Biology subjects

Janssens, G.

Publications and source records attributed to Janssens, G..

4 recordsLinked to original sources

bioRxiv2019

Mitochondrial translation and dynamics synergistically extend lifespan in C. elegans through HLH-30

Mitochondrial form and function, such as translation, are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, which is accompanied by a fragmented mitochondrial network. However, the causality between mitochondrial translation and morphology in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by either blocking fission or fusion synergizes with the reduced mitochondrial translation to substantially prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous abrogation of fission and fusion reverses the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic connections between mitochondrial translation and dynamics in regulating longevity. SUMMARYMitochondrial form and function are intimately intertwined. Liu et al. find the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan. This synergy is dependent on the induction of lysosome biogenesis through the nuclear localization of HLH-30.

cell biology↗

bioRxiv2018

A genome-wide screen identifies genes that suppress the accumulation of spontaneous mutations in young and aged yeast cells

To ensure proper transmission of genetic information, cells need to preserve and faithfully replicate their genome, and failure to do so leads to genome instability, a hallmark of both cancer and aging. Defects in genes involved in guarding genome stability cause several human progeroid syndromes, and an age-dependent accumulation of mutations has been observed in different organisms, from yeast to mammals. However, it is unclear if the spontaneous mutation rate changes during aging, and if specific pathways are important for genome maintenance in old cells. We developed a high-throughput replica-pinning approach to screen for genes important to suppress the accumulation of spontaneous mutations during yeast replicative aging. We found 13 known mutation suppression genes, and 31 genes that had no previous link to spontaneous mutagenesis, and all acted independently of age. Importantly, we identified PEX19, encoding an evolutionarily conserved peroxisome biogenesis factor, as an age-specific mutation suppression gene. While wild-type and pex19{Delta} young cells have similar spontaneous mutation rates, aged cells lacking PEX19 display an elevated mutation rate. This finding suggests that functional peroxisomes are important to preserve genome integrity specifically in old cells, possibly due to their role in reactive oxygen species metabolism.\n\nAuthor SummarySpontaneous mutations arise as a consequence of improper repair of DNA damage caused by intracellular (i.e. toxic by-products of normal cellular metabolism or inaccurate DNA replication) or external (e.g. UV light or chemotherapy) sources. Elevated mutagenesis is implicated in tumorigenesis, and an age-dependent accumulation of mutations has been observed in many organisms. However, it is still unclear how and at which rate mutations accumulate during aging. It is also unknown if specific mechanisms exist that protect the genome of aged cells. We developed a high-throughput, genome-wide approach to identify genes that suppress the accumulation of mutations during yeast replicative aging. Yeast replicative aging refers to the decline in viability a single cell experiences with increasing number of mitotic divisions. We identified a number of new genes that counteract the accumulation of mutations independently of age. Moreover, we discovered that PEX19, a gene involved in the biogenesis of peroxisomes, is important to prevent the accumulation of mutations in aged cells. Since PEX19 is conserved in humans, our work might help understand how human cells could better protect their genome from mutations during aging.

genetics↗

bioRxiv2018

Age-dependent deterioration of nuclear pore assembly in mitotic cells decreases transport dynamics

Nuclear transport is facilitated by the Nuclear Pore Complex (NPC) and is essential for life in eukaryotes. The NPC is a long-lived and exceptionally large structure. We asked whether NPC function is compromised in ageing mitotic cells. By imaging of single yeast cells during ageing, we show that the abundance of several NPC components and NPC assembly factors decreases while signs of misassembled NPCs appear. Consequently, nuclear permeability decreases, resulting in decreased dynamics of transcription factor shuttling and increased nuclear compartmentalisation. In support that declining NPC quality control is important in mitotic ageing, we find that the transport kinetics observed in ageing is mimicked in an NPC assembly mutant. Additionally, the single cell life histories reveal that cells that better maintain NPC function are longer lived. We conclude that assembly and quality control of NPCs are major challenges for ageing mitotic cells.

cell biology↗

bioRxiv2018

Saccharomyces cerevisiae goes through distinct metabolic phases during its replicative lifespan

A comprehensive description of the phenotypic changes during cellular aging is key towards unraveling its causal forces. Using recently developed experimental tools, which previously had enabled us to map age related changes in proteome and transcriptome (Janssens et al., 2015), and model-based inference methods, here, we generated a comprehensive account of the metabolic changes during the entire replicative life of Saecharomyces cerevisiae. With age, we found decreasing metabolite levels, decreasing growth and substrate uptake rates accompanied by a switch from aerobic fermentation to a respiratory metabolism, with increased glycerol and acetate production. The identification of intracellular metabolic fluxes revealed an increase in redox cofactor turnover, likely to combat the increased production of reactive oxygen species. The identified metabolic changes possibly reflect a dynamic adaptation to the age-associated, non- homeostatic increase in volume. With metabolism being an important factor of the cellular phenotype, this work complements our recent mapping of the transcriptomic and proteomic changes towards a holistic description of the cellular processes during aging.

cell biology↗