Carnitine: The carrier transporting fatty acyls into mitochondria by means of an electrochemical gradient of H+

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Abstract

The functions of carnitine as a carrier have been studied to verify the hypothesis of the electrophoretic transport of the fatty acyl carnitine cation into mitochondria.

It has been found that both l- and d-palmitoyl carnitines can exist in the form of cations which easily penetrate through phospholipid membranes. Palmitoyl carnitine greatly decreases the electrical resistance of phospholipid membranes, the effect being due to the transmembrane diffusion of the palmitoyl carnitine cation. The concentration gradient of the palmitoyl carnitine cation across the phospholipid membrane, created by transmembrane differences in total palmitoyl carnitine or in pH values, generates a membrane potential with “plus” on the side of the lower cation concentration. The magnitudes of this potential correspond closely to those calculated from the Nernst equation for a singly charged ion, i.e. 59 mV per 10-fold ion gradient.

Carnitine and acetyl carnitine do not affect the electric characteristics of the phospholipid membrane, which indicates that the cationic forms of these compounds are non-penetrating in the membrane studied. Palmitate induces some decrease in the phospholipid membrane resistance but at concentrations much higher than those of palmitoyl carnitine.

In rat liver mitochondria, it has been found that both l-and d-palmitoyl carnitines, like other penetrating cations, induce the energy-dependent swelling of the mitochondrial matrix, which is shown by the decreased light scattering of the mitochondrial suspension and by characteristic changes in the appearance of the mitochondria in the electron micrographs. The swelling can be supported by respiration or ATP hydrolysis. It is sensitive to the respiratory chain inhibitors in the former, to rutamycin in the latter, and to uncouplers, in both cases.

In polarographic experiments it has been observed that fast oxidation of added l-palmitoyl carnitine requires this compound to be in contact with energized mitochondria for at least several seconds. Energization can be supported by respiration or ATP hydrolysis, rutamycin being inhibitory in the later case. Uncouplers prevent l-palmitoyl carnitine oxidation when added before it, and stimulate oxidation when added after preincubation of mitochondria with l-palmitoyl carnitine.

The data obtained are in agreement with the concept according to which the transport of palmitoyl carnitine into mitochondria is a movement of the protonated cationic form of this compound down electrochemical gradient of H+ which is generated by the redox chain or ATPase.

References (39)

  • I.B. Fritz et al.

    J. Lipid Res.

    (1963)
  • E.A. Liberman et al.

    Biochim. Biophys. Acta

    (1970)
  • V.P. Skulachev

    Curr. Top. Bioenerg.

    (1971)
  • L.E. Bakeeva et al.

    Biochim. Biophys. Acta

    (1970)
  • P. Mueller et al.

    Curr. Top. Bioenerg.

    (1969)
  • L.L. Grinius et al.

    Biochim. Biophys. Acta

    (1970)
  • K.S. Cho et al.

    Biochim. Biophys. Acta

    (1969)
  • K.S. Cho et al.

    Biochim. Biophys. Acta

    (1971)
  • I.C. West

    Biochem. Biophys. Res. Commun.

    (1970)
  • D.W. Yates et al.

    Biochem. Biophys. Res. Commun.

    (1966)
  • E.A. Khairallah et al.

    J. Biol. Chem.

    (1967)
  • M.A. Mehlman et al.

    Life Sci.

    (1969)
  • L.L. Bieber et al.

    J. Biol. Chem.

    (1969)
  • M. Habibulla et al.

    J. Insect Physiol.

    (1969)
  • T. Unemoto et al.

    Biochim. Biophys. Acta

    (1966)
  • W. Gulewitsch et al.

    Hoppe Seyler's Z. Physiol. Chem.

    (1905)
  • I.B. Fritz
  • J. Bremer
  • R. Bressler

    Compr. Biochem.

    (1970)
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