Figure 9.

Mitochondrial and lysosomal impact on intracellular Ca²⁺ signal. (A) Primary components of Ca²⁺ signaling at the mitochondrial associated membranes (MAMs) include IP₃R3 on the endoplasmic reticulum, VDAC1 on the outer mitochondrial membrane, and MCU complex on the inner mitochondrial membrane [151,154,156,161]. Transport of Ca²⁺ ions from ER to mitochondria plays a crucial role in cellular metabolism (autophagy), cell survival (during unfolded protein response and impinging cell death signals), lipid production, and distribution [162,163,164,165,166]. For these cellular processes to proceed normally, the integrity of MAMs is essential. Various tethering proteins regulate MAM structural integrity. Such secondary MAM components include GRP75, PML, GRP78 (or BiP), mitofusins (MFN1 and 2), and phosphofurin acidic cluster sorting protein (PACS2) [158,159,160,164,167,168,169]. Localized to the ER side of MAMs, growth factor-activated mTORC2 utilizes phosphorylated PACS2 (via Akt) to help avoid structural disruption of this sub-compartment [170]. It also phosphorylates IP3R3 to promote Ca²⁺ release at MAM sites. Other key MAM localized proteins maintain Ca²⁺ homeostasis in the region. These are calreticulin and calmodulin in the ER lumen, and SERCA on the ER membrane (184). Excessive Ca²⁺ ions in the mitochondrial matrix are extruded mainly by a permeability transition pore (mPTP). This Ca²⁺ efflux pore is situated on the inner mitochondrial membrane and is comprised of F1F0 ATPase with cyclophilin D (CyPD), adenine nucleotide translocase (ANT), and mitochondrial phosphate carrier (PiC) as its regulators [171,172]. Proapoptotic molecules Bax and Bak influence mPTP opening by controlling outer mitochondrial membrane permeability [173]. Ca²⁺ exchangers such as NCLX and HCX are less understood efflux mechanisms that may prevent overload of these cations in the organelle [151,174]; (B) Lysosomal Ca²⁺ promotes IP₃R3 mediated Ca²⁺ release from the endoplasmic reticulum [175,176]. Activated by NAADP, two-pore channels (TPCs) and TRPMLs are the main mode of Ca²⁺ extrusion from lysosomes. Multi-subunit V-ATPases actively transport hydrogen ions into the lysosomal lumen to maintain acidic pH that has been previously considered as the driving force for Ca²⁺ entry into lysosomes via HCX. Although any direct association between acidic lumen and Ca²⁺ store maintenance is now considered controversial, any indirect impact on lysosomal Ca²⁺ stores has not been ruled out. Parallel to this, the dependence of lysosomal Ca²⁺ uptake on ER Ca²⁺ stores is speculated [177]. Lysosomes can also play a more active role in intracellular Ca²⁺ homeostasis as indicated by their inhibition of SOCE [178]. Akt, a serine-threonine kinase; BiP, binding immunoglobulin protein; CyPD, cyclophilin D or peptidyl-prolyl cis-trans isomerase D; EMRE, essential mitochondria regulator; GRP75, glucose-regulated protein 75; HCX, hydrogen-Ca²⁺ exchanger; MCU; mitochondrial Ca²⁺ uniporter; MCUR1, mitochondrial Ca²⁺ uniporter regulator 1; MICU1/2, mitochondrial Ca²⁺ uptake 1 or 2; MFN1/2, mitofusin 1 or 2; mPTP, mitochondrial permeability transition pore; ML-SA1, mucolipin synthetic agonist 1; mTORC2, mTOR complex 2; NAADP, nicotinic acid adenine dinucleotide phosphate; NCLX, mitochondrial sodium Ca²⁺ exchanger; PML, promyeloctic leukemia protein; PACS2, phosphofurin acidic cluster sorting protein 2; SERCA, sarcoendoplasmic reticulum Ca²⁺ ATPase; Sig1R, sigma 1 receptor; TFEB, transcription factor EB; TPC, two-pore channel; TRPML, transient receptor potential mucolipin channel; V-ATPase, vacuolar ATPase; VDAC, voltage-dependent anion channel.