title: PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity.
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.
authors.affiliation: Imperial College London, Centre for Pharmacology and Therapeutics, Department of Medicine, London, United Kingdom.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Dabrowska
authors.affiliation: Departamento de Bioquímica y Biología Molecular. Facultad de Farmacia, Universidad de Sevilla, C/Prof. García González, Sevilla, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Venero
authors.affiliation: Imperial College London, Centre for Pharmacology and Therapeutics, Department of Medicine, London, United Kingdom.
authors.forename: Ryota
authors.initials: R
authors.lastname: Iwasawa
authors.affiliation: Integrated Research and Treatment Centre for Adiposity Diseases, Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Mohammed-Khair
authors.initials: MK
authors.lastname: Hankir
authors.affiliation: Imperial College London, Centre for Pharmacology and Therapeutics, Department of Medicine, London, United Kingdom.
authors.forename: Sunniyat
authors.initials: S
authors.lastname: Rahman
authors.affiliation: Imperial College London, Centre for Pharmacology and Therapeutics, Department of Medicine, London, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Boobis
authors.affiliation: Imperial College London, Centre for Pharmacology and Therapeutics, Department of Medicine, London, United Kingdom.
authors.forename: Nabil
authors.initials: N
authors.lastname: Hajji
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects; D020263:Lead Poisoning, Nervous System / Q000235:genetics* / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics; D063154:Mitochondrial Dynamics / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology; D001678:Organelle Biogenesis; D009942:Organometallic Compounds / Q000633:toxicity; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C547159:Bcap31 protein, rat; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; C008261:lead acetate
keywords: BAP3; Drp1; Lead; PGC-1α; calcium; mitochondrial biogenesis and dynamics; neurotoxicity