Phytochemicals differentially modulate mitochondrial bioenergetics: roles of F₁F_O-ATPase, respiratory complexes, and...

Phytochemicals can modulate mitochondrial function, but their specific actions on bioenergetic pathways are not fully defined. Here, isolated mitochondria were exposed to three phytocompounds, S-allyl cysteine (SAC), benzyl isothiocyanate (BITC), and epicatechin (EPC), and key mitochondrial parameters were assessed, including F₁F_O-ATPase activity, NADH- and succinate-driven respiration, and mitochondrial permeability transition pore (mPTP) opening. Mechanistic insights were obtained through kinetic analyses and by probing redox sensitivity using dithiothreitol-treated mitochondria. SAC increased F₁F_O-ATPase activity, displaying cooperative behaviour and multiple inhibitory/activating components consistent with uncompetitive and competitive interactions, while leaving respiration unchanged; it also reduced mPTP sensitivity, indicating desensitization of pore dynamics. In contrast, BITC produced mixed-type inhibition of F₁F_O-ATPase and significantly impaired respiration, with a stronger impact on Complex I-linked (NADH-driven) flux; BITC additionally delayed mPTP opening through a redox-dependent mechanism. EPC did not significantly alter F₁F_O-ATPase activity, respiration, or mPTP opening under the experimental conditions. Overall, these findings demonstrate compound-specific modulation of mitochondrial bioenergetics by phytochemicals, supporting their potential relevance for therapeutic strategies targeting oxidative stress and mitochondrial dysfunction.