Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals

Enzo Nisoli, Sestina Falcone, Cristina Tonello, Valeria Cozzi, Letizia Palomba, Mara Fiorani, Addolorata Pisconti, Silvia Brunelli, Annalisa Cardile, Maura Francolini, Orazio Cantoni, Michele O. Carruba, Salvador Moncada, Emilio Clementi

    Research output: Contribution to journalArticlepeer-review


    We recently found that long-term exposure to nitric oxide (NO) triggers mitochondrial biogenesis in mammalian cells and tissues by activation of guanylate cyclase and generation of cGMP. Here, we report that the NO/cGMP-dependent mitochondrial biogenesis is associated with enhanced coupled respiration and content of ATP in U937, L6, and PC12 cells. The observed increase in ATP content depended entirely on oxidative phosphorylation, because ATP formation by glycolysis was unchanged. Brain, kidney, liver, heart, and gastrocnemius muscle from endothelial NO synthase null mutant mice displayed markedly reduced mitochondrial content associated with significantly lower oxygen consumption and ATP content. In these tissues, ultrastructural analyses revealed significantly smaller mitochondria. Furthermore, a significant reduction in the number of mitochondria was observed in the subsarcolemmal region of the gastrocnemius muscle. We conclude that NO/cGMP stimulates mitochondrial biogenesis, both in vitro and in vivo, and that this stimulation is associated with increased mitochondrial function, resulting in enhanced formation of ATP.
    Original languageEnglish
    Pages (from-to)16507-16512
    Number of pages5
    JournalProceedings of the National Academy of Sciences of the United States of America
    Issue number47
    Publication statusPublished - 23 Nov 2004


    • ATP
    • cGMP
    • Oxygen consumption


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