bims-cesemi 2026-01-18 papers

Issue of 2026–01–18
six papers selected by
Julio Cesar Cardenas, Universidad Mayor

Cell Mol Biol Lett. 2026 Jan 11.

Mitochondria-endoplasmic reticulum contact sites in hepatocytic senescence.

Pavitra Kumar, Mohsin Hassan, Frank Tacke, Cornelius Engelmann.

Inter-organelle communication via membrane contact sites (MCSs) is essential for the efficient functioning of eukaryotic cells, facilitating coordination among approximately 20 distinct organelles, each with unique metabolic profiles. Among these interactions, mitochondria-endoplasmic reticulum (ER) contacts (MERCs) are particularly significant, encompassing about 5% of the mitochondrial surface. Key proteins involved in MERCs include inositol 1,4,5-trisphosphate receptor (IP3R), voltage-dependent anion channel (VDAC), glucose-regulated protein 75 (GRP75), Sigma1 receptor (Sig-1R), vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), protein deglycase DJ-1, and protein tyrosine phosphatase interacting protein 51 (PTPIP51), with new proteins continually being identified for their roles in these structures. At these contact sites, metabolic exchanges involve calcium (Ca2+), lipids, reactive oxygen species (ROS), and proteins. MERCs enable efficient molecular exchanges through temporary bridges mainly formed by the ER, the organelle with the largest surface area. These contacts are crucial for maintaining mitochondrial dynamics, which is essential for cellular homeostasis, and they are notably impacted in pathological states such as metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver diseases (ALD), and viral hepatitis. Dysfunctional MERCs can lead to mitochondrial fragmentation, increased ROS production, impaired autophagy, and disrupted protein trafficking, thereby exacerbating senescence and cellular aging. Senescence is a cell fate initiated by stress, characterized by stable cell-cycle arrest and a hypersecretory state, and is an underlying cause of aging and many chronic conditions, including liver diseases. The hallmarks of senescence-such as macromolecular damage, cell cycle withdrawal, deregulated metabolism, and a secretory phenotype-are well established. However, recent studies have demonstrated that senescence is a heterogeneous process, with molecular markers varying according to the stressors that induce it. This review focuses on the functional aspects of MERCs in hepatic senescence and their impact on liver diseases, and explores the potential of targeting MERCs to address hepatocytic senescence.

Keywords: Calcium; Contact sites; ER; Hepatocyte; MERCs; Mitochondria; Senescence

DOI: https://doi.org/10.1186/s11658-025-00809-4

Nat Commun. 2026 Jan 15.

Inactive ryanodine receptors sustain lysosomal availability for autophagy by promoting ER-lysosomal contact site formation.

Tim Vervliet, Jens Loncke, Marko Sever, Karan Ahuja, Chris Van den Haute, Tomas Luyten, Grace E Stutzmann, Catherine Verfaillie, Tihomir Tomašič, Geert Bultynck.

Lysosomal and endoplasmic reticulum (ER) Ca2+ release mutually influence each other's functions. Recent work revealed that ER-located ryanodine receptor(s) (RyR(s)) Ca2+ release channels suppress autophagosome turnover by the lysosomes. In familial Alzheimer's disease, inhibiting RyR hyperactivity restored autophagic flux by normalizing lysosomal vacuolar H+-ATPase (vATPase) levels. However, the mechanisms by which RyRs control lysosomal function and how this involves the vATPase remain unknown. Here, we show that RyRs interact with the ATP6v0a1 subunit of the vATPase, contributing to ER-lysosomal contact site formation. This interaction suppresses RyR-mediated Ca²⁺ release, leading to reduced lysosomal exocytosis. Pharmacological inhibition of RyR activity mimics these effects on lysosomal exocytosis. Retaining lysosomes inside cells via RyR inhibition increases ER-lysosomal contact site formation, rendering lysosomes more available for autophagic flux. In summary, these findings establish RyR/ATP6v0a1 complexes as ER-lysosomal tethers that dynamically and Ca2+ dependently regulate the intracellular availability of lysosomes to participate in autophagic flux.

DOI: https://doi.org/10.1038/s41467-025-68054-z

Nature. 2026 Jan 14.

Cancer might evade immune defences by stealing mitochondria.

Laura Dattaro.

Keywords: Cancer; Immunology; Metabolism

DOI: https://doi.org/10.1038/d41586-026-00123-9

FEBS J. 2026 Jan 16.

A perilysosomal feedforward mechanism regulates starvation-induced calcium signaling.

