Abstract

Mitochondrial dysfunction, particularly the imbalance between oxidative phosphorylation and reactive oxygen species (ROS) production, is central to numerous liver pathologies. This study investigates the bioenergetic effects of two fatty acid derivatives, $\omega$-hydroxypalmitic acid ($\omega$-HPA) and $\alpha,\omega$-hexadecanedioic acid ($\alpha,\omega$-HDA), on isolated rat liver mitochondria. The primary objective was to characterize their influence on respiratory control and $\text{H}_2\text{O}_2$ generation. Using high-resolution respirometry, we demonstrate that both $\omega$-HPA and $\alpha,\omega$-HDA act as potent activators of free, or uncoupled, respiration in a concentration-dependent manner. This effect is consistent with their role as protonophores, facilitating proton leak across the inner mitochondrial membrane and dissipating the membrane potential ($\Delta\Psi_m$). Crucially, this uncoupling activity was directly correlated with a significant inhibition of $\text{H}_2\text{O}_2$ production, measured by Amplex Red fluorescence, particularly under conditions favoring reverse electron transport. These findings suggest that $\omega$-HPA and $\alpha,\omega$-HDA modulate mitochondrial efficiency by promoting mild uncoupling, a mechanism that can mitigate oxidative stress by lowering the $\Delta\Psi_m$ and reducing the probability of electron leakage. The results highlight the potential therapeutic utility of these dicarboxylic fatty acids as endogenous regulators of mitochondrial function and cellular redox state in the context of liver disease.