| Summary: | Health risks associated with acrylamide (ACR) or high-fat diet (HFD) exposure alone have been widely concerned in recent years. In a realistic situation, ACR and HFD are generally co-existence, and both are risk factors for the development of neurological diseases. The purpose of the present study was to investigate the combined effects of ACR and HFD on the motor nerve function. As a result, neurobehavioral tests and Nissl staining disclosed that long-term HFD exacerbated motor dysfunction and the damage of spinal cord motor neurons in ACR-exposed mice. Co-exposure of ACR and HFD resulted in morphological changes in neuronal mitochondria of the spinal cord, a significantly reduced mitochondrial subunits NDUFS1, UQCRC2, and MTCO1, released the mitochondrial DNA (mtDNA) into the cytoplasm, and promoted the production of reactive oxygen species (ROS). Combined exposure of HFD and ACR activated the calpain/CDK5/Drp1 axis and caused the mitochondrial excessive division, ultimately increasing MLKL-mediated necroptosis in spinal cord motor neurons. Meanwhile, HFD significantly exacerbated ACR-induced activation of NFkB, NLRP3 inflammasome, and cGAS-STING pathway. Taken together, our findings demonstrated that combined exposure of ACR and HFD aggravated the damage of spinal cord motor neurons via neuroinflammation and necroptosis signaling pathway, pointing to additive effects in mice than the individual stress effects.
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