It was suggested that mitochondrial abnormalities might primarily contribute to the X-ALD pathology and possibly lead to the accumulation of very long chain fatty acids (VLCFA) the pathonomonic marker in X-ALD. Thus in cooperation with Reginald Bittner (Medical University Vienna, Austria) and Ronald Wanders (Academic Medical Center, Amsterdam, The Netherlands) we have performed polarographic analysis of the respiratory chain, enzyme assays, and electron microscopy in X-ALD mouse model and mitochondrial oxidative phosphorylation in permeabilized human skin fibroblasts of X-ALD patients and controls. We conclude that the accumulation of VLCFA per se does not cause mitochondrial abnormalities and vice versa- mitochondrial abnormalities are not responsible for the accumulation of VLCFA in X-ALD mice. These results do not exclude that other factors in the context of VLCFA accumulation contribute to mitochondrial dysfunction and oxidative damage in pathologically affected cell types.
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Representative oxygen concentration (thick line) and oxygen consumption rate (thin line) derived from a multiple-substrate-inhibitor analysis of isolated skeletal muscle mitochondria from Abcd1-deficient mice. Addition of the various substrates and inhibitors is indicated. After addition of the inhibitor antimycin A and ascorbat/TMPD in panel (A) and atractyloside in panel (B) the chamber was re-oxygenated to derive oxygen consumption rates at comparable O2 concentrations.
