Biology subjects

Dengler, L.

Publications and source records attributed to Dengler, L..

6 recordsLinked to original sources

bioRxiv2026

Swe1 delays cell cycle progression during impaired mitochondrial inheritance to promote mitochondrial homeostasis

Mitochondrial homeostasis is essential for cellular health. To maintain mitochondrial homeostasis in proliferating cells, mitochondrial inheritance to daughter cells must be tightly coordinated with growth and cell division. In budding yeast, mitochondrial inheritance is ensured by active transport into the growing bud. Although inheritance defects are well known to affect cell physiology, the regulatory mechanisms linking mitochondrial inheritance to cell cycle control remain unclear. Here, we use the inheritance defect of cells depleted of the mitochondrial inheritance adaptor Mmr1 to investigate this coordination. Time-resolved analysis of more than 8,000 budding events revealed that budding duration is directly linked to the time of mitochondrial inheritance. To understand the underlying mechanism, we performed a genetic interaction screen using the auxin-inducible degron library. Strains depleted of cell cycle regulators, particularly those involved in mitotic progression, were highly enriched in clones with synthetic growth defects. Among these, Swe1, the bud morphogenesis checkpoint kinase, emerged as a key candidate affecting budding duration in response to impaired mitochondrial inheritance. Co-depletion of Mmr1 and Swe1 strongly reduces the mitochondrial inheritance-dependent lengthening of budding duration, leading to a large fraction of daughter cells with insufficient mitochondrial content. Thus, Swe1-mediated mitotic delay contributes to slowing cell cycle progression in response to defective mitochondrial inheritance. We suggest calling this regulatory loop MIBA: mitochondrial inheritance-dependent budding adaptation. Together, our findings reveal a mechanism by which cells couple mitochondrial inheritance to cell cycle progression and highlight the importance of this coupling for mitochondrial homeostasis across the population.

cell biology↗

bioRxiv2025

Tsa1-Mediated Regulation of PKA Tunes Trehalose Metabolism in Saccharomyces cerevisiae

Cells must continuously adapt their metabolism, growth, and division to fluctuating nutrient availability. In Saccharomyces cerevisiae, this coordination is largely governed by the Ras/cAMP/PKA pathway, which promotes fermentative growth under glucose-rich conditions and is rapidly downregulated upon glucose depletion. This downregulation enables stress responses, global metabolic rewiring, and entry into quiescence. While PKA is known to integrate multiple environmental cues with glucose availability, the crosstalk to other stress-responsive signaling mechanisms remains incompletely understood. Here, we identify the peroxiredoxin Tsa1, a central player in oxidative stress protection and redox signaling, as a key modulator of PKA activity during glucose depletion and stationary phase entry. Combining live-cell imaging of Msn2, analysis of STRE-dependent gene expression, Nth1 phosphorylation assays, and metabolic flux modelling, we show that loss of Tsa1 leads to incomplete downregulation of PKA signaling. Consequently, tsa1{Delta} cells display delayed transition to respiratory growth, reduced gluconeogenic capacity, and impaired accumulation of storage carbohydrates. Failure to properly attenuate PKA activity also disrupts accurate cell cycle control upon glucose depletion, resulting in abnormally small cells that contribute to the reduced chronological lifespan and delayed recovery upon nutrient repletion. Together, our findings establish Tsa1 as a critical link between redox regulation and nutrient signaling, ensuring proper metabolic adaptation and cellular fitness during glucose exhaustion.

molecular biology↗

bioRxiv2025

When mitochondria fall apart: Unbalanced mitochondrial segregation triggers loss of mtDNA in the absence of mitochondrial fusion

