MiP2005: Session 7

Mitochondrial Physiology Network 10.9: 86 (2005) - download pdf


Protection of oxidatively damaged mitochondria by novel chromanol-type antioxidants.

Katrin Staniek1, T Rosenau2, W Gregor1, H Nohl1, L Gille1

1Research Institute for Biochemical Pharmacology and Molecular Toxicology, University of Veterinary Medicine; 2Department of Chemistry, University of Natural Resources and Applied Life Sciences, Vienna, Austria. – katrin.staniek@vu-wien.ac.at

    Vitamin E is the most important lipophilic antioxidant protecting biomembranes from lipid peroxidation (LPO). Therefore, vitamin E and its derivatives are frequently used in the therapy or prevention of oxygen radical-induced diseases [1]. In the present study, novel chromanol-type antioxidants [2] such as the dimeric twin-chromanol, cis- and trans-oxachromanol as well as the well-known short-chain analogue of vitamin E, pentamethyl-chromanol, were tested for their antioxidative potency in rat heart mitochondria (RHM). As a prerequisite for a beneficial effect in mitochondria the tested substances should not disturb the highly sensitive function of the inner mitochondrial membrane. Bioenergetic parameters of isolated RHM, determined with the complex I substrates glutamate+malate, were not significantly changed in the presence of the highest concentration of chromanols under study (50 nmol/mg mitochondrial protein).

    Exposure of RHM to an LPO-inducing system (50 µM cumene hydroperoxide plus 50 µM Fe2+) significantly deteriorated their bioenergetic function. Alterations of bioenergetic parameters were partially abolished by preincubating RHM with antioxidants before adding the radical-generating system. In the lower concentration range twin-chromanol turned out to be more efficient than pentamethyl-chromanol, both being far more protective than cis- and trans-oxachromanol. Whether this protective effect was due to their antioxidative action was assessed from the measurements of protein-bound SH-groups, an indirect indicator of protein oxidation, and thiobarbituric acid-reactive substances, an indicator of LPO. For both parameters it was shown that oxidant-induced changes were partially prevented by a preincubation of RHM with chromanols.

    Accumulation of increased levels of LPO products is usually accompanied or preceded by decreased α-tocopherol concentrations in lipid membranes [3]. HPLC measurements of α-tocopherol and its first stable oxidation product, tocopheryl quinone, in mitochondrial membranes have shown that α-tocopherol was rapidly consumed after the initiation of LPO. Pentamethyl-chromanol and twin-chromanol were similarly effective in preventing the decay of α-tocopherol and the increase of tocopheryl quinone levels in mitochondrial membranes. For both chromanols a concentration of 5 nmol/mg protein was required to protect endogenous α-tocopherol against oxidation, while a concentration of 1 nmol/mg protein was insufficient.

    In conclusion, the new chromanol-type antioxidants, especially twin-chromanol, were able to improve bioenergetic and biochemical parameters of mitochondria exposed to oxidative stress.

     Supported by the Austrian Science Foundation (FWF, Grant P16244-B08).

1.  Chow CK (1991) Vitamin E and oxidative stress. Free Radic. Biol. Med. 11: 215-232.

2.  Gregor W, Grabner G, Adelwöhrer C, Rosenau T, Gille L (2005) Antioxidant properties of natural and synthetic chromanol derivatives: Study by fast kinetics and electron spin resonance spectroscopy. J. Org. Chem. 70: 3472-3483.

3.  Scheschonka A, Murphy ME, Sies H (1990) Temporal relationships between the loss of vitamin E, protein sulfhydryls and lipid peroxidation in microsomes challenged with different prooxidants. Chem. Biol. Interact. 74: 233-252.

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