Rotenone-induced oxidative stress triggers peroxisomal alterations in BV-2 microglial cells.

Introduction: Peroxisomes are highly dynamic organelles that contribute to cellular homeostasis by coordinating lipid metabolism, reactive oxygen species handling, and adaptive responses to metabolic stress. Their plasticity is particularly relevant in the nervous system, where peroxisomes cooperate with mitochondria to maintain redox and metabolic balance in neuronal and glial cells. Peroxisome proliferator-activated receptor alpha (PPARα), together with its coactivator PGC-1α, represents a major transcriptional regulator of peroxisomal and mitochondrial metabolic programs. Methods: BV2 microglial cells were exposed to rotenone to investigate how mitochondrial oxidative stress influences the peroxisomal compartment. Mitochondrial and peroxisomal morphology, intracellular distribution, oxidative damage, and the expression of proteins involved in peroxisomal metabolism and PPARα signaling were evaluated. Results: Rotenone induced a stress-associated microglial phenotype characterized by cytoskeletal remodeling, mitochondrial network disruption, and oxidative damage. These alterations were accompanied by a coordinated reorganization of the peroxisomal compartment, including increased abundance of peroxisomal membrane markers, redistribution of peroxisomes toward the perinuclear region, and enhanced expression of enzymes associated with peroxisomal fatty acid oxidation. An increased spatial association between peroxisomes and mitochondria was also observed, suggesting that peroxisomal remodeling forms part of a broader inter-organelle adaptation to mitochondrial dysfunction. These changes occurred together with increased nuclear phosphorylated PPARα and enhanced PGC-1α immunoreactivity, supporting the engagement of a PPARα-PGC-1α-related transcriptional response. Discussion: Overall, our findings suggest that mitochondrial dysfunction in microglial cells activates a PPARα-associated adaptive program that promotes peroxisomal remodeling and strengthens mitochondria-peroxisome coordination. This response may represent an attempt to preserve lipid and redox homeostasis during cellular stress and identifies PPARα-regulated peroxisomal pathways as potentially relevant components of microglial metabolic adaptation in neurodegenerative conditions.