Effect of mitochEffect of mitochondrial complex III chronic inhibition on mitochondrial proteomic landscapeondrial complex III chronic inhibition on mitochondrial proteomic landscape

The mitochondria play a vital role in controlling cell metabolism and regulating crucial cellular outcomes. We previously demonstrated that chronic inhibition of the mitochondrial complex III in rats by Antimycin A (AA) induced pulmonary vasoconstriction. On the metabolic level, AA-induced mitochondrial dysfunction resulted in a glycolytic shift that was reported as the primary contributor to pulmonary hypertension pathogenesis. However, the regulatory proteins driving this metabolic shift with complex III inhibition are yet to be explored. Therefore, to delineate the mechanisms, we followed the rat lung mitochondrial proteomics. Rats treated with the complex III inhibitor, Antimycin-A for up to 24 days, showed a disturbed mitochondrial proteome with significant changes in 28 proteins (p<0.05). We observe a time-dependent decrease in the expression of key proteins that regulate fatty acid oxidation, the tricarboxylic acid cycle, electron transport chain, and amino acid metabolism, indicating diminished mitochondrial function. We also found a significant dysregulation in proteins that control protein import, and the clearance and detoxification of oxidatively damaged peptides via proteolysis and mitophagy. This could lead to the onset of mitochondrial toxicity due to the misfolded protein's stress. We conclude that chronic inhibition of the mitochondrial complex III attenuates mitochondrial function by disruption of global mitochondrial metabolism. This potentially aggravates cellular proliferation by initiating a glycolytic switch and thereby leading to pulmonary hypertension.