Abstract

The mitochondrial permeability transition pore (mPTP) is a critical regulator of mitochondrial function and cellular fate, and its opening is a key event in cell death pathways. The mPTP is known to be inhibited by Cyclosporin A, indicating its cyclosporin-dependent nature. Acylcarnitines, which are essential intermediates in fatty acid transport and metabolism, can accumulate under conditions of metabolic stress and are known to exert toxic effects on mitochondria. This study was designed to investigate the direct effects of various acylcarnitines on the induction of the cyclosporin-dependent mPTP, with a specific focus on how their concentration and carbon chain length modulate this process. Using isolated rat liver mitochondria, we assessed mPTP opening by measuring mitochondrial swelling in the presence of different concentrations of D, L-acylcarnitines with varying chain lengths. Our results demonstrate that acylcarnitines are potent inducers of mPTP opening, and this effect is strongly dependent on both their concentration and the length of the acyl chain. Specifically, long-chain acylcarnitines exhibited a significantly higher potency in inducing the pore compared to their shorter-chain counterparts. These findings suggest that the accumulation of specific acylcarnitine species, particularly long-chain ones, represents a direct mechanism for mitochondrial dysfunction and cell injury in metabolic disorders. The data underscore the importance of acylcarnitine profile as a determinant of mitochondrial vulnerability and provide a molecular basis for therapeutic strategies targeting mPTP in conditions associated with fatty acid metabolism dysregulation.