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Vol. 14, Issue 3, 958-972, March 2003

Global Transcription Analysis of Krebs Tricarboxylic Acid Cycle Mutants Reveals an Alternating Pattern of Gene Expression and Effects on Hypoxic and Oxidative Genes

Mark T. McCammon,^* Charles B. Epstein,^# Beata Przybyla-Zawislak,^§ Lee McAlister-Henn,^* and Ronald A. Butow^#

 ^*Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900;  ^#Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148

To understand the many roles of the Krebs tricarboxylic acid (TCA) cycle in cell function, we used DNA microarrays to examine gene expression in response to TCA cycle dysfunction. mRNA was analyzed from yeast strains harboring defects in each of 15 genes that encode subunits of the eight TCA cycle enzymes. The expression of >400 genes changed at least threefold 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 caused by 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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Online version of this article contains supplementary dataset material. The online version is available at www.molbiolcell.org.

Corresponding author. E-mail address: mccammon{at}uthscsa.edu.

Present addresses: Aventis Pharmaceuticals, Inc., Cambridge Genomics Center, Cambridge, MA 02139; ^§Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, AR 72079.

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Molecular Biology of the Cell
Vol. 14, 958-972, March 2003
Copyright © 2003 by The American Society for Cell Biology

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