Biology subjects

Penkov, S.

Publications and source records attributed to Penkov, S..

4 recordsLinked to original sources

bioRxiv2022

Activation of mTOR by release of extracellular cholesterol stores controls the transition from quiescence to growth in C. elegans

Recovery from the quiescent developmental stage called dauer is an essential process in C. elegans and provides an excellent model to understand how metabolic transitions contribute to developmental plasticity. We here show that the depletion of sterol-binding proteins SCL-12 and SCL-13 is the key change in the C. elegans proteome in early dauer recovery. This process releases a cholesterol store that is sequestered in the gut lumen during the dauer state to facilitate the transition into reproductive development. First, the stored cholesterol undergoes endocytosis into the lysosomes of the intestinal cells, where it activates mTOR to promote protein synthesis and growth. Second, it is used for the production of dafachronic acids that switch metabolic programs at the transcriptional level. These processes are essential for population fitness and survival, as loss of SCL-12 and SCL-13, depletion of sterols, and loss of mTOR precludes quiescence exit, ultimately leading to the expiration of the entire population.

cell biology↗

bioRxiv2021

Periodic ethanol supply as a path towards unlimited lifespan of C.elegans dauer larvae

The dauer larva is a specialized stage of development optimized for survival under harsh conditions that has been used as a model for stress resistance, metabolic adaptations, and longevity. Recent findings suggest that the dauer larva of C.elegans may utilize external ethanol as an energy source to extend their lifespan. It was shown that while ethanol may serve as an effectively infinite source of energy, some toxic compounds accumulating as byproducts of its metabolism may lead to the damage of mitochondria and thus limit the lifespan of larvae. A minimal mathematical model was proposed to explain the connection between the lifespan of dauer larva and its ethanol metabolism. To explore theoretically if it is possible to extend even further the lifespan of dauer larvae, we incorporated two natural mechanisms describing the recovery of damaged mitochondria and elimination of toxic compounds, which were previously omitted in the model. Numerical simulations of the revised model suggest that while the ethanol concentration is constant, the lifespan still stays limited. However, if ethanol is supplied periodically, with a suitable frequency and amplitude, the dauer could survive as long as we observe the system. Analytical methods further help to explain how the feeding frequency and amplitude affect the lifespan extension. Based on comparison of the model with experimental data for fixed ethanol concentration, we propose the range of feeding protocols that could lead to even longer dauer survival and can be tested experimentally.

biophysics↗

bioRxiv2021

OAC-39 is an O-acyltransferase required for the synthesis of maradolipids in the dauer larva of C. elegans

Upon overcrowding or low food availability, the nematode C. elegans enters a specialized diapause stage for survival, called the dauer larva. The growth-arrested, non-feeding dauer larva undergoes a profound metabolic and physiologic switch underlying its extraordinary stress resistance and longevity. One of the metabolic signatures of dauer larvae is the accumulation of the disaccharide trehalose, which lowers the sensitivity of worms to desiccation and hyperosmotic shock. Previously, we have found that trehalose is incorporated as a headgroup into dauer-specific 6,6-di-O-acyltrehalose lipids, named maradolipids. Despite comprising a bulk fraction of the polar lipids in dauer larvae, little is known about the physiological function of maradolipds because the enzyme(s) involved in their synthesis has not yet been identified. Here, we report that the dauer-upregulated O-acyltransferase homolog OAC-39 is essential for the synthesis of maradolipids. This enzyme is enriched at the apical region of the intestinal cells of dauer larvae, where it might participate in the structuring of the gut lumen. As OAC-39 is most probably responsible for the last step of maradolipid synthesis, its identification will pave the way for the elucidation of the function of this obscure class of lipids.

biochemistry↗

bioRxiv2018

An insulin, AMPK, and steroid hormone-mediated metabolic switch regulates the transition between growth and diapause in C. elegans

The balance between growth and quiescence depends on the global metabolic state. The dauer larva of C. elegans, a developmentally arrested stage for survival under adverse environment, undergoes a major metabolic transition. Here, we show that this switch involves the concerted activity of several regulatory pathways. Whereas the steroid hormone receptor DAF-12 controls dauer morphogenesis, the insulin pathway maintains low energy expenditure through DAF-16/FoxO, which also requires AAK-2/AMPK. DAF-12 and AAK-2 separately promote a shift in the molar ratios between competing enzymes at two key branch points within the central carbon metabolic pathway. This way, carbon atoms are diverted from the TCA cycle and directed to gluconeogenesis. When both AAK-2 and DAF-12 are suppressed, the TCA cycle is active and the developmental arrest is bypassed. Hence, the metabolic status of each developmental stage is defined by stoichiometric ratios within the constellation of metabolic enzymes and controls the transition between growth and quiescence.

biochemistry↗