MTCH2 & Mitochondrial Dynamics

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. Also, mitochondrial carrier homolog 2 (MTCH2) plays a role in mitochondrial fusion, however its exact function remains unresolved.

MTCH2 overexpression enforces MFN2-indepdendent mitochondrial fusion, and it was proposed to enforce this process by modulating the phospholipid lysophosphatidic acid (LPA), which is synthetized in both the ER and 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 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 rescue MTCH2. Loss of either MTCH2, MFN2 or GPATi do not impair stress-induced mitochondrial fusion, whereas loss of MTCH2 in combination with GPATi or loss of MTCH2 and MFN2 do. Thus, we unmask two cooperative mechanisms that sustain mitochondrial fusion.

Goldman, A…Gross, A. EMBO Rep. 2024 Jan;25(1):45-67.