Mitochondrial Apolipoprotein MIC26 is a metabolic rheostat regulating central cellular fuel pathways

Mitochondria play central roles in metabolism and metabolic disorders such as type 2 diabetes. MIC26, a MICOS complex subunit, was linked to diabetes and modulation of lipid metabolism. Yet, the functional role of MIC26 in regulating metabolism under hyperglycemia is not understood. We employed a multi-omics approach combined with functional assays using WT andMIC26KO cells cultured in normoglycemia or hyperglycemia, mimicking altered nutrient availability. We show that MIC26 has an inhibitory role in glycolysis and cholesterol/lipid metabolism under normoglycemic conditions. Under hyperglycemia, this inhibitory role is reversed demonstrating that MIC26 is critical for metabolic adaptations. This is partially mediated by alterations of mitochondrial metabolite transporters. Furthermore,MIC26deletion led to a major metabolic rewiring of glutamine utilization as well as oxidative phosphorylation. We propose that MIC26 acts as a metabolic ‘rheostat’, that modulates mitochondrial metabolite exchange via regulating mitochondrial cristae, allowing cells to cope with nutrient overload.