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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Dr. Anna Fusco
Anna Fusco (Italy)
List of Authors: Anna Fusco, Gaetano Santulli, Daniela Sorriento, Ersilia Cipolletta, Corrado Garbi, Gerald W. Dorn II, Bruno Trimarco, Antonio Feliciello, Guido Iaccarino
Background: Recent studies demonstrate the role of GRK2 in the control of insulin signaling and cellular metabolism. Here, we investigate the role of this kinase in cellular energy production. Methods & Results: In HEK-293 cells, GRK2 overexpression increases while inactive GRK2 decreases cellular and mitochondrial ATP levels. Since increased mitochondrial DNA content often associates with elevated oxidative respiratory chain activity, we assessed mitochondria biogenesis by means of mitochondrial DNA copy numbers and expression. In HEK-293s, stable overexpression of GRK2, increases two mitochondrial genes, NADHd and cytochrome B, in copy numbers and expression. The reciprocal evidence was collected in aorta cells from recombinant mice harbouring flox sequences flanking the GRK2 gene (GRK2f/f), in which the knock out was obtained after exposure of cells to CRE recombinase adenoviruses (AdCRE). In this setup, we found a reduction in the copy numbers and level of expression of the NADHd and cytocrome B as compared to control cells. To explore the possible mechanism of GRK2 on mitochondria, we assess whether GRK2 can localize with the organelle. Indeed, we found that GRK2 targets mitochondrial outer membranes through means of its RH domain located within the amino-terminus. Acute hypoxia promotes a transient increase of mitochondria-associated GRK2 levels, reduced by oxygen replenishment. Interestingly, ATP cell content decreases during hypoxia and slowly returns to basal levels after oxygen replenishment. The overexpression of GRK2 attenuates hypoxia-induced loss of ATP. To explore the physiological relevance of these findings, in homozygous GRK2f/f mice, GRK2 gene deletion by injection of AdCRE in the skeletal muscle causes a significant reduction of ATP levels under basal conditions and attenuates the recovery of ATP levels following ischemia/reperfusion. Conclusions: Our data show an unexpected role of GRK2 in the mitochondria, supporting a positive regulation of the bioenergetic pathway.
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