Aging-related cell surface ECTO-NOX protein, arNOX, a preventive target to reduce atherogenic risk in the elderly
D. James Morré and Dorothy M. Morré
Departments of Medicinal Chemistry & Molecular Pharmacology and Foods & Nutrition, Purdue University, West Lafayette, Indiana 47907, USA
We have identified a family of constitutive cell surface ECTO-NOX
proteins capable of oxidizing reduced quinones. Initially described as
NADH oxidases, oxidation of external NADH was subsequently determined
not to be a physiological substrate but rather a convenient method for
measurement of the activity. The presence of these enzymes at the cell
surface and the demonstration of an ability to oxidize reduced quinones
of the plasma membrane, e.g., ubiquinol, has offered an opportunity to
formulate, for the first time, a complete electron transport chain from
the cytosol to oxygen at the cell surface with the ECTO-NOX proteins
acting as the terminal oxidase. The ECTO-NOX proteins of the cell
surface have been postulated as well to link the accumulation of
lesions in mitochondrial DNA to cell surface accumulations of reactive
oxygen species as one consequence of their role as a terminal oxidase
in a plasma membrane electron transport chain. Cells with functionally
deficient mitochondria become characterized by an anaerobic
metabolism. Then NADH accumulates from the glycolytic production of
ATP. An elevated plasma membrane electron transport activity then
becomes important to maintain the NAD+/NADH homeostasis
essential for survival. Previous findings demonstrate that the
hyperactivity of the plasma membrane electron transport system and
ultraviolet irradiation results in an NADH oxidase activity capable of
cell surface generation of reactive oxygen species. Because of their
cell surface location, ECTO-NOX proteins capable of superoxide
generation in response to aging would serve to propagate the aging
cascade both to adjacent cells and to oxidize circulating
lipoproteins. Of the several ECTO-NOX proteins now known, one is a
novel cell surface form (arNOX) associated with sera and lymphocytes
of patients of age 50 or older and is capable of directly reducing
ferricytochrome c through the generation of superoxide. This
generation of superoxide associated with aging is inhibited by coenzyme
Q. As such, the findings provide a rational basis for the anti-aging
activity of circulating coenzyme Q in the prevention of atherosclerosis
and other oxidative changes in cell membranes and circulating
lipoproteins.
Key words:
aging, ECTO-NOX proteins, arNOX, atherogenic, superoxide
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