title: Arsenic-induced mitochondrial oxidative damage is mediated by decreased PGC-1α expression and its downstream targets in rat brain.
abstract: The present study was carried out to investigate the molecular mechanism of arsenic-induced mitochondrial oxidative damage and its relation to biogenesis in rat brain. Chronic sodium arsenite (25 ppm, orally) administration for 12 weeks decreased mitochondrial complexes activities and mRNA expression of selective complexes subunits. The expression of mitochondrial biogenesis regulator PGC-1α, and its downstream targets NRF-1, NRF-2 and Tfam were decreased significantly both at mRNA and protein levels suggesting impaired biogenesis following chronic arsenic-exposure. In addition to this, protein expression analysis also revealed activation of Bax and caspase-3, leading to translocation of cytochrome c from mitochondria to cytosol suggesting induction of apoptotic pathway under oxidative stress. This was further confirmed by electron microscopy study which depicted morphological changes in mitochondria in terms of altered nuclear and mitochondrial shape and chromatin condensation in arsenic-treated rats. The immunohistochemical studies showed both nuclear and cytosolic localization of NRF-1 and NRF-2 in arsenic-exposed rat brain further suggesting regulatory role of these transcription factors under arsenic neurotoxicity. The results of present study indicate that arsenic-induced mitochondrial oxidative damage is associated with decreased mitochondrial biogenesis in rat brain that may present as important target to reveal the mechanism for arsenic-induced neurotoxicity.
authors.affiliation: Department of Biochemistry, Maharshi Dayanand University, Rohtak 124001, Haryana, India.
authors.forename: Chandra
authors.initials: C
authors.lastname: Prakash
authors.affiliation: Department of Biochemistry, Maharshi Dayanand University, Rohtak 124001, Haryana, India. Electronic address: vksiwach.biochem@mdurohtak.ac.in.
authors.forename: Vijay
authors.initials: V
authors.lastname: Kumar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001151:Arsenic / Q000009:adverse effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects*; D004785:Environmental Pollutants / Q000009:adverse effects*; D051268:GA-Binding Protein Transcription Factor / Q000032:analysis / Q000235:genetics; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D051266:Nuclear Respiratory Factor 1 / Q000032:analysis / Q000235:genetics; D001678:Organelle Biogenesis; D018384:Oxidative Stress / Q000187:drug effects*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004272:DNA, Mitochondrial; D004785:Environmental Pollutants; D051268:GA-Binding Protein Transcription Factor; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; D001151:Arsenic
keywords: Apoptosis; Arsenic; Mitochondrial biogenesis; Neurodegeneration; Oxidative stress