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J. Biol. Chem., Vol. 279, Issue 7, 5194-5199, February 13, 2004

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Mechanism of Actin Polymerization in Cellular ATP Depletion^*

Simon J. Atkinson, Melanie A. Hosford, and Bruce A. Molitoris

From the Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202

Cellular ATP depletion in diverse cell types results in the net conversion of monomeric G-actin to polymeric F-actin and is an important aspect of cellular injury in tissue ischemia. We propose that this conversion results from altering the ratio of ATP-G-actin and ADP-G-actin, causing a net decrease in the concentration of thymosinactin complexes as a consequence of the differential affinity of thymosin ₄ for ATP- and ADP-G-actin. To test this hypothesis we examined the effect of ATP depletion induced by antimycin A and substrate depletion on actin polymerization, the nucleotide state of the monomer pool, and the association of actin monomers with thymosin and profilin in the kidney epithelial cell line LLC-PK₁. ATP depletion for 30 min increased F-actin content to 145% of the levels under physiological conditions, accompanied by a corresponding decrease in G-actin content. Cytochalasin D treatment did not reduce F-actin formation during ATP depletion, indicating that it was predominantly not because of barbed end monomer addition. ATP-G-actin levels decreased rapidly during depletion, but there was no change in the concentration of ADP-G-actin monomers. The decrease in ATP-G-actin levels could be accounted for by dissociation of the thymosin-G-actin binary complex, resulting in a rise in the concentration of free thymosin ₄ from 4 to 11 µM. Increased detection of profilin-actin complexes during depletion indicated that profilin may participate in catalyzing nucleotide exchange during depletion. This mechanism provides a biochemical basis for the accumulation of F-actin aggregates in ischemic cells.

Received for publication, June 30, 2003 , and in revised form, November 10, 2003.

^* This work was supported by National Institutes of Health Grants P01 DK53465 (to B. A. M.) and R01 DK53194 (to S. J. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Indiana University School of Medicine, Dept. of Medicine-Nephrology, 950 W. Walnut St., R2-202, Indianapolis, IN 46202. Tel.: 317-278-0435; Fax: 317-274-8575; E-mail: satkinso{at}iupui.edu.

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