Abstract
Due to its role in regulation of mitochondrial function, PGC1α is emerging as an important player in ageing and neurodegenerative disorders. PGC1α exerts its neuroprotective effects by promoting mitochondrial biogenesis (MB) and functioning. However, the precise regulatory role of PGC1α in the control of mitochondrial dynamics (MD) and neurotoxicity is still unknown. Here we elucidate the role of PGC1αin 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 PGC1α 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 PGC1α 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 PGC1α expression is a key regulator of MD and the maintenance of tolerated PGC1α expression may offer a promising strategy for neuroprotective therapies.
Highlights
Peroxisome proliferator-activated receptor-γ coactivator1α (PGC-1α) is a transcription factor controlling many aspects of oxidative metabolism, including mitochondrial biogenesis, adaptation, respiration, adaptive thermogenesis, gluconeogenesis and oxidative phosphorylation [1, 2]
Since the protein level of BAP31 increased after exposure to 100μM and 500μM lead (Fig. 5H), we investigated whether BAP31 downregulation had any neuroprotective effect against lead insult. shRNA delivered by a lentiviral vector was used to knock down Bap31 expression in N27 cells (Fig. 5I).shRNA-Bap31 conferred significant protection against lead toxicity (Fig. 5J-M) implying an important role of BAP31 in the response to lead and in calcium pathway regulation
We show for the first time that low levels of lead cause disruption of cellular calcium balance in dopaminergic neurons, involving BAP31-mediated ER-mitochondrial crosstalk, which induces an adaptive response mediated by PGC1α
Summary
Peroxisome proliferator-activated receptor-γ coactivator1α (PGC-1α) is a transcription factor controlling many aspects of oxidative metabolism, including mitochondrial biogenesis, adaptation, respiration, adaptive thermogenesis, gluconeogenesis and oxidative phosphorylation [1, 2]. Signalling for mitochondrial biogenesis (MB) is activated by PGC-1α and involves the expressionof several transcription factors, resulting in the upregulation of proteins encoded by both nuclear and mitochondrial genomes. Many neurodegenerative conditions have been shown to originate from compromised number, morphology and function of mitochondria. PGC1α has previously been reported to play a protective role against neurodegenerative conditions such as Alzheimer’s disease and is known to respond to ROS by the induction of many ROS-detoxifying enzymes, including superoxide dismutase, Gpx1and γ-glutamylcysteine, regulating the biosynthesis of glutathione. Ca2+ and ROS have been shown to regulate mitochondrial biogenesis by activating PGC1α, leading to an increase in mitochondrial mass [3, 4]
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