Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals.
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.
Nisoli
Enzo
E
Department of Preclinical Sciences, Laboratorio Interdisciplinare Technologie Avanzate (LITA) Vialba, University of Milan, 20157 Milan, Italy. enzo.nisoli@unim.it
Falcone
Sestina
S
Tonello
Cristina
C
Cozzi
Valeria
V
Palomba
Letizia
L
Fiorani
Mara
M
Pisconti
Addolorata
A
Brunelli
Silvia
S
Cardile
Annalisa
A
Francolini
Maura
M
Cantoni
Orazio
O
Carruba
Michele O
MO
Moncada
Salvador
S
Clementi
Emilio
E
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010101:Oxygen Consumption; D016716:PC12 Cells; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects; D020298:U937 Cells
D009569:Nitric Oxide; D000255:Adenosine Triphosphate; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat; D006152:Cyclic GMP