A peptide containing residues 26-44 of tau protein impairs mitochondrial oxidative phosphorylation acting at the level of the adenine nucleotide translocator.
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.
Atlante
A
A
Institute of Biomembranes and Bioenergetics, CNR, Bari, Italy. a.atlante@ibbe.cnr.it
Amadoro
G
G
Bobba
A
A
de Bari
L
L
Corsetti
V
V
Pappalardo
G
G
Marra
E
E
Calissano
P
P
Passarella
S
S
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003576:Electron Transport Complex IV / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000235:genetics / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D010446:Peptide Fragments; D016875:tau Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000226:Mitochondrial ADP, ATP Translocases; D003576:Electron Transport Complex IV; D025261:Mitochondrial Proton-Translocating ATPases