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A Transcriptional Switch in the Expression of Yeast Tricarboxylic Acid Cycle Genes in Response to a Reduction or Loss of Respiratory Function
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The Hap2,3,4,5p transcription complex is required for expression of many mitochondrial proteins that function in electron transport and the tricarboxylic acid (TCA) cycle. We show that as the cells' respiratory function is reduced or eliminated, the expression of four TCA cycle genes, CIT1, ACO1, IDH1, and IDH2, switches from HAP control to control by three genes, RTG1, RTG2, and RTG3. The expression of four additional TCA cycle genes downstream of IDH1 and IDH2 is independent of the RTG genes. We have previously shown that the RTG genes control the retrograde pathway, defined as a change in the expression of a subset of nuclear genes, e.g., the glyoxylate cycle CIT2 gene, in response to changes in the functional state of mitochondria. We show that the cis-acting sequence controlling RTG-dependent expression of CIT1 includes an R box element, GTCAC, located 70 bp upstream of the Hap2,3,4,5p binding site in the CIT1 upstream activation sequence. The R box is a binding site for Rtg1p-Rtg3p, a heterodimeric, basic helix-loop-helix/leucine zipper transcription factor complex. We propose that in cells with compromised mitochondrial function, the RTG genes take control of the expression of genes leading to the synthesis of alpha-ketoglutarate to ensure that sufficient glutamate is available for biosynthetic processes and that increased flux of the glyoxylate cycle, via elevated CIT2 expression, provides a supply of metabolites entering the TCA cycle sufficient to support anabolic pathways. Glutamate is a potent repressor of RTG-dependent expression of genes encoding both mitochondrial and nonmitochondrial proteins, suggesting that it is a specific feedback regulator of the RTG system.
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“The Rtg1p/Rtg3p heterodimer binds DNA and activates target gene expression in response to the mitochondrial dysfunction and concomitant decreased glutamate supply”
From Mitochondrial retrograde control of transcription evolves with respiratory stress, metabolic adaptation, and virulence in budding yeasts (2026) · cites this paper as Liu and Butow 1999
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Rua, A. J., Mitchell, W., Claypool, S. M., Alder, N. N., & Alexandrescu, A. T. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107746 · Cited by 6
Metadata
- Authors
- Liu, Z., & Butow, R. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Butow, Ronald A.
- ORCID
- Liu, Zhengchang
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1999-10-01
- Volume
- 19
- Issue
- 10
- Pages
- 6720-6728
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC84662
- OpenAlex
- W2102284511
- Cited by
- 290
- References
- 50
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 14 · 2023: 12 · 2022: 7 · 2021: 9 · 2020: 10 · 2019: 7 · 2018: 8 · 2017: 10 · 2016: 7 · 2015: 7 · 2014: 14 · 2013: 17 · 2012: 13
- FWCI
- 4.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Welch Foundation
- National Institutes of Health
- National Institute of General Medical Sciences (R37GM022525, GM22525)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- transcriptional switch, retrograde signaling, mitochondrial dysfunction, respiratory deficiency, glyoxylate cycle, alpha-ketoglutarate, IDH1, IDH2, ACO1, Saccharomyces cerevisiae
- MeSH terms
- Aconitate Hydratase, Binding Sites, Citrate (si)-Synthase, Citric Acid Cycle, DNA-Binding Proteins, Fungal Proteins, Genes, Fungal, Genes, Switch, Isocitrate Dehydrogenase, Models, Genetic, Oxygen Consumption, Phenotype, Protein Binding, Saccharomyces cerevisiae, Transcription Factors, Gene Expression Regulation, Fungal, Gene Deletion, Genes, Reporter, Glutamic Acid, Saccharomyces cerevisiae Proteins, Intracellular Signaling Peptides and Proteins, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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