FIGURE 2.

Key cellular functions handled at mitochondria–ER contact sites. (A) Ca²⁺ signaling and redox crosstalk occur in MAM. Ca²⁺ flux from ER to mitochondria through MAM tethering complex IP3R/VADC or PTPIP51/VERB and accumulates in the mitochondrial matrix by MCU transportation. The high amount of ROS accumulated at the MAM generates redox nanodomains. Several MAM resident proteins regulate Ca²⁺ signaling and ROS generation. (B) MAMs are hubs for lipid trafficking between the ER and mitochondria. MAM residing enzymes including PSS1, PSS2, PSD, PEMT2, cytochrome P450, SMase, CerS, and DES are responsible for the exchange of phospholipids, cholesterol, and ceramides between these two organelles. Mitochondria take PS from the ER, which is supplied with PE by mitochondria. (C) Mitochondrial fission and fusion are regulated at the interface between the ER and mitochondria. During mitochondrial fission, DRP1 recruited by MiD49/51 and MFF to the mitochondrial surface interacts with the ER-localized STX17. The ER-mitochondria contact is required for mitochondrial pre-constriction. DRP1 activity is modulated by redox signals. Mitochondrial fusion is promoted by trichoplein binding to ER-anchored MFN2, and this interaction favors the interaction of mitochondrion-bound MFN2 and OPA1 to initiate the fusion of mitochondrial membranes. (D) MAMs are involved in the initiation of apoptosis and the regulation of mitophagy/autophagy. MAM tethering complexes FIS1-BAP31, IP3R-GRP75-VDAC1, and MFN2-MFN1/2 bridges the mitochondria and the ER for apoptosis signaling. PACS2 modulates BAP31 function, CDK5 regulates mitochondrial Ca²⁺ homeostasis. Autophagosomes assembly arise from mitochondria-ER contacts, the ER-resident protein STX17 attracts ATG14 and the PI3K complex. Bax, Bcl-2 associated X protein; Bcl-2, B cell CLL/lymphoma 2; cyt. c, cytochrome c; DRP1, dynamin-related protein 1; HK2, hexokinase 2; MCL-1, myeloid cell leukemia sequence 1; MCU, mitochondrial calcium uniporter; mPTP, mitochondrial permeability transition pore; Orai1, ORAI calcium release-activated calcium modulator 1; PML, promyelocytic leukemia protein; PTEN, phosphatase and tensin homolog deleted on chromosome 10; SERCA, sarco/endoplasmatic reticulum Ca²⁺ ATPase; Sig1R, Sigma 1 receptor; STIM1, stromal interaction molecule 1; PA, phosphatidic acid; PS, phosphatidylserine; PE, phosphatidylethanolamine; PC, phosphatidylcholine; Preg, pregnolone; PSS, phosphatidylserine synthase, PSD, phosphatidylserine decarboxylase; PEMT2, phosphatidylethanolamine-N-methyltransferase 2.