Mitochondrial biogenesis and inheritance must be carefully regulated alongside cell division to ensure proper mitochondrial function and cell survival. The dynamics of the mitochondrial network, including fusion and fission, play a crucial role in mitochondrial inheritance by facilitating the distribution and quality control of mitochondria. In budding yeast, simultaneous inhibition of both fusion and fission leads to loss of mitochondrial DNA (mtDNA) integrity, resulting in an increased frequency of petite cells. Loss of mitochondrial fusion alone results in the complete loss of mtDNA. While the loss of mtDNA in the absence of mitochondrial fusion has been known for almost 30 years, the reason remained unclear. Here, we investigate the consequences of impaired mitochondrial fusion through depletion of the mitofusin Fzo1. We follow the emerging phenotype by live-cell imaging and the analysis of more than thirty thousand single cells across their cell cycle. Fzo1 depletion causes rapid mitochondrial fragmentation and a reduction in mitochondrial membrane potential, followed by a progressive decline of mtDNA content and cellular growth rate over several cell divisions. During division, Fzo1-depleted daughters obtain an unusually large amount of mitochondria, leaving the mother with too little. This results in a strong disbalance of mitochondrial mass in the population. Additionally, Fzo1-depleted cells lose the ability to adjust mtDNA synthesis to compensate for a low mitochondrial content. The combined effects of unequal distribution and reduced synthesis drive rapid mtDNA loss. These results show how fusion defects lead to mtDNA loss and mitochondrial dysfunction, contributing to understanding diseases linked to fusion defects.

cell biology↗

bioRxiv2024

Cytosolic peroxiredoxin Tsa1 influences acetic acid metabolism and pH homeostasis in wine yeasts

Acetic acid is a key metabolite in yeast fermentation, influencing wine quality through its role in volatile acidity. In Saccharomyces cerevisiae, acetic acid production involves aldehyde dehydrogenases, primarily Ald6 during fermentation and Ald4 under respiration. However, the regulatory mechanisms of these enzymes throughout fermentation and how they differ in commonly used strains remain partially unclear. This study explores the cytosolic peroxiredoxin Tsa1 as a novel regulator of acetic acid metabolism. TSA1 gene deletion revealed strain-dependent effects on acetic acid metabolism and tolerance, showing reduced production and enhanced consumption in laboratory media. Under respiration, Ald4-driven acetic acid production, which raises extracellular pH, was mitigated by the absence of Tsa1. During wine fermentation, TSA1 deletion decreased the initial acetic acid surge by downregulating ALD6 transcription and enzymatic activity. These findings position Tsa1 as a metabolic regulator and a potential target for modulating acetic acid levels to manage volatile acidity and wine quality.

microbiology↗

bioRxiv2023

The second messenger c-di-AMP controls natural competence via ComFB signaling protein

Natural competence requires a contractile pilus system. Here, we provide evidence that the pilus biogenesis and natural competence in cyanobacteria are regulated by the second messenger c-di-AMP. Furthermore, we show that the ComFB signaling protein is a novel c-di-AMP-receptor protein, widespread in bacterial phyla, and required for pilus biogenesis and DNA uptake.

microbiology↗

bioRxiv2020

Regulation of trehalase activity by multi-site phosphorylation and 14-3-3 interaction

Protein phosphorylation enables a rapid adjustment of cellular activities to diverse intracellular and environmental stimuli. Many phosphoproteins are targeted on more than one site, which allows the integration of multiple signals and the implementation of complex responses. However, the hierarchy and interplay between multiple phospho-sites are often unknown. Here, we study multi-site phosphorylation using the yeast trehalase Nth1 and its activator, the 14-3-3 protein Bmh1, as a model. Nth1 is known to be phosphorylated by the metabolic kinase PKA on four serine residues and by the cell cycle kinase CDK on one residue. However, how these five phospho-sites adjust Nth1 activity remains unclear. Using a novel reporter construct, we investigated the contribution of the individual sites for the regulation of the trehalase and its 14-3-3 interactor. In contrast to the constitutively phosphorylated S20 and S83, the weaker sites S21 and S60 are only phosphorylated by increased PKA activity. For binding Bmh1, S83 functions as the high-affinity "gatekeeper" site, but successful binding of the Bmh1 dimer and thus Nth1 activation requires S60 as a secondary site. Under nutrient-poor conditions with low PKA activity, S60 is not efficiently phosphorylated and the cell cycle dependent phosphorylation of S66 by Cdk1 contributes to Nth1 activity, likely by providing an alternative Bmh1 binding site. Additionally, the PKA sites S20 and S21 modulate the dephosphorylation of Nth1 on downstream Bmh1 sites. In summary, our results expand our molecular understanding of Nth1 regulation and provide a new aspect of the interaction of 14-3-3 proteins with their targets.

biochemistry↗