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

Capps, Denise; Hunter, Arielle; Chiang, Mengying; Pracheil, Tammy; Liu, Zhengchang

doi:10.3390/microorganisms10122370

Cited by 8 publications

(5 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The results also demonstrate that an impairment of respiratory function coupled to RTG -mediated mitochondrial metabolic reprogramming can accelerate osmoadaptation. In this context, HAP4 appears to be a negative regulator in the kinetics of stress response, which agrees with recent studies showing that reduction in HAP4 protein levels may be advantageous to achieving mitochondrial homeostasis by coordinating gene expression between the mitochondrial and nuclear genomes in respiratory-deficient cells [ 29 ].…”

Section: Discussionsupporting

confidence: 88%

Inactivation of HAP4 Accelerates RTG-Dependent Osmoadaptation in Saccharomyces cerevisiae

Noia

Scarcia

Agrimi

et al. 2023

IJMS

View full text Add to dashboard Cite

Mitochondrial RTG (an acronym for ReTroGrade) signaling plays a cytoprotective role under various intracellular or environmental stresses. We have previously shown its contribution to osmoadaptation and capacity to sustain mitochondrial respiration in yeast. Here, we studied the interplay between RTG2, the main positive regulator of the RTG pathway, and HAP4, encoding the catalytic subunit of the Hap2-5 complex required for the expression of many mitochondrial proteins that function in the tricarboxylic acid (TCA) cycle and electron transport, upon osmotic stress. Cell growth features, mitochondrial respiratory competence, retrograde signaling activation, and TCA cycle gene expression were comparatively evaluated in wild type and mutant cells in the presence and in the absence of salt stress. We showed that the inactivation of HAP4 improved the kinetics of osmoadaptation by eliciting both the activation of retrograde signaling and the upregulation of three TCA cycle genes: citrate synthase 1 (CIT1), aconitase 1 (ACO1), and isocitrate dehydrogenase 1 (IDH1). Interestingly, their increased expression was mostly dependent on RTG2. Impaired respiratory competence in the HAP4 mutant does not affect its faster adaptive response to stress. These findings indicate that the involvement of the RTG pathway in osmostress is fostered in a cellular context of constitutively reduced respiratory capacity. Moreover, it is evident that the RTG pathway mediates peroxisomes–mitochondria communication by modulating the metabolic function of mitochondria in osmoadaptation.

show abstract

Section: Discussionsupporting

confidence: 88%

Inactivation of HAP4 Accelerates RTG-Dependent Osmoadaptation in Saccharomyces cerevisiae

Noia

Scarcia

Agrimi

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…Interestingly, within the yeast promoter representation, we identify a few groups of promoters with strong signals for only one or two TFs. For example, Hap4 is known to regulate the expression of key mitochondrial complexes (Cytochrome c and ATP synthase) in the electron transport chain [70]. Remarkably, we find a cluster of promoters with a strong signal for only the Hap4 motif (Table1, cluster F), where 26/29 (90%) are annotated as belonging to protein complexes in the inner mitochondrial membrane.…”

Section: Clusters In the Phylogenetic Average Motif Score Representat...mentioning

confidence: 76%

Functional similarity of non-coding regions is revealed in phylogenetic average motif score representations

Alam

Duncan

Mitchell

et al. 2023

Preprint

View full text Add to dashboard Cite

Here we frame the cis-regulatory code (that connects the regulatory functions of non-coding regions, such as promoters and UTRs, to their DNA sequences) as a representation building problem. Representation learning has emerged as a new approach to understand function of DNA and proteins, by projecting sequences into high-dimensional feature spaces, where the features are learned from data by a neural network. Inspired by these approaches, we seek to define a feature space where non-coding regions with similar regulatory functions are nearby each other. As a first attempt, we engineered features based on matches to biochemically characterized regulatory motifs in the DNA sequences of non-coding regions. Remarkably, we found that functionally similar promoters and 3' UTRs could be grouped together in a feature space defined by simple averages of the best match scores in (unaligned) orthologous non-coding regions, which we refer to as phylogenetic average motif scores. Perhaps most important, because this feature space is based on known motifs and not fit to any data, it is fully interpretable and not limited to any particular cell type or experimental context. We find that we can read off known regulatory relationships and evolutionary rewiring from visualizations of phylogenetic average motif score representations, and that predicted regulatory interactions based on neighbors in the feature space are borne out in transcription factor deletion experiments. Phylogenetic averages of match scores to known motifs is a baseline for representation learning applied to non-coding sequences, and may continue to improve as databases of motifs become more complete.

show abstract

“…It has been previously shown that Hap4 is susceptible to proteasome-mediated degradation [25]. To test whether decreased Hap4 protein levels can be attributed to its increased proteasomal degradation, we treated cells with 200 µM heme in the presence or absence of 75 µM MG132 proteasome inhibitor [26].…”

Section: Resultsmentioning

confidence: 99%

Lifespan regulation by targeting heme signaling in yeast

Patnaik,

Nady,

Barlit

et al. 2024

Preprint

View full text Add to dashboard Cite

Heme is an essential prosthetic group that serves as a co-factor and a signaling molecule. Heme levels decline with age, and its deficiency is associated with multiple hallmarks of aging, including anemia, mitochondrial dysfunction, and oxidative stress. Dysregulation of heme homeostasis has been also implicated in aging in model organisms suggesting that heme may play an evolutionarily conserved role in controlling lifespan. However, the underlying mechanisms and whether heme homeostasis can be targeted to promote healthy aging remain unclear. Here we used Saccharomyces cerevisiae as a model to investigate the role of heme in aging. For this, we have engineered a heme auxotrophic yeast strain expressing a plasma membrane-bound heme permease from Caenorhabditis elegans (ceHRG-4). This system can be used to control intracellular heme levels independently of the biosynthetic enzymes by manipulating heme concentration in the media. We observed that heme supplementation leads to significant lifespan extension in yeast. Our findings revealed that the effect of heme on lifespan is independent of the Hap4 transcription factor. Surprisingly, heme-supplemented cells had impaired growth on YPG medium, which requires mitochondrial respiration to be used, suggesting that these cells are respiratory deficient. Together, our results demonstrate that heme homeostasis is fundamentally important for aging biology and manipulating heme levels can be used as a promising therapeutic target for promoting longevity.

show abstract

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

Cited by 8 publications

References 66 publications

Inactivation of HAP4 Accelerates RTG-Dependent Osmoadaptation in Saccharomyces cerevisiae

Inactivation of HAP4 Accelerates RTG-Dependent Osmoadaptation in Saccharomyces cerevisiae

Functional similarity of non-coding regions is revealed in phylogenetic average motif score representations

Lifespan regulation by targeting heme signaling in yeast

Contact Info

Product

Resources

About