine regulation of Ca signaling, it is perhaps unsurprising that dysregulated mitochondrial Ca has been implicated in several neurodegenerative diseases, while the catalogue of tumor suppressors includes a few that are enriched at the MAM.