Tubulin hyperacetylation drives HMGB1 nuclear exit via the ROS-PARP1 axis leading to rotenone-induced G2/M Arrest

Rotenone, a lipophilic pesticide, is strongly linked to dopaminergic neuronal loss in Parkinsons disease (PD), primarily through mitochondrial complex I inhibition. While rotenone induces G2/M arrest in dividing cells, the underlying molecular events remain unclear. We identify HMGB1 as a key player in this process. HMGB1, known for its roles in genomic integrity and inflammation, exits the nucleus during rotenone-induced G2/M arrest, whereas its nuclear retention protects against mitotic DNA damage. We further reveal that tubulin hyperacetylation precedes HMGB1 nuclear release. Notably, reducing tubulin acetyltransferase lowers mitochondrial ROS (mtROS), preventing HMGB1 nuclear exit and mitotic DNA damage. Additionally, inhibiting PARP1 hyperactivation with PJ34 blocks HMGB1 exit and prevents G2/M arrest. These findings suggest that ROS-induced DNA damage elevates PARP1 activity, promoting HMGB1 nuclear exit and interfering with DNA repair. This tubulin acetylation/mtROS/HMGB1 axis may underlie rotenone-induced neurotoxicity, contributing to dopaminergic neuron vulnerability in PD and offering potential neuroprotective targets.