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Nitrite activates AMP kinase to stimulate mitochondrial biogenesis independent of soluble guanylate cyclase.

Authors: Mo, L  Wang, Y  Geary, L  Corey, C  Alef, MJ  Beer-Stolz, D  Zuckerbraun, BS  Shiva, S 
Citation: Mo L, etal., Free Radic Biol Med. 2012 Oct 1;53(7):1440-50. doi: 10.1016/j.freeradbiomed.2012.07.080. Epub 2012 Aug 4.
Pubmed: (View Article at PubMed) PMID:22892143
DOI: Full-text: DOI:10.1016/j.freeradbiomed.2012.07.080

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 PGC1alpha, 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 PGC1alpha 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.


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CRRD Object Information
CRRD ID: 7242065
Created: 2013-03-26
Species: All species
Last Modified: 2013-03-26
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.