bims-mecosi 2026-02-01 papers

Issue of 2026–02–01
seven papers selected by
Verena Kohler, Umeå University

Curr Issues Mol Biol. 2026 Jan 12. pii: 75. [Epub ahead of print]48(1):

Mitochondria-Associated Endoplasmic Reticulum Membrane Biomarkers in Coronary Heart Disease and Atherosclerosis: A Transcriptomic and Mendelian Randomization Study.

Junyan Zhang, Ran Zhang, Li Rao, Chenyu Tian, Shuangliang Ma, Chen Li, Yong He, Zhongxiu Chen.

BACKGROUND: Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide. Mitochondria-associated endoplasmic reticulum membranes (MAMs) have recently emerged as critical mediators in cardiovascular pathophysiology; however, their specific contributions to CHD pathogenesis remain largely unexplored.
OBJECTIVE: This study aimed to identify and validate MAM-related biomarkers in CHD through integrated analysis of transcriptomic sequencing data and Mendelian randomization, and to elucidate their underlying mechanisms.
METHODS: We analyzed two gene expression microarray datasets (GSE113079 and GSE42148) and one genome-wide association study (GWAS) dataset (ukb-d-I9_CHD) to identify differentially expressed genes (DEGs) associated with CHD. MAM-related DEGs were filtered using weighted gene co-expression network analysis (WGCNA). Functional enrichment analysis, Mendelian randomization, and machine learning algorithms were employed to identify biomarkers with direct causal relationships to CHD. A diagnostic model was constructed to evaluate the clinical utility of the identified biomarkers. Additionally, we validated the two hub genes in peripheral blood samples from CHD patients and normal controls, as well as in aortic tissue samples from a low-density lipoprotein receptor-deficient (LDLR-/-) atherosclerosis mouse model.
RESULTS: We identified 4174 DEGs, from which 3326 MAM-related DEGs (DE-MRGs) were further filtered. Mendelian randomization analysis coupled with machine learning identified two biomarkers, DHX36 and GPR68, demonstrating direct causal relationships with CHD. These biomarkers exhibited excellent diagnostic performance with areas under the receiver operating characteristic (ROC) curve exceeding 0.9. A molecular interaction network was constructed to reveal the biological pathways and molecular mechanisms involving these biomarkers. Furthermore, validation using peripheral blood from CHD patients and aortic tissues from the Ldlr-/- atherosclerosis mouse model corroborated these findings.
CONCLUSIONS: This study provides evidence supporting a mechanistic link between MAM dysfunction and CHD pathogenesis, identifying candidate biomarkers that have the potential to serve as diagnostic tools and therapeutic targets for CHD. While the validated biomarkers offer valuable insights into the molecular pathways underlying disease development, additional studies are needed to confirm their clinical relevance and therapeutic potential in larger, independent cohorts.

Keywords: Mitochondria-associated endoplasmic reticulum membranes (MAMs); coronary heart disease; diagnostic model; machine learning; mendelian randomization

DOI: https://doi.org/10.3390/cimb48010075

Int J Mol Sci. 2026 Jan 08. pii: 630. [Epub ahead of print]27(2):

Cystinosis and Cellular Energy Failure: Mitochondria at the Crossroads.

Francesco Bellomo, Domenico De Rasmo.

Cystinosis is a rare lysosomal storage disorder characterized by defective cystine transport and progressive multi-organ damage, with the kidney being the primary site of pathology. In addition to the traditional perspective on lysosomal dysfunction, recent studies have demonstrated that cystinosis exerts a substantial impact on cellular energy metabolism, with a particular emphasis on oxidative pathways. Mitochondria, the central hub of ATP production, exhibit structural abnormalities, impaired oxidative phosphorylation, and increased reactive oxygen species. These factors contribute to proximal tubular cell failure and systemic complications. This review highlights the critical role of energy metabolism in cystinosis and supports the emerging idea of organelle communication. A mounting body of evidence points to a robust functional and physical association between lysosomes and mitochondria, facilitated by membrane contact sites, vesicular trafficking, and signaling networks that modulate nutrient sensing, autophagy, and redox balance. Disruption of these interactions in cystinosis leads to defective mitophagy, accumulation of damaged mitochondria, and exacerbation of oxidative stress, creating a vicious cycle of energy failure and cellular injury. A comprehensive understanding of these mechanisms has the potential to reveal novel therapeutic avenues that extend beyond the scope of cysteamine, encompassing strategies that target mitochondrial health, enhance autophagy, and restore lysosome-mitochondria communication.

