Regev, L. | Search bioRxiv

bioRxiv2023

High-energy demand and nutrient exhaustion in MTCH2 knockout cells

Mitochondrial carrier homolog 2 (MTCH2) is a regulator of apoptosis, mitochondrial dynamics, and metabolism. Loss of MTCH2 results in mitochondrial fragmentation, an increase in whole-body energy utilization, and protection from diet-induced obesity. We now show using temporal metabolomics that MTCH2 deletion results in a high ATP demand, an oxidized environment, a high lipid/amino acid/carbohydrate metabolism, and in the decrease of many metabolites. Lipidomics analyses show a strategic adaptive decrease in membrane lipids and an increase in storage lipids in MTCH2 knockout cells. Importantly, all the metabolic changes in the MTCH2 knockout cells were rescued by MTCH2 re-expression. Interestingly, this imbalance in energy metabolism and reductive potential triggered by MTCH2-deletion inhibits adipocyte differentiation, an energy consuming reductive biosynthetic process. In summary, loss of MTCH2 results in an increase in energy demand that triggers a catabolic and oxidizing environment, which fails to fuel the anabolic processes during adipocyte differentiation.

cell biology↗

bioRxiv2022

MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion

Mitochondrial dynamics is critical to sustain normal mitochondrial function and is linked to the response of cells to stressful conditions. 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 to this process is less understood. Mitochondrial carrier homolog 2 (MTCH2) was shown to compensate for MFN2s loss, however its exact function in mitochondrial fusion remains poorly understood. Here we determined the mitochondrial fusion-interplay between MFN1, MFN2 and MTCH2 and demonstrate that MFN2 and MTCH2 play separate, but redundant, roles required for mitochondrial fusion. Loss of either MFN2 or MTCH2 elicits mitochondrial fragmentation that retains mitochondrial plasticity, while loss of both proteins completely impairs mitochondrial fusion. We also show that expression of an MFN2 mutant targeted to the endoplasmic reticulum (ER) is sufficient to restore mitochondrial elongation in MTCH2 KO cells and that this restoration depends on the synthesis of the pro-mitochondrial fusion lipid lysophosphatidic acid (LPA). Moreover, silencing of MFN2 or inhibition of de novo LPA synthesis, revealed the requirement of MTCH2 to sustain mitochondrial plasticity in response to stress. Thus, we unmask two cooperative mechanisms that sustain mitochondrial fusion: one in the OMM, dependent on MTCH2 and MFN1, and independent of MFN2; and a second mechanism in the ER that relies on MFN2 and LPA synthesis.

cell biology↗