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.
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.