New focuses on roles of communications between endoplasmic reticulum and mitochondria in identification of biomarkers and targets

Abstract

The communication between endoplasmic reticulum (ER) and mitochondria (Mt) plays important roles in maintenance of intra- and extra-cellular microenvironment, metabolisms, signaling activities and cell-cell communication. The present review aims to overview the advanced understanding about roles of ER-Mt structural contacts, molecular interactions and chemical exchanges, signal transmissions and inter-organelle regulations in ER-Mt communication. We address how the ER-Mt communication contributes to the regulation of lipid, amino acid and glucose metabolisms by enzymes, transporters and regulators in the process of biosynthesis. We specially emphasize the importance of deep understanding about molecular mechanisms of ER-Mt communication for identification and development of biology-specific, disease-specific and metabolism-specific biomarkers and therapeutic targets for human diseases. The inhibitors and modulators of the ER-Mt communication are categorized according to therapeutic targets. Rapid development of biotechnologies will provide new insights for spatiotemporally understanding the molecular mechanisms of ER-Mt communication.

Keywords: communications; contacts; diseases; endoplasmic reticulum; homeostasis; mitochondria.

FIGURE 1

The main molecular domains located on the ER‐ Mt contacts sites were summarized. VAPB can bind to several mitochondrial proteins including MIGA2, OPR5/8, PTPIP15 and MOSPD2 (A). These tethers involve their role in the delivery of Ca²⁺ to mitochondria from ER. PACS2 is a cytosolic multifunctional sorting protein, essential for ER‐mitochondria Ca²⁺ transfer and apoptosis by the recruitment of CNX. GRP75 links IP3R1 on ER and VDAC1 on OMM to regulate Ca²⁺ efflux from ER to mitochodnria. FUNDC1, an integral mitochondrial outer‐membrane protein, can bind IP3R2 to modulate Ca²⁺ efflux from ER. FIS1 can convey an apoptosis signal from the mitochondria to the ER by interacting with BAP31, recruiting and activating procaspase‐8 (B). WASF3 can interact with ATAD3A and GRP78, which may provide a bridge between ER and mitochondria. MFN2 on the ER can bridge the two organelles by engaging in homotypic and heterotypic complexes with MFN1/2 on OMM (C). Mitochondrial fission occurs at ER‐mitochondria contact site where Spire1c promotes actin assembly on the surface of mitochondria through interacting with INF2 on ER. Then, DRP1 are recruited and interact with MFF and/or MiD94/51. ATAD3A dimerization is required for DRP1‐mediated mitochondrial fission. In addition, DRP1 can interact with STX17, playing an important role in mitophagy (D). Abbreviations: Mt, mitochondria; ER, endoplasmic reticulum; VAPB, vesicle‐associated membrane protein‐associated protein B; MIGA2, mitoguardin 2; OPR, oxo‐phytodienoic acid reductase; PTPIP15, protein tyrosine phosphatase‐interacting protein 51; MOSPD2, motile sperm domain‐containing protein 2; PACS2, phosphofurin acidic cluster sorting protein 2; CNX, calnexin; GRP, glucose‐regulated protein; VDAC, voltage‐dependent anion channel 1; OMM, outer membrane of mitochondria; FUNDC1, FUN14 domain containing 1; IP3R, inositol 1,4,5‐trisphosphate receptor; FIS1, fission protein 1; WASF, Wiskott–Aldridge syndrome family; ATAD, ATPase family AAA‐domain containing protein; MFN, mitofusin; INF, inverted formin 2; DRP1, dynamin‐related protein 1; MFF, mitochondrial fission factor; STX17, syntaxin‐17; MCU, mitochondrial calcium uniporter; BAP31, B cell receptor‐associated protein 31; Spire1C, splice‐isoform of Spire1

FIGURE 2

The synthesis and transport of lipids through the contact between Mt and ER also called MAM or Mt‐ER contact (MERCs) (A). The accumulation of cholesterol and sphingolipids in MAM is related to increased Caveolin‐1, which regulates the transfer of ER‐mitochondrial cholesterol. DAG is converted to PA by DGK. DAG is the predecessor of PI and PS in ER, to synthesize PI and PS through PA. PS is synthesized in the ER by the MAM enzymes PSS1 and PSS2. ER provides PI and PS to Mt, which are transferred through lipid transfer proteins ORP5 and ORP8 (B). After then, the newly formed PS is transferred to the inner Mt membrane through MAM. IMM contains PSD, which converts PS to PE. Therefore, PS is transferred to OMM first, transferred to IMM and then converted to PE. Subsequently, PE returns to the ER, where PEMT2 mediates the synthesis of PC, and the PC is transferred from the ER to Mt. PA is an important raw material for the synthesis of CL. It is transferred from ER to OMM, then to IMM and converted to CDP‐DAG through Mt TAM41 in IMM. CDP‐DAG is catalyzed by PGS1 to synthesize PGP, and further through PTPM1 to generate PG, which synthesizes CL under the catalysis of CL synthase CRLS1 (C and D). Abbreviations: IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; PA, phosphatidic acid; PS, phosphatidylserine; PC, phosphatidylcholine; PI, phosphatidylinositol; Chol, cholesterol; PG, phosphatidylglycerol; PE, phosphatidylethanolamine; CL, cardiolipin; CDP‐DAG, cytidine diphosphate diacylglycerol; PGP, glyceraldehyde 3‐phosphate; PSD, PH and SEC7 domain‐containing protein 1; DGK, diacylglycerol kinase; PSS, phosphatidylserine synthase; ORP, OSBP‐related protein; TAM41, translocator assembly and maintenance protein 41 homolog; PEMT2, phosphatidyle thanolamine N‐methyltransferase 2; CRLS1, Cardiolipin Synthase 1; PGS1, Phosphatidylglycerophosphate Synthase 1; PTPM1, phosphatidylglycerophosphatase and protein‐tyrosine phosphatase 1; CDS, CDP‐diacylglycerol synthases; CDIPT, CDP‐diacylglycerol‐inositol 3‐phosphatidyltransferase

