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Aging (Albany NY). 2015 Sep;7(9):629-47.

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

Author information

1
Imperial College London, Centre for Pharmacology and Therapeutics, Department of Medicine, London, United Kingdom.
2
Departamento de Bioquímica y Biología Molecular. Facultad de Farmacia, Universidad de Sevilla, C/Prof. García González, Sevilla, Spain.
3
Integrated Research and Treatment Centre for Adiposity Diseases, Department of Medicine, University of Leipzig, Leipzig, Germany.

Erratum in

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.

KEYWORDS:

BAP3; Drp1; Lead; PGC-1α; calcium; mitochondrial biogenesis and dynamics; neurotoxicity

PMID:
26363853
PMCID:
PMC4600622
DOI:
10.18632/aging.100790
[Indexed for MEDLINE]
Free PMC Article

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