Article

A peptide containing residues 26–44 of tau protein impairs mitochondrial oxidative phosphorylation acting at the level of the adenine nucleotide translocator

Institute of Biomembranes and Bioenergetics, CNR, Bari, Italy.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 09/2008; 1777(10):1289-300. DOI: 10.1016/j.bbabio.2008.07.004
Source: PubMed

ABSTRACT

Having confirmed that adenovirus-mediated overexpression of NH(2)-tau fragment lacking the first 25 aminoacids evokes a potent neurotoxic effect, sustained by protracted stimulation of NMDA receptors, in primary neuronal cultures we investigated whether and how chemically synthesized NH(2)-derived tau peptides, i.e. NH(2)-26-44 and NH(2)-1-25 fragments, affect mitochondrial function. We tested both fragments on each step of the processes leading to ATP synthesis via oxidative phosphorylation: i) electron flow via the respiratory chain from physiological substrates to oxygen with the activity of each individual complex of the respiratory chain investigated in some detail, ii) membrane potential generation arising from externally added succinate and iii) the activity of both the adenine nucleotide translocator and iv) ATP synthase. Oxidative phosphorylation is not affected by NH(2)-1-25 tau fragment, but dramatically impaired by NH(2)-26-44 tau fragment. Both cytochrome c oxidase and the adenine nucleotide translocator are targets of NH(2)-26-44 tau fragment, but adenine nucleotide translocator is the unique mitochondrial target responsible for impairment of oxidative phosphorylation by the NH(2)-26-44 tau fragment, which then exerts deleterious effects on cellular availability of ATP synthesized into mitochondria.

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Available from: Giuseppe Pappalardo
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    • "Complex IV, i.e. COX, was measured by recording the decrease in absorbance during the cyanide-sensitive oxidation of 10 μM ferrocytochrome c (reduced with substoichiometric concentrations of potassium ascorbate) at 548–540 nm, in the presence of 3 μM rotenone and 0.8 μM antimycin A (Atlante et al., 2008). Absorbance change was recorded with a Jasco double beam/double-wavelength spectrophotometer UV-550 and the rate of ferrocytochrome c oxidation , obtained as tangent to the initial parts of the progress curves, was expressed as nmol min −1 mg −1 cell protein. "
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    • "The ADP/ATP carrier, that mediates the exchange transport of ADP and ATP in mitochondria, is essential for the synthesis of ATP by oxidative phosphorylation which supplies bioenergy for various biochemical reactions. Furthermore we have recently demonstrated that NH 2 htau and Aβ1-42 impair mitochondrial ANT-1 [17] [18]. "
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    • "Additional experiments showed that fibrillar A␤1– 42 only impaired the ADP— but not the carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-stimulated oxygen consumption (not shown), suggesting that decrease of oxygen uptake by mitochondria was only due to ADP-linked processes and that the common steps between the two processes were not responsible for the ATP production impairment. This finding, together with the lack of effect on ATP synthase activity by A␤1– 42 (not shown), strongly indicated that only ANT-1 was a target of A␤1– 42, as previously reported for NH 2 26 – 44-tau fragment (see Atlante et al., 2008). "
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