The regulation of cell energetics and mitochondrial signaling by nitric oxide

BOVERIS A, CARRERAS MC, PODEROSO JJ

Nitric Oxide Biology and Pathobiology

Academic Press

Lugar: San Diego; Año: 2010; p. 441 - 482

The recognition that nitric oxide (NO) acts as a reversible inhibitor of cytochrome oxidase activity competitively with O 2 produced a Copernican revolution in the understanding of the regulation of respiration, especially at low tissue pO 2 . It is now understood that tissue O2 uptake depends on the O2 /NO ratio, a concept that has both experimental and mathematical support. Mitochondrial O2  production, stimulated by NO itself, prevents the inhibition of cytochrome oxidase by NO, providing the reversibility of the regulatory mechanism. The calculated intramitochondrial NO levels (100 – 360 nM) are in the range of concentrations, 80 – 200 nM NO, that inhibit by 50% cytochrome oxidase activity. Mitochondria have their own source of NO with mtNOS, a transcript of nNOS- α . This is an integral protein of the inner membrane and a voltage-dependent enzyme, and its activity inhibits mitochondrial O 2 uptake. Mitochondrial NO plays a role in cell signaling: decreased mtNOS activity leads to cell proliferation and increased mtNOS activity leads to cell arrest. Over-stimulated mtNOS activity and increased NO mitochondrial levels are associated with mitochondrial dysfunction, and nitrative and nitrosative stress under a range of pathophysiological conditions.