Quercetin protects against aluminium induced oxidative stress and promotes mitochondrial biogenesis via activation of the PGC-1α signaling pathway

• Published in: Neurotoxicology (Park Forest South) Vol. 51; pp. 116 - 137
• Main Authors: Sharma, Deep Raj, Sunkaria, Aditya, Wani, Willayat Yousuf, Sharma, Reeta Kumari, Verma, Deepika, Priyanka, Kumari, Bal, Amanjit, Gill, Kiran Dip
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2015
• Subjects: Aluminium; Aluminum - toxicity; Animals; Brain - drug effects; Brain - enzymology; Brain - metabolism; Corpus Striatum - drug effects; Corpus Striatum - enzymology; Corpus Striatum - metabolism; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; DNA, Mitochondrial - drug effects; DNA, Mitochondrial - metabolism; Electron Transport - drug effects; Electron transport chain; Hippocampus - drug effects; Hippocampus - enzymology; Hippocampus - metabolism; Male; Mitochondria - drug effects; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial biogenesis; Mitochondrial Proteins - drug effects; Mitochondrial Proteins - metabolism; Neurodegeneration; Oxidative Stress - drug effects; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Quercetin; Quercetin - administration & dosage; Rats; Rats, Wistar; Reactive oxygen species; Reactive Oxygen Species - metabolism; RNA, Messenger - metabolism; Signal Transduction - drug effects; Transcription Factors - metabolism; MtDNA; Reactive oxygen species; PGC-1α; Aluminium; CS; Electron transport chain; Mitochondrial biogenesis; ETC; Neurodegeneration; NRF-2; ROS; NRF-1; Quercetin; Tfam; HC
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2015.10.002

•Quercetin increases the mRNA levels of mitochondrial and nuclear encoded subunits.•It increases the mtDNA copy number and mitochondrial content in rat brain.•It also up regulates mRNA and protein levels of PGC-1α, NRF-1, NRF-2 and Tfam.•Finally, it also increases mitochondrial number in HC and CS regions of rat brain. The present investigation was carried out to elucidate a possible molecular mechanism related to the protective effect of quercetin administration against aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of PGC-1α and its downstream targets, i.e. NRF-1, NRF-2 and Tfam in mitochondrial biogenesis. Aluminium lactate (10mg/kg b.wt./day) was administered intragastrically to rats, which were pre-treated with quercetin 6h before aluminium (10mg/kg b.wt./day, intragastrically) for 12 weeks. We found a decrease in ROS levels, mitochondrial DNA oxidation and citrate synthase activity in the hippocampus (HC) and corpus striatum (CS) regions of rat brain treated with quercetin. Besides this an increase in the mRNA levels of the mitochondrial encoded subunits – ND1, ND2, ND3, Cyt b, COX1, COX3 and ATPase6 along with increased expression of nuclear encoded subunits COX4, COX5A and COX5B of electron transport chain (ETC). In quercetin treated group an increase in the mitochondrial DNA copy number and mitochondrial content in both the regions of rat brain was observed. The PGC-1α was up regulated in quercetin treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1α. Electron microscopy results revealed a significant decrease in the mitochondrial cross-section area, mitochondrial perimeter length and increase in mitochondrial number in case of quercetin treated rats as compared to aluminium treated ones. Therefore it seems quercetin increases mitochondrial biogenesis and makes it an almost ideal flavanoid to control or limit the damage that has been associated with the defective mitochondrial function seen in many neurodegenerative diseases.