L'interazione tra la dinamica mitocondriale e il metabolismo cellulare

Mitochondrial morphology and cellular metabolism are intricately linked, with the balance between mitochondrial fusion and fission playing a crucial role in adapting mitochondrial function to meet metabolic demands. Opa1 is a mitochondrial shaping protein important for inner membrane fusion and cristae maintenance, forming high molecular weight complexes that stabilize mitochondrial ultrastructure. Here, we report that monomerization of the mitochondrial aspartate-glutamate carrier (Agc1) favors Opa1 oligomerization. Biochemical and bimolecular studies confirmed the interaction between Opa1 and Agc1 identified in cardiac mitochondria complexomic analyses. Functionally, during starvation Agc1 monomerized, mitochondrial NADH levels were reduced, Opa1 oligomerized and cristae were tightened. Agc1 genomic ablation was sufficient to reduce mitochondrial NADH and Opa1 oligomerization levels also in nutrient rich conditions, deranging mitochondrial cristae. In cells expressing dimerization-incompetent Agc1 mutants, Opa1 oligomerization was promoted, indicating that Opa1 oligomerization is favored when Agc1 is monomeric and mitochondrial NADH levels are low. Thus, the dimerization of Agc1 couples cytosolic NADH levels to mitochondrial cristae shape through Opa1 oligomerization regulation. While the impact of mitochondrial dynamics on cell function is well established, its connection to metabolism remains less clear. To explore the broader metabolic implications of disrupting mitochondrial dynamics, we used acute genetic deletions of the fusion gene Opa1 and the fission genes Drp1 and Fis1, combined with metabolomic analysis of mouse embryonic fibroblasts cultured in a plasma-like medium. We identified distinct and overlapping metabolic changes associated with altered mitochondrial dynamics. Across all models, we observed increased flux through the pentose phosphate pathway, along with elevated nucleotide and glutathione levels, while amino acid metabolism and nitrogen disposal were reduced. In Opa1-/- and Drp1-/- cells, fatty acid levels were decreased, and β-oxidation was increased, whereas in Fis1-/- cells, both fatty acid synthesis and degradation were upregulated. Notably, Opa1 deletion was specifically linked to a TCA cycle disruption, characterized by increased levels of phosphoenolpyruvate, citrate, and isocitrate, and decreased levels of lactate, succinate, and fumarate. Our findings suggest that enhanced carbon flux through the pentose phosphate pathway plays a crucial role in maintaining redox homeostasis in response to imbalances in mitochondrial dynamics.