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


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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    ABSTRACT: Functional as well as structural alterations in mitochondria size, shape and distribution are precipitating, early events in progression of Alzheimer's Disease (AD). We reported that a 20–22 kDa NH2-tau fragment (aka NH2htau), mapping between 26 and 230 amino acids of the longest human tau isoform, is detected in cellular and animal AD models and is neurotoxic in hippocampal neurons. The NH2htau –but not the physiological full-length protein– interacts with Aβ at human AD synapses and cooperates with it in inhibiting the mitochondrial ANT-1-dependent ADP/ATP exchange. Here we show that the NH2htau also adversely affects the interplay between the mitochondria dynamics and their selective autophagic clearance. Fragmentation and perinuclear mislocalization of mitochondria with smaller size and density are early found in dying NH2htau-expressing neurons. The specific effect of NH2htau on quality control of mitochondria is accompanied by (i) net reduction in their mass in correlation with a general Parkin-mediated remodeling of membrane proteome; (ii) their extensive association with LC3 and LAMP1 autophagic markers; (iii) bioenergetic deficits and (iv) in vitro synaptic pathology. These results suggest that NH2htau can compromise the mitochondrial biology thereby contributing to AD synaptic deficits not only by ANT-1 inactivation but also, indirectly, by impairing the quality control mechanism of these organelles.
    Full-text · Article · Feb 2014 · Neurobiology of Disease
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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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    ABSTRACT: To find out whether and how the adenine nucleotide translocator-1 (ANT-1) inhibition due to NH2htau and Aβ1-42 is due to an interplay between these two Alzheimer's peptides, ROS and ANT-1 thiols, use was made of mersalyl, a reversible alkylating agent of thiol groups that are oriented toward the external hydrophilic phase, to selectively block and protect, in a reversible manner, the -SH groups of ANT-1. The rate of ATP appearance outside mitochondria was measured as the increase in NADPH absorbance which occurs, following external addition of ADP, when ATP is produced by oxidative phosphorylation and exported from mitochondria in the presence of glucose, hexokinase and glucose-6-phosphate dehydrogenase. We found that the mitochondrial superoxide anions, whose production is induced at the level of Complex I by externally added Aβ1-42 and whose release from mitochondria is significantly reduced by the addition of the VDAC inhibitor DIDS, modify the thiol group/s present at the active site of mitochondrial ANT-1, impair ANT-1 in a mersalyl-prevented manner and abrogate the toxic effect of NH2htau on ANT-1 when Aβ1-42 is already present. A molecular mechanism is proposed in which the pathological Aβ-NH2htau interplay on ANT-1 in Alzheimer's neurons involves the thiol redox state of ANT-1 and the Aβ1-42-induced ROS increase. This result represents an important innovation because it suggests the possibility of using various strategies to protect cells at the mitochondrial level, by stabilizing or restoring mitochondrial function or by interfering with the energy metabolism providing a promising tool for treating or preventing AD.
    Preview · Article · Apr 2013 · Biochimica et Biophysica Acta
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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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    ABSTRACT: Although amyloid beta (Aβ) peptide can promote tau pathology and its toxicity is concurrently tau-dependent, the underlying mechanisms of the in vivo interplay of these proteins remain unsolved. Structural and functional mitochondrial alterations play an early, precipitating role in synaptic failure of Alzheimer's disease (AD) pathogenesis and an aggravated mitochondrial impairment has been described in triple APP/PS/tau transgenic mice carrying both plaques and tangles, if compared with mice overexpressing tau or amyloid precursor protein (APP) alone. Here, we show that a neurotoxic aminoterminal (NH(2))-derived tau fragment mapping between 26 and 230 amino acids of the human tau40 isoform (441 amino acids)-but not the physiological full-length protein-preferentially interacts with Aβ peptide(s) in human AD synapses in association with mitochondrial adenine nucleotide translocator-1 (ANT-1) and cyclophilin D. The two peptides-Aβ 1-42 and the smaller and more potent NH(2)-26-44 peptide of the longest 20-22 kDa NH(2)-tau fragment-inhibit the ANT-1-dependent adenosine diphosphate-adenosine triphosphate (ADP/ATP) exchange in a noncompetitive and competitive manner, respectively, and together further aggravate the mitochondrial dysfunction by exacerbating the ANT-1 impairment. Taken together, these data establish a common, direct and synergistic toxicity of pathological APP and tau products on synaptic mitochondria and suggest potential, new pathway(s) and target(s) for a combined, more efficient therapeutic intervention of early synaptic dysfunction in AD.
    Full-text · Article · Sep 2011 · Neurobiology of aging
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