Nitrite activates AMP kinase to stimulate mitochondrial biogenesis independent of soluble guanylate cyclase.
Nitrite, a dietary constituent and endogenous signaling molecule, mediates a number of physiological responses including modulation of ischemia/reperfusion injury, glucose tolerance, and vascular remodeling. Although the exact molecular mechanisms underlying nitrite's actions are unknown, the current paradigm suggests that these effects depend on the hypoxic reduction of nitrite to nitric oxide (NO). Mitochondrial biogenesis is a fundamental mechanism of cellular adaptation and repair. However, the effect of nitrite on mitochondrial number has not been explored. Herein, we report that nitrite stimulates mitochondrial biogenesis through a mechanism distinct from that of NO. We demonstrate that nitrite significantly increases cellular mitochondrial number by augmenting the activity of adenylate kinase, resulting in AMP kinase phosphorylation, downstream activation of sirtuin-1, and deacetylation of PGC1α, the master regulator of mitochondrial biogenesis. Unlike NO, nitrite-mediated biogenesis does not require the activation of soluble guanylate cyclase and results in the synthesis of more functionally efficient mitochondria. Further, we provide evidence that nitrite mediates biogenesis in vivo. In a rat model of carotid injury, 2 weeks of continuous oral nitrite treatment postinjury prevented the hyperproliferative response of smooth muscle cells. This protection was accompanied by a nitrite-dependent upregulation of PGC1α and increased mitochondrial number in the injured artery. These data are the first to demonstrate that nitrite mediates differential signaling compared to NO. They show that nitrite is a versatile regulator of mitochondrial function and number both in vivo and in vitro and suggest that nitrite-mediated biogenesis may play a protective role in the setting of vascular injury.
Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Li
L
Mo
Yinna
Y
Wang
Lisa
L
Geary
Catherine
C
Corey
Matthew J
MJ
Alef
Donna
D
Beer-Stolz
Brian S
BS
Zuckerbraun
Sruti
S
Shiva
D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology; D020212:Carotid Artery Injuries / Q000188:drug therapy / Q000201:enzymology; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D063269:Mitochondrial Turnover / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D061251:Primary Cell Culture; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D012977:Sodium Nitrite / Q000494:pharmacology* / Q000627:therapeutic use; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D000263:Adenylate Kinase; D056564:Sirtuin 1; D006162:Guanylate Cyclase; D012977:Sodium Nitrite