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

Dabrowska, A; Venero, JL; Iwasawa, R; Hankir, MK; Rahman, S; Boobis, A; Hajji, N; (2015) PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity. Aging (Albany NY) , 7 (9) pp. 629-647. 10.18632/aging.100790. Green open access

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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.

Type: Article
Title: PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.18632/aging.100790
Publisher version: http://dx.doi.org/10.18632/aging.100790
Language: English
Additional information: Copyright © Dabrowska et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Keywords: BAP3, Drp1, Lead, PGC-1α, calcium, mitochondrial biogenesis and dynamics, neurotoxicity, Aging, Animals, Apoptosis, Cell Death, Cell Line, Dopaminergic Neurons, Endoplasmic Reticulum, Lead Poisoning, Nervous System, Membrane Proteins, Mitochondrial Dynamics, Neuroprotective Agents, Organelle Biogenesis, Organometallic Compounds, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Rats, Signal Transduction, Transcription Factors
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/1502781
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