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Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression

Deep Raj Sharma1, Aditya Sunkaria, Willayat Yousuf Wani

  • 1Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.

Toxicology and Applied Pharmacology
|October 3, 2013
PubMed

Insights

Aluminium exposure causes oxidative stress and mitochondrial damage in rat brains, down-regulating key factors like PGC-1α, NRF-1, NRF-2, and Tfam. This highlights PGC-1α as a target for mitigating aluminium neurotoxicity and mitochondrial dysfunction.

Area of Science:

  • Neuroscience
  • Mitochondrial Biology
  • Toxicology

Background:

  • Aluminium exposure is linked to neurodegenerative diseases.
  • Oxidative stress and mitochondrial dysfunction are implicated in neurotoxicity.
  • The role of mitochondrial biogenesis regulators in aluminium neurotoxicity requires further elucidation.

Purpose of the Study:

  • To investigate the molecular mechanisms of aluminium-induced oxidative stress in rat brain mitochondria.
  • To examine the impact of aluminium on mitochondrial respiratory complexes and biogenesis pathways.
  • To elucidate the role of Peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α) and its downstream targets in aluminium neurotoxicity.

Main Methods:

  • Rats were administered aluminium lactate (10mg/kgb.wt./day) intragastrically for 12 weeks.
  • Assessed oxidative stress markers (ROS, DNA oxidation), mitochondrial DNA copy number, and citrate synthase activity.
  • Evaluated mRNA and protein expression of mitochondrial respiratory chain subunits and biogenesis factors (PGC-1α, NRF-1, NRF-2, Tfam).
  • Utilized electron microscopy to analyze mitochondrial morphology.

Main Results:

  • Aluminium exposure increased ROS levels, mitochondrial DNA oxidation, and decreased citrate synthase activity in the hippocampus and corpus striatum.
  • Reduced mRNA levels of mitochondrial-encoded (ND, Cytb, COX, ATPase) and nuclear-encoded (COX4, COX5A, COX5B) electron transport chain subunits were observed.
  • Down-regulation of PGC-1α, NRF-1, NRF-2, and Tfam was evident in aluminium-treated rats.
  • Electron microscopy showed increased mitochondrial swelling, loss of cristae, and decreased mitochondrial number.

Conclusions:

  • Aluminium induces significant oxidative stress and mitochondrial dysfunction in specific brain regions.
  • The down-regulation of the PGC-1α pathway is a key mechanism in aluminium neurotoxicity.
  • Targeting the PGC-1α pathway may offer a strategy to counteract aluminium-induced mitochondrial damage and neurodegeneration.
Keywords:
ATP synthaseATPaseAluminiumCOXCSCorpus striatumCyt bCytochrome bCytochrome oxidaseETCElectron transport chainHCHippocampusMitochondrial biogenesisMitochondrial transcription factor ANADH dehydrogenaseNDNRF-1NRF-2NeurodegenerationNuclear respiratory factor-1Nuclear respiratory factor-2PGC-1αPeroxisome proliferator activated receptor gamma co-activator 1aROSReactive oxygen speciesTfam

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