Biology subjects

Sedlackova, L.

Publications and source records attributed to Sedlackova, L..

3 recordsLinked to original sources

bioRxiv2026

Declines in mRNA synthesis set the rate of organismal aging

The abundance of mRNA sets a ceiling on a cells capacity to produce protein and carry out its functions. Here, we describe a pathological decline in absolute mRNA abundance that occurs in most cell types during invertebrate and mammalian aging, caused by decreases in mRNA synthesis capacity. In C. elegans, decreases in mRNA abundance are tightly coupled to declines in RNA Polymerase II (Pol II) protein abundance. Measuring Pol II abundance dynamics in vivo, we find that individuals enter adulthood with a four-fold excess of Pol II, whose kinetic equilibration towards its homeostatic set point drives reductions in mRNA abundance and, in turn, organismal aging. Briefly accelerating Pol II declines produces permanent, dose-dependent reductions in healthspan and lifespan, whereas deceleration extends both. Although disrupted cellular homeostasis is conventionally seen as a consequence of aging, our results reveal how an out-of-equilibrium state established during development provides a driving force for aging.

systems biology↗

bioRxiv2020

mTORC1 activity is supported by spatial association with focal adhesions

The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the cell periphery1-4. Here we show that translocation of lysosomes towards the cell periphery brings mTORC1 into proximity with focal adhesions (FAs). We demonstrate that FAs constitute discrete plasma membrane hubs mediating growth factor signaling and amino acid input into the cell. FAs, as well as the translocation of lysosome-bound mTORC1 to their vicinity, are necessary for both peripheral and intracellular mTORC1 activity. Conversely, lysosomal distribution to the cell periphery is dispensable for the activation of mTORC1 constitutively targeted to FAs. This study advances our understanding of spatial mTORC1 regulation by demonstrating that the localization of mTORC1 to FAs is both necessary and sufficient for its activation by growth-promoting stimuli.

cell biology↗

bioRxiv2020

Autophagy promotes cell and organismal survival by maintaining NAD(H) pools

Autophagy is an essential catabolic process that promotes clearance of surplus or damaged intracellular components1. As a recycling process, autophagy is also important for the maintenance of cellular metabolites during periods of starvation2. Loss of autophagy is sufficient to cause cell death in animal models and is likely to contribute to tissue degeneration in a number of human diseases including neurodegenerative and lysosomal storage disorders3-7. However, it remains unclear which of the many cellular functions of autophagy primarily underlies its role in cell survival. Here we have identified a critical role of autophagy in the maintenance of nicotinamide adenine dinucleotide (NAD+/NADH) levels. In respiring cells, loss of autophagy caused NAD(H) depletion resulting in mitochondrial membrane depolarisation and cell death. We also found that maintenance of NAD(H) is an evolutionary conserved function of autophagy from yeast to human cells. Importantly, cell death and reduced viability of autophagy-deficient animal models can be partially reversed by supplementation with an NAD(H) precursor. Our study provides a mechanistic link between autophagy and NAD(H) metabolism and suggests that boosting NAD(H) levels may be an effective intervention strategy to prevent cell death and tissue degeneration in human diseases associated with autophagy dysfunction.

cell biology↗