Mitochondrial epigenetic remodeling and integrated stress response induced by microcystin-LR: Experimental evidence...

MC-LR, a potent cyanotoxin produced by specific kinds of cyanobacteria, is widely acknowledged for its cytotoxic effects; however, its role in mitochondrial-mediated epigenetic regulation remains poorly characterized. This study examined the mitochondrial integrated stress response and associated epigenetic changes following exposure to varying concentrations of MC-LR. Elevated mitochondrial reactive oxygen species (mtROS) indicated disrupted mitochondrial function and dynamics, potentially contributing to reduced cell viability. Gene expression profiling revealed dose-dependent upregulation of key regulators of mitochondrial fission and fusion (Drp1, Fis1, MFN1, MFN2), integrated stress response mediators (OMA1, DELE1, HRI), and epigenetic modifiers (DNMTs, TFAM, TET). Significant shifts were also observed in DNA and RNA methylation levels, along with increased pro-inflammatory cytokine expression. Correlation and regression analyses revealed a clear dose-dependent activation of several gene pathways, with DNA repair enzymes and DNMTs exhibiting the highest EC₅₀ values. To assess preliminary insight into potential structural interactions, we conducted exploratory molecular docking using the Schrödinger Suite, focusing on the interaction of MC-LR fragments with the catalytic subunit of protein phosphatase 2A (PP2A; PDB: 3DW8). The results suggested favorable binding energies for specific fragments, indicating PP2A as a possible target of MC-LR, which may contribute to its mitochondrial effects. Overall, these findings provide new insights into the mitochondrial-associated epigenetic consequences of MC-LR exposure and suggest possible structural interactions with PP2A. This work enhances the understanding of the mito-epigenetic disruptions caused by MC-LR. It points to structural mechanisms that need further experimental investigation, which may also help inform future environmental toxicity evaluations.