Editing Mitochondrion (section)

====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{{sup|2+}} channels localized to the outer mitochondrial membrane seemed to contradict this organelle's purported responsiveness to changes in intracellular Ca{{sup|2+}} flux.<ref name="Rizzuto-2009"/><ref name="Santulli-2015b">{{cite journal | vauthors = Santulli G, Marks AR | title = Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging | journal = Current Molecular Pharmacology | volume = 8 | issue = 2 | pages = 206–222 | date = 2015 | pmid = 25966694 | doi = 10.2174/1874467208666150507105105 }}</ref> But the presence of the MAM resolves this apparent contradiction: the close physical association between the two organelles results in Ca{{sup|2+}} microdomains at contact points that facilitate efficient Ca{{sup|2+}} transmission from the ER to the mitochondria.<ref name="Rizzuto-2009"/> Transmission occurs in response to so-called "Ca{{sup|2+}} puffs" generated by spontaneous clustering and activation of [[IP3R]], a canonical ER membrane Ca{{sup|2+}} channel.<ref name="Rizzuto-2009"/><ref name="Hayashi-2009"/>

The fate of these puffs—in particular, whether they remain restricted to isolated locales or integrated into Ca{{sup|2+}} waves for propagation throughout the cell—is determined in large part by MAM dynamics. Although reuptake of Ca{{sup|2+}} by the ER (concomitant with its release) modulates the intensity of the puffs, thus insulating mitochondria to a certain degree from high Ca{{sup|2+}} exposure, the MAM often serves as a firewall that essentially buffers Ca{{sup|2+}} puffs by acting as a sink into which free ions released into the cytosol can be funneled.<ref name="Rizzuto-2009"/><ref name="Kopach-2008">{{cite journal | vauthors = Kopach O, Kruglikov I, Pivneva T, Voitenko N, Fedirko N | title = Functional coupling between ryanodine receptors, mitochondria and Ca(2+) ATPases in rat submandibular acinar cells | journal = Cell Calcium | volume = 43 | issue = 5 | pages = 469–481 | date = May 2008 | pmid = 17889347 | doi = 10.1016/j.ceca.2007.08.001 }}</ref><ref name="Csordás-2001">{{cite journal | vauthors = Csordás G, Hajnóczky G | title = Sorting of calcium signals at the junctions of endoplasmic reticulum and mitochondria | journal = Cell Calcium | volume = 29 | issue = 4 | pages = 249–262 | date = April 2001 | pmid = 11243933 | doi = 10.1054/ceca.2000.0191 }}</ref> This Ca{{sup|2+}} tunneling occurs through the low-affinity Ca{{sup|2+}} receptor [[VDAC1]], which recently has been shown to be physically [[tether (cell biology)|tethered]] to the IP3R clusters on the ER membrane and enriched at the MAM.<ref name="Rizzuto-2009"/><ref name="Hayashi-2009"/><ref name="Decuypere-2011">{{cite journal | vauthors = Decuypere JP, Monaco G, Bultynck G, Missiaen L, De Smedt H, Parys JB | title = The IP(3) receptor-mitochondria connection in apoptosis and autophagy | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1813 | issue = 5 | pages = 1003–1013 | date = May 2011 | pmid = 21146562 | doi = 10.1016/j.bbamcr.2010.11.023 | doi-access =  }}</ref> The ability of mitochondria to serve as a Ca{{sup|2+}} sink is a result of the electrochemical gradient generated during oxidative phosphorylation, which makes tunneling of the cation an exergonic process.<ref name="Decuypere-2011"/> Normal, mild calcium influx from cytosol into the mitochondrial matrix causes transient depolarization that is corrected by pumping out protons.

But transmission of Ca{{sup|2+}} is not unidirectional; rather, it is a two-way street.<ref name="Santulli-2015b"/> The properties of the Ca{{sup|2+}} pump SERCA and the channel IP3R present on the ER membrane facilitate feedback regulation coordinated by MAM function. In particular, the clearance of Ca{{sup|2+}} by the MAM allows for [[spatio-temporal pattern]]ing of Ca{{sup|2+}} signaling because Ca{{sup|2+}} alters IP3R activity in a biphasic manner.<ref name="Rizzuto-2009"/> [[SERCA]] is likewise affected by mitochondrial feedback: uptake of Ca{{sup|2+}} by the MAM stimulates ATP production, thus providing energy that enables SERCA to reload the ER with Ca{{sup|2+}} for continued Ca{{sup|2+}} efflux at the MAM.<ref name="Kopach-2008"/><ref name="Decuypere-2011"/> Thus, the MAM is not a passive buffer for Ca{{sup|2+}} puffs; rather it helps modulate further Ca{{sup|2+}} signaling through feedback loops that affect ER dynamics.

Regulating ER release of Ca{{sup|2+}} at the MAM is especially critical because only a certain window of Ca{{sup|2+}} uptake sustains the mitochondria, and consequently the cell, at homeostasis. Sufficient intraorganelle Ca{{sup|2+}} signaling is required to stimulate metabolism by activating dehydrogenase enzymes critical to flux through the citric acid cycle.<ref name="Diercks-2017">{{cite journal | vauthors = Diercks BP, Fliegert R, Guse AH | title = Mag-Fluo4 in T cells: Imaging of intra-organelle free Ca<sup>2+</sup> concentrations | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1864 | issue = 6 | pages = 977–986 | date = June 2017 | pmid = 27913206 | doi = 10.1016/j.bbamcr.2016.11.026 | doi-access = free }}</ref><ref name="Hajnóczky-2011">{{cite journal | vauthors = Hajnóczky G, Csordás G, Yi M | title = Old players in a new role: mitochondria-associated membranes, VDAC, and ryanodine receptors as contributors to calcium signal propagation from endoplasmic reticulum to the mitochondria | journal = Cell Calcium | volume = 32 | issue = 5–6 | pages = 363–377 | year = 2011 | pmid = 12543096 | doi = 10.1016/S0143416002001872 }}</ref> However, once Ca{{sup|2+}} 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.<ref name="Rizzuto-2009"/> 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{{sup|2+}} filling of the ER, leading to reduced efflux at the MAM and preventing collapse of the mitochondrial membrane potential post-apoptotic stimuli.<ref name="Rizzuto-2009"/> Given the need for such fine regulation of Ca{{sup|2+}} signaling, it is perhaps unsurprising that dysregulated mitochondrial Ca{{sup|2+}} has been implicated in several neurodegenerative diseases, while the catalogue of tumor suppressors includes a few that are enriched at the MAM.<ref name="Decuypere-2011"/>