FIGURE 3

ER‐ Mt regulation of Ca²⁺ transport (A), amino acids and protein metabolism. ER‐Mt communication sites contain several components to impact Ca²⁺ transport including the membrane protein complex IP3R‐VDAC (B), protein degradation, proper protein folding and protein transport. Amino acids are the vital components of polypeptide and can be used to the Mt electron transport chain (C). Abbreviations: Glu, glutamic acid; Gln, glutamine; α‐KG, alpha‐ketoglutarate; TCA cycle, tricarboxylic acid cycle; MPC1, mitochondrial pyruvate carrier 1; MPC2, mitochondrial pyruvate carrier 2; SLC25A12, solute carrier family 25 member 12; SLC25A13, solute carrier family 25 member 13; SLC1A5, solute carrier family 1 member 5; ER, endoplasmic reticulum; Mt, mitochondria; AMFR, autocrine motility factor receptor; GRP78, the 78 kDa glucose‐regulated protein; WASF3, WASP family member 3; ATAD3A, ATPase family AAA domain containing 3A; BAP31, B cell receptor‐associated protein 31; FIS1, fission, mitochondrial 1; EMC, ER membrane protein complex; TOM5, translocase of outer mitochondrial membrane 5; BiP, binding immunoglobulin protein; Sec61, SEC61 translocon; Sec62, SEC62 homolog, preprotein translocation factor; Sec63, SEC63 homolog, protein translocation regulator; OMM, outer mitochondrial membranes; IMM, inner mitochondrial membranes; SERCA, sarco‐endoplasmic reticulum Ca²⁺‐ATPase; ERAD, endoplasmic reticulum‐associated degradation; XBP1, X‐box binding protein 1; IP3R, inositol 1,4,5‐triphosphate (IP3) receptor; VDAC, voltage‐dependent anion channel; mtCU, mitochondrial calcium uniporter; PERK, protein kinase R‐like ER kinase; IRE1, inositol‐requiring enzyme 1; ATF6, activating transcription factor 6

FIGURE 4

The ER is the endomembrane compartment organelle in the cytoplasm. It serves many major functions in protein synthesis, ER calcium homeostasis and lipid metabolism. IP3R and VDAC regulate Ca²⁺ uptake at mitochondria. Xestopongin C is an inhibitor of IP3R (A). Inhibitors of BiP are HA15, VER155008 and YUM70 (B). STX17 and ATAD3A play a significant role in mitophagy. Inhibitor of STX17 is EACC (C). SERCA, IP3R and RYR play significant roles on maintaining calcium homeostasis. Inhibitors of SERCA are thapsigargin, CDN1163, BHQ and Saikosaponin D (D). Ruthenium red is an inhibitor of RYR (E). The accumulation of unfolded proteins triggers ER stress in its lumen by activating the unfolded protein response (UPR). PERK, IRE1, ATF6 and BiP are involved in this process. Unfolded proteins are eliminated through ER‐associated degradation (ERAD). Melatonin (NSC 113928) inhibits ATF6 (F). IRE1 inhibitors are 4μ8C, APY29, MKC8866, Kira6, Sunitinib (SU11248) malate and 6‐Bromo‐2‐hydroxy‐3‐methoxybenzaldehyde (G). WASF3, providing a bridge between the ER and mitochondria, combine with ATAD3A and BiP. Inhibitors of PERK are GSK2606414 and GSK2656157 (H). The sterol regulatory element‐binding protein family of cholesterol sensors is contained in ER to ensure cholesterol homeostasis. Fatostatin inhibits SREBP and SCAP (J). Betulin also inhibits SCAP (I). Abbreviations: PERK, PKR‐like ER kinase; IRE1, inositol‐requiring enzyme 1; ATF6, activating transcription factor 6; BiP, binding immunoglobulin protein; SREBP, sterol regulatory element‐binding protein; SCAP, SREBP cleavage‐activating protein; SERCA, sarco‐endoplasmic reticulum Ca²⁺‐ATPases; IP3R, inositol‐1,4,5‐triphosphate [IP3] receptors; RYR, ryanodine receptors; CaM, calmodulin; CnA, calcineurin; CRTC2, CREB‐regulated transcription coactivator 2; NFAT, nuclear factor of activated T cells; JNK, c‐Jun N‐terminal kinase; CREB, cAMP‐response element binding protein; eIF2α, eukaryotic translation initiation factor 2α; ATF4, activating transcription factor 4; XBP1, X‐box binding protein 1; EDEM, ER degradation enhancing α‐mannosidase‐like protein; VDAC, voltage‐dependent anion channel 1; WASF, Wiskott–Aldridge syndrome family; STX17, syntaxin‐17; ATAD3A, ATPase family AAA domain containing 3A