Jennifer Giles, Abbie Sesker, Marcos Gonzalez, Abel Ferow, Elizabeth McConnaha, Quang-Kim Tran.

Nutrient depletion triggers a starvation-induced calcium (Ca2+) signal (SICS) that promotes Ca2+-dependent responses. However, the components and regulations of SICS are unclear. Here, we explored SICS components and their regulation by the Ca2+ sensor calmodulin (CaM). Overexpression of the stromal interaction molecule 1 (STIM1), a key switcher of store-operated Ca2+ entry (SOCE), enhances SICS by fourfold. This effect is abolished by the truncation of the Ca2+-binding loop within STIM1. Consistently, SOCE inhibition strongly suppresses SICS. Nutrient removal or stimulation of the transient receptor potential mucolipin-1 (TRPML1, encoded by the Mcoln1 gene) triggers intracellular Ca2+ release that is prevented by pre-emptying of endoplasmic reticulum (ER) Ca2+. In the presence of extracellular Ca2+, inhibition and silencing of Mcoln1 reduces SICS by 35-40%. We identified a CaM-binding site in the second cytoplasmic loop of TRPML1 that interacts with Ca2+-bound CaM. Mcoln1 overexpression enhances the upstroke and peak of SICS, effects that are absent with a mutated CaM-binding domain. Further, we generated a genetically encoded biosensor for TRPML1 (BS-ML1). BS-ML1 produces a robust signal upon nutrient deprivation, which is substantially reduced with the Mcoln1 mutant. The response of BS-ML1 to nutrient depletion is equally reduced by extracellular Ca2+ removal or SOCE inhibition. Reduced CaM availability significantly prolongs SICS, consistent with an ~40% reduction in cytoplasmic Ca2+ removal rate. Our data thus indicate that (1) SICS comprises multiple components, including linked Ca2+ release from the lysosome and ER and subsequent SOCE; and (2) CaM regulates the kinetics and magnitude of SICS by controlling cytoplasmic Ca2+ removal and a perilysosomal feedforward mechanism that promotes TRPML1 activity. The dynamics of this feedforward mechanism likely regulate subsequent tissue responses to nutrient starvation.

Keywords: SOCE; TRPML1; calcium; calmodulin; nutrient starvation

DOI: https://doi.org/10.1111/febs.70406

Nat Metab. 2026 Jan 15.

The differential impact of three different NAD+ boosters on circulatory NAD and microbial metabolism in humans.

Stefan Christen, Karine Redeuil, Laurence Goulet, Maria-Pilar Giner, Isabelle Breton, Riccardo Rota, Adrien Frézal, Atiye Nazari, Pieter Van den Abbeele, Jean-Philippe Godin, Sophie Nutten, Bernard Cuenoud.

Nicotinamide adenine dinucleotide (NAD(H)) and its phosphorylated form NADP(H) are vitamin B3-derived redox cofactors essential for numerous metabolic reactions and protein modifications. Various health conditions are associated with disturbances in NAD+ homeostasis. To restore NAD+ levels, the main biosynthetic pathways have been targeted, with nicotinamide (Nam), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) being the most prominent boosters. However, while many preclinical studies have examined the effects of these precursors, a direct comparison in humans is lacking, and recent rodent research suggests that the NAD+-boosting effects of NR and NMN may depend on their microbial conversion to nicotinic acid (NA), a mechanism not yet confirmed in humans. Here we show in a randomized, open-label, placebo-controlled study in 65 healthy participants that 14 days of supplementation with NR and NMN, but not Nam, comparably increases circulatory NAD+ concentrations in healthy adults. Unlike the chronic effect, only Nam acutely and transiently affects the whole-blood NAD+ metabolome. Using ex vivo fermentation with human microbiota, we identify that NR and NMN give rise to NA and specifically enhance microbial growth and metabolism. We further demonstrate ex vivo in whole blood that NA is a potent NAD+ booster, while NMN, NR and Nam are not. Ultimately, we propose a gut-dependent model for the modes of action of the three NAD+ precursors with NR and NMN elevating circulatory NAD+ via the Preiss-Handler pathway, while rapidly absorbed Nam acutely affects NAD+ levels via the salvage pathway. Overall, these results indicate a dual effect of NR and NMN and their microbially produced metabolite NA: a sustained increase in systemic NAD+ levels and a potent modulator of gut health. ClinicalTrials.gov identifier: NCT05517122 .

DOI: https://doi.org/10.1038/s42255-025-01421-8