PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity

Due to its role in regulation of mitochondrial function, PGC1 alpha is emerging as an important player in ageing and neurodegenerative disorders. PGC1 alpha exerts its neuroprotective effects by promoting mitochondrial biogenesis (MB) and functioning. However, the precise regulatory role of PGC1 alpha in the control of mitochondrial dynamics (MD) and neurotoxicity is still unknown. Here we elucidate the role of PGC1 alpha in vitro and in vivo in the regulatory context of MB and MD in response to lead (II) acetate as a relevant model of neurotoxicity. We show that there is an adaptive response (AR) to lead, orchestrated by the BAP31-calcium signalling system operating between the ER and mitochondria. We find that this hormetic response is controlled by a cell-tolerated increase of PGC1 alpha expression, which in turn induces a balanced expression of fusion/fission genes by binding to their promoters and implying its direct role in regulation of MD. However, dysregulation of PGC1 alpha expression through either stable downregulation or overexpression, renders cells more susceptible to lead insult leading to mitochondrial fragmentation and cell death. Our data provide novel evidence that PGC1 alpha expression is a key regulator of MD and the maintenance of tolerated PGC1 alpha expression may offer a promising strategy for neuroprotective therapies.