BNIP3L‐Mediated Mitophagy Inhibits Cadmium‐Induced Apoptosis in the Rat Cerebral Cortex

Cadmium (Cd) is a common environmental contaminant that poses significant concern due to its neurotoxic effects. Mitophagy and apoptosis are two critical processes involved in Cd-induced central nervous system disorders, but the molecular mechanisms remain inadequately understood. Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L) is a crucial receptor protein that facilitates mitophagy. The study aimed to determine the precise mechanisms by which BNIP3L protects against Cd-induced neurotoxicity in the rat cerebral cortex. Following BNIP3L knockdown in the cerebral cortices, 24 male Sprague-Dawley rats were exposed to 50 mg/L Cd for 90 days. Histological alterations in the cerebral cortex were assessed using Nissl staining and transmission electron microscopy. Mitophagy- and apoptosis-related biomarkers were assessed using western blot analysis, immunofluorescence staining, and TUNEL staining. Our results revealed that BNIP3L knockdown increased COX IV expression, abolished the co-localization of LC3 and TOMM20, inhibited mitophagosome formation, and exacerbated Cd-induced cerebral cortex damage in rats. Moreover, BNIP3L knockdown exacerbated Cd-induced apoptosis and upregulated the Bax/Bcl-2 ratio, as well as the expression of cleaved caspase-9 and cleaved caspase-3. Collectively, our findings demonstrate that BNIP3L-mediated mitophagy provides neuroprotection in the rat cerebral cortex by inhibiting mitochondrial pathway-mediated apoptosis. Targeting mitophagy may have therapeutic promise for Cd-induced neurotoxicity.