Abstract

The Mitochondrial Permeability Transition Pore (mPTP) is a critical regulator of cell fate, and its aberrant opening is implicated in various pathologies, including ischemia-reperfusion injury. This study investigates the modulatory effects of L-Arginine (L-Arg) and Nitric Oxide (NO) donors on the induction of mPTP opening, which was triggered by the combined action of calcium ions ($\text{Ca}^{2+}$) and the fatty acid metabolite, palmitoylcarnitine. Using isolated mitochondrial preparations, we assessed mPTP activity by monitoring mitochondrial swelling and $\text{Ca}^{2+}$ retention capacity. Our findings demonstrate that both L-Arg and NO donors significantly inhibit the $\text{Ca}^{2+}$ and palmitoylcarnitine-induced mPTP opening, suggesting a protective role. Furthermore, the observed inhibitory effect was sensitive to inhibitors of the cGMP-dependent protein kinase (PKG), strongly supporting the hypothesis that the mitochondrial NO/cGMP/PKG signaling system is involved in the regulation of mPTP. These results highlight a novel mechanism by which the NO signaling cascade, potentially acting locally within the mitochondria, confers protection against mPTP-mediated mitochondrial dysfunction, offering potential therapeutic targets for conditions involving mitochondrial stress.