Mitochondrial membrane synthesis, remodelling and cellular trafficking

Abstract

Mitochondria are dynamic cellular organelles with complex roles in metabolism and signalling. Primary mitochondrial disorders are a group of approximately 400 monogenic disorders arising from pathogenic genetic variants impacting mitochondrial structure, ultrastructure and/or function. Amongst these disorders, defects of complex lipid biosynthesis, especially of the unique mitochondrial membrane lipid cardiolipin, and membrane biology are an emerging group characterised by clinical heterogeneity, but with recurrent features including cardiomyopathy, encephalopathy, neurodegeneration, neuropathy and 3-methylglutaconic aciduria. This review discusses lipid synthesis in the mitochondrial membrane, the mitochondrial contact site and cristae organising system (MICOS), mitochondrial dynamics and trafficking, and the disorders associated with defects of each of these processes. We highlight overlapping functions of proteins involved in lipid biosynthesis and protein import into the mitochondria, pointing to an overarching coordination and synchronisation of mitochondrial functions. This review also focuses on membrane interactions between mitochondria and other organelles, namely the endoplasmic reticulum, peroxisomes, lysosomes and lipid droplets. We signpost disorders of these membrane interactions that may explain the observation of secondary mitochondrial dysfunction in heterogeneous pathological processes. Disruption of these organellar interactions ultimately impairs cellular homeostasis and organismal health, highlighting the central role of mitochondria in human health and disease.

Keywords: MAM; MERC; MICOS; cardiolipin; cell trafficking; mitochondrial lipid biosynthesis; organellar crosstalk; primary mitochondrial disease.

FIGURE 1

(A) Mitochondrial membrane structure with localisation of enzymes involved in cardiolipin biosynthesis, MICOS complex and mitochondrial cristae structure, and components involved in mitochondrial dynamics and trafficking and their interactions. AGK, acylglycerol kinase; CL, cardiolipin; CRLS, cardiolipin synthase; DRP1, dynamin‐related protein 1; FIS1, mitochondrial fission protein 1; IMM, Inner Mitochondrial Membrane; IMS, Inter Membrane Space; iPLA2γ, calcium‐independent phospholipase A2; MCU, mitochondrial calcium uniporter; MFF, mitochondrial fission factor; MFN1/2, mitofusin 1/2; MIB, mitochondrial intermembrane space bridging complex; MICOS, mitochondrial contact site and cristae organizing system; MiD49/51, mitochondrial dynamics protein of 49/51 kDa; OMM, Outer Mitochondrial Membrane; OPA1, Optic Atrophy Type 1; PISD, phosphatidylserine decarboxylase; PTPMT1, protein tyrosine phosphatase mitochondrion 1; SAMM50, sorting and assembly machinery 50 kDa; TIMM14 translocase of IMM 14; TIMM22, translocase of IMM 22; TIMM23 translocase of IMM 23; TOM, translocase of the outer mitochondrial membrane; TRAK, trafficking of kinesin‐binding; VDAC, voltage‐dependent anion‐selective channel. (B) Details of cardiolipin biosynthesis pathway. The black markers identify enzymatic defects leading to disease. AGK, acylglycerol kinase encoded by AGK; CDP‐DAG, cytidine diphosphate‐diacylglycerol encoded by TAMM41; CL, cardiolipin; CRLS, cardiolipin synthase encoded by CRLS1; DAG, diacylglycerol; MLCL, monolysocardiolipin; PA, phosphatidic acid; PGP, phosphatidylglycerolphosphate; PTPMT1, protein tyrosine phosphatase mitochondrion 1 encoded by PTPMT1; PG, phosphatidylglycerol; PC/PE, phosphatidylcholine/phosphatidylethanolamine; 1‐LPC/1‐LPE, 1‐lysophosphatidylcholine/1‐lysophosphatidylethanolamine.

FIGURE 2

Mitochondrial network and interaction with cellular organelles. BAP31, B‐cell receptor‐associated protein 31; FIS1, mitochondrial fission protein 1; IP3R, inositol triphosphate receptor; MFN2, mitofusin 2; PTPIP51, protein tyrosine phosphatase interacting protein 51; TOMM40, translocase of the OMM 40; TBC1D15, TBC1 Domain Family Member 15; VAPB, vesicle‐associated membrane protein‐associated protein B; VDAC, voltage‐dependent anion‐selective channel; VPS13D, vacuole protein sorting homologue 13D.