Biology subjects

Ermolaeva, M.

Publications and source records attributed to Ermolaeva, M..

5 recordsLinked to original sources

bioRxiv2024

Circadian clock disruption engages the DREAM complex in suppressing cellular health.

Circadian clock disruption and lack of sleep impair organismal health, but remedies remain elusive. Here, we used multi-omics, molecular and functional assays in C. elegans, human retinal cells and mouse brain to identify the DREAM complex as a conserved mediator of sleep and clock benefits at the cellular level. We show that DREAM abundance is under circadian control with high levels seen during wakefulness. DREAM elevation confers increased chromatin compaction and shields DNA from damage while altering fundamental cellular processes such as translation, stress responses and OXPHOS. Conversely, DREAM levels are lowered during sleep enabling cellular maintenance and repair. When sleep or clock are altered, DREAM levels remain high, and repair activities remain suppressed triggering cellular and organismal deterioration that can be reversed by genetic and pharmacological inhibition of DREAM in vivo and in vitro. We thus reveal the potential of DREAM inhibitors to replicate the benefits of sleep in sleep-deprived and clock-impaired organisms.

physiology↗

bioRxiv2024

Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.

Mitochondrial dysfunction is a prominent hallmark of aging contributing to the functional decline of metabolic plasticity in late life. While genetic distortions of mitochondrial integrity elicit premature aging, the mechanisms leading to "natural" aging of mitochondria are less clear. Here we initially used proteomics, genetics and functional tests in wild type C. elegans and long-lived clk-1(qm30) and isp-1(qm150) mitochondrial mutants to identify molecular pathways that safeguard longevity amid persistent mitochondrial inefficiency. Strikingly, these analyses and subsequent transcriptomic and functional tests in the human system revealed aging-associated decline of phosphatidylcholine (PC) synthesis as a trigger of mitochondrial network disruption, which contributes to mitochondrial dysfunction during normal aging. Moreover, we found that ectopic boosting of PC levels via diet restores late life mitochondrial integrity in vivo and rescues metabolic plasticity in cell culture tests. Our work thus uncovered a novel natural driver of mitochondrial aging that is malleable by dietary interventions.

cell biology↗

bioRxiv2024

Ultraviolet B acts as a dietary restriction mimetic by targeting mitochondrial bioenergetics.

Ultraviolet (UV) light is a common environmental stimulus, and UV exposure confers health benefits, with cellular targets still unclear. Here, we show that ultraviolet B (UVB) exposure alters mitochondrial bioenergetics in C. elegans and human skin fibroblasts triggering loss of membrane potential, mitochondrial fission and calcium release. This initial stress is followed by a recovery process relying on mitochondrial biogenesis and fusion, which prevents lasting mitochondrial damage. Strikingly, the transient decline of ATP synthesis caused by UVB-induced mitochondrial changes triggers a swift metabolic re-wiring response that resembles effects of dietary restriction (DR) at the organismal and molecular levels. Both recovery from UVB and DR-mimetic UVB effects require mitochondrial fusion, and we found that dysfunction of fusion during aging abrogates UVB benefits and sensitizes old nematodes to UVB toxicity. Finally, UVB irradiation of the skin was effective in inducing organismal fasting-like phenomena in proof-of-concept tests in young mice. We thus uncovered a novel evolutionary conserved cellular mechanism connecting UV light and metabolism. Our findings illuminate potential DR-mimetic properties of UVB and explain late life-specific UVB intolerance.

cell biology↗

bioRxiv2019

Late life metformin treatment limits cell survival and shortens lifespan by triggering an aging-associated failure of energy metabolism.

The diabetes drug metformin is to be clinically tested in aged humans to achieve health span extension, but little is known about responses of old non-diabetic individuals to this drug. By in vitro and in vivo tests we found that metformin shortens life span and limits cell survival when provided in late life, contrary to its positive early life effects. Mechanistically, metformin exacerbates aging-associated mitochondrial dysfunction towards respiratory failure, aggravated by the inability of old cells to upregulate glycolysis in response to metformin, leading to ATP exhaustion. The beneficial dietary restriction effect of metformin on lipid reserves is abrogated in old animals, contributing to metabolic failure, while ectopic stabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo. The toxicity is also suspended in nematodes carrying diabetes-like insulin receptor insufficiency and showing prolonged resilience to metabolic stress induced by metformin. In sum, we uncovered an alarming metabolic decay triggered by metformin in late life which may limit its benefits for non-diabetic elderly patients. Novel regulators of life extension by metformin are also presented. HighlightsO_LILate life metformin treatment limits cell survival and shortens lifespan. C_LIO_LIMetformin exacerbates aging-associated mitochondrial dysfunction causing fatal ATP exhaustion. C_LIO_LIOld cells fail to upregulate glycolysis as a compensatory response to metformin. C_LIO_LIThe dietary restriction (DR) mimetic response to metformin is abrogated in old animals. C_LIO_LIPKA and not AMPK pathway instigates the early life DR response to metformin. C_LIO_LIStabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo. C_LI

physiology↗

bioRxiv2017

Species comparison of liver proteomes reveals enhanced lipid metabolism, reduced mitochondrial respiration and enhanced expression of detoxifying enzymes in the long-lived naked mole-rat.

Mammals display wide range of variation in their lifespan. Investigating the molecular networks that distinguish long-from short-lived species has proven useful to identify determinants of longevity. Here, we compared the liver of long-lived naked mole-rats (NMRs) and the phylogenetically closely related, shorter-lived, guinea pigs using an integrated omic approach. We found that NMRs livers display a unique expression pattern of mitochondrial proteins that result in distinct metabolic features of their mitochondria. For instance, we observed a generally reduced respiration rate associated with lower protein levels of respiratory chain components, particularly complex I, and increased capacity to utilize fatty acids. Interestingly, we show that the same molecular networks are affected during aging in both NMR and humans, supporting a direct link to the extraordinary longevity of both species. Finally, we identified a novel longevity pathway and validated it experimentally in the nematode C. elegans.

systems biology↗