Microcystin-LR induces neuronal damage through mitophagy defects resulted from the downregulated transcription of Scd2 by directly targeting IGF-1R

Abstract

Microcystin-LR (MC-LR), a prevalent cyanotoxin present in hazardous cyanobacterial blooms, is recognized as a neurotoxic environmental pollutant that induces brain damage and neurobehavioral deficits. However, the mechanisms underlying MC-LR-induced neurotoxicity remain unclear. This study aims to elucidate the role of mitophagy in MC-LR-induced neurotoxicity both in vitro and in vivo. We found that administration of 10 μg/kg body weight (intraperitoneally) MC-LR impaired learning and memory abilities and induced neuronal damage and apoptosis in the CA1 region of the hippocampus in rats. Exposure to MC-LR (1 μM to 10 μM) resulted in cellular damage and apoptosis in PC-12 and HT22 cells. MC-LR induced mitophagy through the PINK1/Parkin pathway but hindered mitophagy progression by repressing Scd2 transcription in neurons. These inhibitory effects were reversed by Scd2 overexpression. Furthermore, MC-LR was found to repress Scd2 transcription by directly binding to type 1 insulin-like growth factor receptor (IGF-1R) and competitively inhibiting its activation by Insulin-like growth factor 1 (IGF-1). Overexpression of IGF-1R and administration of exogenous IGF-1 mitigated the MC-LR-induced inhibition of Scd2 and the associated mitophagy defects. These findings indicate that IGF-1R is the direct target of MC-LR in neurons. MC-LR initiates mitophagy defects and apoptosis by inhibiting Scd2 transcription through binding to IGF-1R.