Biology subjects

Morlot, S.

Publications and source records attributed to Morlot, S..

3 recordsLinked to original sources

bioRxiv2021

Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

The formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient material and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but the causalities remained unclear. We used yeast as model system to analyze the relevance of mitochondrial processes for the behavior of an aggregation-prone polyQ protein derived from human huntingtin. Induction of Q97-GFP rapidly leads to insoluble cytosolic aggregates and cell death. Although this aggregation impairs mitochondrial respiration only slightly, it interferes with efficient import of mitochondrial precursor proteins. Mutants in the import component Mia40 are hypersensitive to Q97-GFP. Even more surprisingly, Mia40 overexpression strongly suppresses the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the posttranslational import into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Owing to its rate-limiting role for mitochondrial protein import, Mia40 acts as a regulatory component in this competition. This role of Mia40 as dynamic regulator in mitochondrial biogenesis can apparently be exploited to stabilize cytosolic proteostasis. (174/175 words)

biochemistry↗

bioRxiv2019

Proteostasis collapse halts G1 progression and delimits replicative lifespan

Loss of proteostasis and cellular senescence are key hallmarks of cell aging, but whether they are subject to direct cause-effect relationships is not known. We show that most yeast cells arrest in G1 before death with low nuclear levels of cyclin Cln3, a key activator of Start extremely sensitive to chaperone status. Chaperone availability is seriously compromised in aged cells, and the G1 arrest coincides with massive aggregation of a metastable chaperone-activity reporter. A mathematical model integrating autocatalytic protein aggregation and a minimal Start network recapitulates empirical observations. As key predictions, G1-cyclin overexpression increases lifespan in a chaperone-dependent manner, and lifespan reduction by enforced protein aggregation is greatly alleviated by increased expression of specific chaperones or cyclin Cln3. Overall, our data indicate the crucial role of chaperone malfunction in setting lifespan in yeast cells, and configure a molecular pathway whereby proteostasis breakdown acts as a direct effector of cell senescence.

cell biology↗

bioRxiv2018

Nucleolar stress triggers the irreversible cell cycle slow down leading to cell death during replicative aging in Saccharomyces cerevisiae

The accumulation of Extrachromosomal rDNA Circles (ERCs) and their asymmetric segregation upon division have been hypothesized to be responsible for replicative senescence in mother yeasts and rejuvenation in daughter cells. However, it remains unclear by which molecular mechanisms ERCs would trigger the irreversible cell cycle slow-down leading to cell death. We show that ERCs accumulation is concomitant with a nucleolar stress, characterized by a massive accumulation of pre-rRNAs in the nucleolus, leading to a loss of nucleus-to-cytoplasm ratio, decreased growth rate and cell-cycle slow-down. This nucleolar stress, observed in old mothers, is not inherited by rejuvenated daughters. Unlike WT, in the long-lived mutant fob1{triangleup}, a majority of cells is devoid of nucleolar stress and does not experience replicative senescence before death. Our study provides a unique framework to order the successive steps that govern the transition to replicative senescence and highlights the causal role of nucleolar stress in cellular aging.

cell biology↗