The role of lipoylation in mitochondrial adaptation to methionine restriction

BioEssays, Год журнала: 2024, Номер 46(6)

Опубликована: Апрель 14, 2024

Abstract Dietary methionine restriction (MR) is associated with a spectrum of health‐promoting benefits. Being conducive to prevention chronic diseases and extension life span, MR can activate integrated responses at metabolic, transcriptional, physiological levels. However, how the mitochondria influence metabolic phenotypes remains elusive. Here, we provide summary cellular functions metabolism an overview current understanding effector mechanisms MR, focus on aspect mitochondria‐mediated responses. We propose that sense respond through modulatory role lipoylation, mitochondrial protein modification sensitized by MR.

Язык: Английский

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Predicting substrates for orphan Solute Carrier Proteins using multi-omics datasets

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 24, 2024

Abstract Solute carriers (SLC) are integral membrane proteins responsible for transporting a wide variety of metabolites, signaling molecules and drugs across cellular membranes. Despite key roles in metabolism, pharmacology, around one third SLC ‘orphans’ whose substrates unknown. Experimental determination is technically challenging given the range possible physiological candidates. Here, we develop predictive algorithm to identify correlations between expression levels intracellular metabolite concentrations by leveraging existing cancer multi-omics datasets. Our predictions recovered known SLC-substrate pairs with high sensitivity specificity compared simulated random pairs. CRISPR loss-of-function screen data metabolic pathway adjacency further improved performance our algorithm. In parallel, combined drug profiles predict new SLC-drug interactions. Together, provide novel bioinformatic pipeline substrate SLCs, offering opportunities de-orphanise SLCs important implications understanding their health disease.

Язык: Английский

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Predicting substrates for orphan Solute Carrier Proteins using multi- omics datasets

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Авг. 5, 2024

Solute carriers (SLC) are integral membrane proteins responsible for transporting a wide variety of metabolites, signaling molecules and drugs across cellular membranes. Despite key roles in metabolism, pharmacology, around one third SLC ‘orphans’ whose substrates unknown. Experimental determination is technically challenging given the range possible physiological candidates. Here, we develop predictive algorithm to identify correlations between expression levels intracellular metabolite concentrations by leveraging existing cancer multi-omics datasets. Our predictions recovered known SLC-substrate pairs with high sensitivity specificity compared simulated random pairs. CRISPR loss-of-function screen data metabolic pathway adjacency further improved performance our algorithm. In parallel, combined drug profiles predict new SLC-drug interactions. Together, provide novel bioinformatic pipeline substrate SLCs, offering opportunities de-orphanise SLCs important implications understanding their health disease.

Язык: Английский

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Accumulation of S-adenosyl-L-homocysteine impairs methylation and development in Saccharomyces cerevisiae and Drosophila melanogaster

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Сен. 24, 2024

S-adenosyl-L-homocysteine (SAH), the product inhibitor of S-adenosyl-L-methionine (SAM)-dependent methyltransferases, and its degradation homocysteine (Hcy) are evolutionarily conserved master regulators methylation metabolism. They can affect more than 200 methyltransferases in humans interfering with numerous methylation-dependent processes. Hyperhomocysteinemia (HHcy), characterized by elevated Hcy levels blood, is an independent risk factor for atherosclerosis a strong predictor cardiovascular mortality, yet, mechanisms which contributes to pathological consequences remain poorly understood. Here we developed Drosophila dietary HHcy model, as well genetic SAH hydrolase (SAHH) in vivo knockdown model compared them corresponding yeast models reveal developmental effects pattern changes. Feeding Hcy-containing diet or growing on Hcy-supplemented medium similarly genetically blocking leads accumulation, delay growth defects. Furthermore, supplementation induced accumulation impaired protein phospholipid (PL) both organisms. While total arginine significantly decreased wild type grown presence ∆sah1 mutant, it unaffected larvae raised diet. In contrast, histone affected yeast, but exhibited differences responses particular sites. Similarly, PL was reduced organisms resulted deregulation lysoPL metabolism suggesting remodeling. Functional characterization evolutionary Hcy/SAH-dependent targets will toxicity may be operative HHcy-associated human pathologies.

Язык: Английский

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Fantastic proteins and where to find them – histones, in the nucleus and beyond

Journal of Cell Science, Год журнала: 2024, Номер 137(24)

Опубликована: Дек. 15, 2024

Animal genomes are packaged into chromatin, a highly dynamic macromolecular structure of DNA and histone proteins organised nucleosomes. This accommodates packaging lengthy genomic sequences within the physical confines nucleus while also enabling precise regulation access to genetic information. However, histones existed before chromatin have lesser-known functions beyond genome regulation. Most notably, potent antimicrobial agents, release extracellular space is defence mechanism nearly as ancient widespread itself. Histone changed very little throughout evolution, suggesting possibility that some their 'non-canonical' at play in parallel or concert with regulatory functions. In this Review, we take an evolutionary perspective histone, nuclear biology describe known extranuclear histones. We detail molecular mechanisms sensing, discuss roles physiology disease. Finally, present evidence give on potential act bioactive, cell modulatory factors.

Язык: Английский

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