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Mn2+ sequestration by mitochondria and inhibition of oxidative phosphorylation

C E Gavin1, K K Gunter, T E Gunter

  • 1Department of Obstetrics and Gynecology, University of Rochester Medical Center, New York 14642.

Toxicology and Applied Pharmacology
|July 1, 1992
PubMed

Insights

Manganese (Mn2+) accumulates in mitochondria, potentially interfering with cellular energy production (oxidative phosphorylation). This accumulation in brain mitochondria may explain the neurological damage seen in manganism.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Neuroscience

Background:

  • Manganese is known to accumulate in mitochondria and mitochondria-rich tissues.
  • Calcium ions (Ca2+) enhance mitochondrial manganese uptake, but ATP-bound Mn2+ is not sequestered by mitochondria.
  • The polyamine spermine influences Mn2+ uptake at physiological calcium concentrations.

Purpose of the Study:

  • To investigate the interaction of manganese (Mn2+) with mitochondrial function.
  • To determine the effects of Mn2+ on cellular respiration and oxidative phosphorylation.
  • To explore the potential role of mitochondrial manganese accumulation in the pathology of manganism.

Main Methods:

  • Studied Mn2+ uptake in isolated rat brain and liver mitochondria.
  • Measured oxygen consumption rates using various substrates (succinate, glutamate/malate) and conditions (ADP, uncoupler).
  • Assessed the effect of Mn2+ on mitochondrial respiration and membrane integrity.

Main Results:

  • Physiological spermine levels enhanced Mn2+ uptake in mitochondria.
  • Mn2+ inhibited ADP-stimulated respiration with both succinate and glutamate/malate substrates.
  • Mn2+ also slightly inhibited uncoupler-stimulated respiration, suggesting interference with oxidative phosphorylation, likely via F1 ATPase binding.

Conclusions:

  • Manganese (Mn2+) directly interferes with oxidative phosphorylation in mitochondria.
  • Mitochondrial Mn2+ accumulation may contribute to the neurological damage observed in manganism.
  • The findings suggest Mn2+ binding to F1 ATPase is a key mechanism of toxicity.

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