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Structural determinants of fluorochemical-induced mitochondrial dysfunction.

A A Starkov1, K B Wallace

  • 1Department of Biochemistry and Molecular Biology, University of Minnesota School of Medicine, 10 University Drive, Duluth, Minnesota, USA.

Toxicological Sciences : an Official Journal of the Society of Toxicology
|March 16, 2002
PubMed
Summary

Perfluorooctanoic acid (PFOA) and related compounds can disrupt mitochondrial function. Specifically, certain perfluorooctane sulfonamides act as potent uncouplers of oxidative phosphorylation, impacting cellular energy production.

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Area of Science:

  • Environmental Toxicology
  • Mitochondrial Physiology
  • Biochemistry

Background:

  • Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) are implicated in peroxisome proliferation and mitochondrial metabolic disruption.
  • Previous studies suggest PFOA and perfluorooctane sulfonamide (FOSA) uncouple mitochondrial respiration by increasing proton conductance.

Purpose of the Study:

  • To characterize the structural determinants responsible for the mitochondrial uncoupling effects of various structurally related fluorochemicals.
  • To investigate the mechanisms by which these compounds interfere with mitochondrial respiration and membrane potential.

Main Methods:

  • Tested compounds included PFOA, PFOS, FOSA, FOSAA, N-EtFOSA, N-EtFOSE, and N-EtFOSAA.
  • Rat liver mitochondria were energized with substrate, and respiration and membrane potential were measured using an oxygen electrode and TPP+ -selective electrode, respectively.

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  • Compounds were added directly to the incubation medium containing mitochondria.

    • Main Results:

    • All tested compounds interfered with mitochondrial respiration at high concentrations via different mechanisms and potencies.
    • PFOA, PFOS, and N-EtFOSE caused a slight increase in proton leak, suggesting surfactant-like membrane alterations.
    • FOSA, N-EtFOSA, and FOSAA acted as potent protonophoric uncouplers, with FOSA showing an IC50 of approximately 1 microM.
    • N-EtFOSAA induced mitochondrial permeability transition, evidenced by swelling, respiration inhibition, and cytochrome c release.

    Conclusions:

    • The presence of a protonated nitrogen atom with a suitable pKa is crucial for the uncoupling activity of perfluorooctane sulfonamides.
    • These findings highlight the diverse mechanisms by which fluorochemicals can disrupt mitochondrial function, potentially linking to in vivo effects like peroxisome proliferation.