Fusion of the outer mitochondrial membrane (OMM) is regulated by mitofusin 1 (MFN1) and 2 (MFN2), yet the differential contribution of each of these proteins is less understood. Mitochondrial carrier homolog 2 (MTCH2) also plays a role in mitochondrial fusion, but its exact function remains unresolved. MTCH2 overexpression enforces MFN2-independent mitochondrial fusion, proposedly by modulating the phospholipid lysophosphatidic acid (LPA), which is synthesized by glycerol-phosphate acyl transferases (GPATs) in the endoplasmic reticulum (ER) and the OMM. Here we report that MTCH2 requires MFN1 to enforce mitochondrial fusion and that fragmentation caused by loss of MTCH2 can be specifically counterbalanced by overexpression of MFN2 but not MFN1, partially independent of its GTPase activity and mitochondrial localization. Pharmacological inhibition of GPATs (GPATi) or silencing ER-resident GPATs suppresses MFN2’s ability to compensate for the loss of MTCH2. Loss of either MTCH2, MFN2, or GPATi does not impair stress-induced mitochondrial fusion, whereas the combined loss of MTCH2 and GPATi or the combined loss of MTCH2 and MFN2 does. Taken together, we unmask two cooperative mechanisms that sustain mitochondrial fusion.
Synopsis: MTCH2 and MFN2 govern two redundant and complementary pathways required to sustain normal mitochondrial architecture and plasticity.MTCH2 enforces mitochondrial fusion through MFN1.MFN2 specifically restores mitochondrial fusion in MTCH2 knockout cells, partially independent of its fusion activity.MFN2’s rescue ability is sensitive to loss of the pro-fusion lipid LPA.Loss of either MTCH2 in combination with GPAT inhibition (GPATi) or loss of both MTCH2 and MFN2 impairs mitochondrial plasticity.
MTCH2 and MFN2 govern two redundant and complementary pathways required to sustain normal mitochondrial architecture and plasticity.