Multiple Defects in the Respiratory Chain Lead to the Repression of Genes Encoding Components of the Respiratory Chain and TCA Cycle Enzymes

Bourges, Ingrid; Mucchielli, Marie-Hélène; Herbert, Christopher J.; Guiard, Bernard; Dujardin, Geneviève; Meunier, Brigitte

doi:10.1016/j.jmb.2009.02.039

Cited by 6 publications

(9 citation statements)

References 43 publications

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“…Yeast cells become ρ 0 petites after losing mitochondrial DNA (mtDNA). It was reported that the Hap4 protein level is reduced by 2-fold in ρ 0 cells grown in rich galactose media in comparison to that in ρ + cells containing wild-type mtDNA [24]. Although it was suggested that transcriptional regulation was not involved, the underlying mechanism was unclear.…”

Section: Hap4 Expression Is Affected By the Functional State Of Mitoc...mentioning

confidence: 99%

“…Together, these data support the notion that varying Hap4 protein levels lead to a graded transcriptional response of the target genes of the Hap2/3/4/5 complex, rather than an all-or-none effect. Since the Hap2/3/4/5 complex mediates the expression of many mitochondrial proteins [13,17,24], by modulating Hap4 protein levels, yeast cells are able to fine-tune mitochondrial biogenesis to meet changing energetic and metabolic requirements in cells.…”

Section: Transcriptional Regulation Of Kgd1 a Target Of The Hap2/3/4/...mentioning

confidence: 99%

“…In ρ 0 cells, the expression of the rest of the tricarboxylic acid cycle is reduced, suggesting that the activity of the Hap2/3/4/5 complex is suppressed. Genome-wide transcriptional profiling reveals reduced expression of many Hap2/3/4/5-target genes as a result of reduced Hap4 protein level [24]. Other studies have shown that Hap4 is a highly unstable protein, whose turnover is affected by the cellular environment [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, an increase in the cellular heme level and glutathione redox state stabilizes Hap4, resulting in increased mitochondrial biogenesis [27]. Based on the findings that the HAP4 transcript level does not change in ρ 0 cells and that Hap4 overexpression leads to its localization in the vacuole, Bourges and colleagues have proposed that a vacuolar degradation mechanism might be behind reduced Hap4 protein levels in ρ 0 cells [24]. It has also been suggested that reactive oxygen species may not be involved in the downregulation of Hap4 in response to mitochondrial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Ubiquitin-Conjugating Enzymes Ubc1 and Ubc4 Mediate the Turnover of Hap4, a Master Regulator of Mitochondrial Biogenesis in Saccharomyces cerevisiae

et al. 2022

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Mitochondrial biogenesis is tightly regulated in response to extracellular and intracellular signals, thereby adapting yeast cells to changes in their environment. The Hap2/3/4/5 complex is a master transcriptional regulator of mitochondrial biogenesis in yeast. Hap4 is the regulatory subunit of the complex and exhibits increased expression when the Hap2/3/4/5 complex is activated. In cells grown under glucose derepression conditions, both the HAP4 transcript level and Hap4 protein level are increased. As part of an inter-organellar signaling mechanism coordinating gene expression between the mitochondrial and nuclear genomes, the activity of the Hap2/3/4/5 complex is reduced in respiratory-deficient cells, such as ρ0 cells lacking mitochondrial DNA, as a result of reduced Hap4 protein levels. However, the underlying mechanism is unclear. Here, we show that reduced HAP4 expression in ρ0 cells is mediated through both transcriptional and post-transcriptional mechanisms. We show that loss of mitochondrial DNA increases the turnover of Hap4, which requires the 26S proteasome and ubiquitin-conjugating enzymes Ubc1 and Ubc4. Stabilization of Hap4 in the ubc1 ubc4 double mutant leads to increased expression of Hap2/3/4/5-target genes. Our results indicate that mitochondrial biogenesis in yeast is regulated by the functional state of mitochondria partly through ubiquitin/proteasome-dependent turnover of Hap4.

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Section: Hap4 Expression Is Affected By the Functional State Of Mitoc...mentioning

confidence: 99%

Section: Transcriptional Regulation Of Kgd1 a Target Of The Hap2/3/4/...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ubiquitin-Conjugating Enzymes Ubc1 and Ubc4 Mediate the Turnover of Hap4, a Master Regulator of Mitochondrial Biogenesis in Saccharomyces cerevisiae

et al. 2022

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“…1). Hap4 regulates the expression of genes involved in mitochondrial respiratory metabolism including those encoding the TCA cycle enzymes and components of the respiratory chain complex genes 252627. Adr1 regulates genes involved in peroxisomal biogenesis, β-oxidation and utilization of non-fermentable carbon sources 28, whereas Cat8 regulates genes encoding gluconeogenic and glyoxylate cycle enzymes 29.…”

Section: Introductionmentioning

confidence: 99%

The transcription factors ADR1 or CAT8 are required for RTG pathway activation and evasion from yeast acetic acid-induced programmed cell death in raffinose

Laera¹,

Guaragnella²,

Ždralević³

et al. 2016

Microb Cell

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Yeast Saccharomyces cerevisiae grown on glucose undergoes programmed cell death (PCD) induced by acetic acid (AA-PCD), but evades PCD when grown in raffinose. This is due to concomitant relief of carbon catabolite repression (CCR) and activation of mitochondrial retrograde signaling, a mitochondria-to-nucleus communication pathway causing up-regulation of various nuclear target genes, such as CIT2, encoding peroxisomal citrate synthase, dependent on the positive regulator RTG2 in response to mitochondrial dysfunction. CCR down-regulates genes mainly involved in mitochondrial respiratory metabolism. In this work, we investigated the relationships between the RTG and CCR pathways in the modulation of AA-PCD sensitivity under glucose repression or de-repression conditions. Yeast single and double mutants lacking RTG2 and/or certain factors regulating carbon source utilization, including MIG1, HXK2, ADR1, CAT8, and HAP4, have been analyzed for their survival and CIT2 expression after acetic acid treatment. ADR1 and CAT8 were identified as positive regulators of RTG-dependent gene transcription. ADR1 and CAT8 interact with RTG2 and with each other in inducing cell resistance to AA-PCD in raffinose and controlling the nature of cell death. In the absence of ADR1 and CAT8, AA-PCD evasion is acquired through activation of an alternative factor/pathway repressed by RTG2, suggesting that RTG2 may play a function in promoting necrotic cell death in repressing conditions when RTG pathway is inactive. Moreover, our data show that simultaneous mitochondrial retrograde pathway activation and SNF1-dependent relief of CCR have a key role in central carbon metabolism reprogramming which modulates the yeast acetic acid-stress response.

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Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism☆

Pathania¹,

Millard²,

Neamati³

2009

Advanced Drug Delivery Reviews

233

179

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Multiple Defects in the Respiratory Chain Lead to the Repression of Genes Encoding Components of the Respiratory Chain and TCA Cycle Enzymes

Cited by 6 publications

References 43 publications

Ubiquitin-Conjugating Enzymes Ubc1 and Ubc4 Mediate the Turnover of Hap4, a Master Regulator of Mitochondrial Biogenesis in Saccharomyces cerevisiae

Ubiquitin-Conjugating Enzymes Ubc1 and Ubc4 Mediate the Turnover of Hap4, a Master Regulator of Mitochondrial Biogenesis in Saccharomyces cerevisiae

The transcription factors ADR1 or CAT8 are required for RTG pathway activation and evasion from yeast acetic acid-induced programmed cell death in raffinose

Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism☆

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