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The specificity and Kd at physiological ionic strength of an ATP-binding site on cytochrome c suit it to a regulatory role.

ABSTRACT: Cytochrome c binds ATP with marked specificity at a site that contains the evolutionarily invariant residue Arg-91. The binding of ATP to this site was studied using equilibrium gel filtration, equilibrium dialysis and affinity chromatography. At physiological ionic strength the affinity is such that the major change in occupancy coincides with the normal cellular ATP concentration range, and the degree of saturation is proportional to the ratio of [ATP]/[ADP]. The specificity of binding at this site is more a function of the degree of phosphorylation of the nucleotide, than of the nature of the nucleoside moiety. Thus under physiological conditions the degree of occupancy of this site is proportional to the energy state of the cell, providing a means for the regulation of the respiratory chain which is sensitive to cytoplasmic ATP levels.

SUBMITTER: Craig DB

PROVIDER: S-EPMC1151514 | biostudies-other | 1991 Nov

REPOSITORIES: biostudies-other

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Project description:Misfolded ?-synuclein is a key factor in the pathogenesis of Parkinson's disease (PD). However, knowledge about a physiological role for the native, unfolded ?-synuclein is limited. Using brains of mice lacking ?-, ?-, and ?-synuclein, we report that extracellular monomeric ?-synuclein enters neurons and localizes to mitochondria, interacts with ATP synthase subunit ?, and modulates ATP synthase function. Using a combination of biochemical, live-cell imaging and mitochondrial respiration analysis, we found that brain mitochondria of ?-, ?-, and ?-synuclein knock-out mice are uncoupled, as characterized by increased mitochondrial respiration and reduced mitochondrial membrane potential. Furthermore, synuclein deficiency results in reduced ATP synthase efficiency and lower ATP levels. Exogenous application of low unfolded ?-synuclein concentrations is able to increase the ATP synthase activity that rescues the mitochondrial phenotypes observed in synuclein deficiency. Overall, the data suggest that ?-synuclein is a previously unrecognized physiological regulator of mitochondrial bioenergetics through its ability to interact with ATP synthase and increase its efficiency. This may be of particular importance in times of stress or PD mutations leading to energy depletion and neuronal cell toxicity. SIGNIFICANCE STATEMENT:Misfolded ?-synuclein aggregations in the form of Lewy bodies have been shown to be a pathological hallmark in histological staining of Parkinson's disease (PD) patient brains. It is known that misfolded ?-synuclein is a key driver in PD pathogenesis, but the physiological role of unfolded monomeric ?-synuclein remains unclear. Using neuronal cocultures and isolated brain mitochondria of ?-, ?-, and ?-synuclein knock-out mice and monomeric ?-synuclein, this current study shows that ?-synuclein in its unfolded monomeric form improves ATP synthase efficiency and mitochondrial function. The ability of monomeric ?-synuclein to enhance ATP synthase efficiency under physiological conditions may be of importance when ?-synuclein undergoes the misfolding and aggregation reported in PD.

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The specificity and Kd at physiological ionic strength of an ATP-binding site on cytochrome c suit it to a regulatory role.

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