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A more recent version of this article appeared on March 1, 2003
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Submitted on July 23, 2002
Revised on October 25, 2002
Accepted on November 18, 2002
1 Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio Texas 78229-3900
2 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148 (present address: Aventis Pharmaceuticals, Inc., Cambridge Genomics Center, Cambridge, MA 02139)
3 Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, AR 72079
4 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148
* Corresponding author. E-mail address: mccammon{at}uthscsa.edu.
To understand the many roles of the Krebs tricarboxylic acid (TCA) cycle in cell function, we have used DNA microarrays to examine gene expression in response to TCA cycle dysfunction. mRNA was analyzed from yeast strains harboring defects in each of fifteen genes that encode subunits of the eight TCA cycle enzymes. The expression of over 400 genes changed at least three-fold in response to TCA cycle dysfunction. Many genes displayed a common response to TCA cycle dysfunction indicative of a shift away from oxidative metabolism. Another set of genes displayed a pairwise, alternating pattern of expression in response to contiguous TCA cycle enzyme defects: expression was elevated in aconitase and isocitrate dehydrogenase mutants, diminished in 
-ketoglutarate dehydrogenase and succinyl-CoA ligase mutants, elevated again in succinate dehydrogenase and fumarase mutants, and diminished again in malate dehydrogenase and citrate synthase mutants. This pattern correlated with previously defined TCA cycle growth enhancing mutations and suggested a novel metabolic signaling pathway monitoring TCA cycle function. Expression of hypoxic/anaerobic genes was elevated in -ketoglutarate dehydrogenase mutants, whereas expression of oxidative genes was diminished, consistent with a heme signaling defect due to inadequate levels of the heme precursor, succinyl-CoA. These studies have revealed extensive responses to changes in TCA cycle function and have uncovered new and unexpected metabolic networks that are wired into the TCA cycle.
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