SLC25A39: A Guardian against Cadmium-Induced PleiotropicDisruption of Mitochondrial Homeostasis in Rat Neuronal Cells

Abstract Cadmium (Cd) is a neurotoxic heavy metal, and mitochondrial homeostasis disruption is a key mechanism underlying its neurotoxicity. SLC25A39, a mitochondrial transporter, maintains the mitochondrial homeostasis. This study investigated the role of SLC25A39 in the Cd-induced disruption of mitochondrial homeostasis in rat neuronal cells. The results revealed that Cd exposure markedly upregulated the SLC25A39 protein levels in neuronal cells. SLC25A39 deficiency further aggravated Cd-induced mitochondrial oxidative-stress-related abnormalities, including mitochondrial glutathione (mtGSH) depletion, elevated lipid peroxidation, mitochondrial reactive oxygen species (mtROS) accumulation, and reduced mitochondrial SOD2 protein levels. Moreover, SLC25A39 deficiency aggravated Cd-induced mitochondrial dysfunction, suppressed biogenesis, disrupted the dynamic balance, and hyperactivated mitophagy. Notably, DRP1 inhibition suppressed the Cd-induced upregulation of Pink1 and Parkin in SLC25A39-deficient PC12 cells. Collectively, SLC25A39 confers resistance to Cd-induced pleiotropic mitochondrial injuries, including oxidative stress, dysfunction, impaired biogenesis, dynamic imbalance, and excessive mitophagy. In PC12 cells, SLC25A39 may limit excessive mitophagy by negatively regulating the DRP1 activity.