Keywords: bioenergetics; cAMP; cysteamine; cystinosis; flavonoids; ketogenic diet; lysosomal storage diseases; mitochondria; mitophagy

DOI: https://doi.org/10.3390/ijms27020630

FEBS J. 2026 Jan 29.

ER proteostasis meets mitochondrial function: contact sites as hubs of communication and therapeutic targets.

Giorgia Maria Renna, Alessandro Cherubini, Ersilia Varone, Serena Germani, Alice Marrazza, Ester Zito.

Proteostasis maintains the balance between protein synthesis, folding, and degradation within the endoplasmic reticulum (ER). This quality-control system ensures that proteins undergo proper post-translational modifications-such as PDI-ERO1-mediated oxidative folding and STT3-dependent N-glycosylation-so that only correctly folded proteins proceed through the secretory pathway. Impairment of protein load, folding capacity, or degradation via the ER-associated degradation (ERAD) pathway leads to the accumulation of unfolded proteins, triggering ER stress and activating the unfolded protein response (UPR), which, in the first instance, is an adaptive signaling network designed to restore homeostasis by adjusting protein synthesis, enhancing folding capacity, and promoting the clearance of misfolded proteins. During ER stress, the ER undergoes morphological and functional remodeling to manage the increased folding burden, including an increase of ER-mitochondria contact sites (ERMCs). These nanometric junctions (~10-100 nm) facilitate lipid and metabolite exchange and mediate calcium and reactive oxygen species signaling to support cellular metabolism. However, chronic ER stress can further tighten ERMCs, leading to calcium overload, mitochondrial dysfunction, and apoptosis. This review examines the core mechanisms underlying ER proteostasis in the context of ER stress and explores how ER stress first boosts mitochondrial activity and later impairs it through ERMCs, contributing to cell death and disease. Finally, emerging therapeutic strategies aimed at restoring proteostasis and modulating the dynamics of ERMCs are highlighted as promising interventions for conditions, such as cancer and congenital myopathies, where ER and mitochondrial dysfunction play central roles in pathogenesis.

Keywords: ERMC; cancer; mitochondria metabolism; neuromuscular diseases; proteostasis

DOI: https://doi.org/10.1111/febs.70431

J Cell Biol. 2026 Apr 06. pii: e202502035. [Epub ahead of print]225(4):

Landscape expansion microscopy reveals interactions between membrane and phase-separated organelles.

Yinyin Zhuang, Zhao Zhang, Zhipeng Dai, Xiaoyu Shi.

Landscape expansion microscopy (land-ExM) is a light microscopy technique that visualizes both the lipid and protein ultrastructural context of cells. Achieving this level of detail requires both superresolution and a high signal-to-noise ratio. Although expansion microscopy (ExM) provides superresolution, obtaining high signal-to-noise images of both proteins and lipids remains challenging. land-ExM overcomes this limitation by using self-retention trifunctional anchors to significantly enhance protein and lipid signals in expanded samples. This improvement enables the accurate visualization of diverse membrane organelles and phase separations, as well as the 3D visualization of their contact sites. As a demonstration, we revealed triple-organellar contact sites among the stress granule, the nuclear tunnel, and the nucleolus. Overall, land-ExM offers a high-contrast superresolution platform that advances our understanding of how cells spatially coordinate interactions between membrane organelles and phase separations.

DOI: https://doi.org/10.1083/jcb.202502035

Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00028-6. [Epub ahead of print]

Mitochondria as sources and targets of cellular signaling.

Anna Meichsner, Verian Bader, Konstanze F Winklhofer.

Mitochondria are multifunctional organelles that, in addition to providing energy, coordinate various signaling pathways essential for maintaining cellular homeostasis. Their suitability as signaling organelles arises from a unique combination of structural and functional plasticity, allowing them to sense, integrate, and respond to a wide variety of cellular cues. Mitochondria are highly dynamic-they can fuse and divide, pinch off vesicles, and move around, facilitating interorganellar communication. Moreover, their ultrastructural peculiarities enable tight regulation of fluxes across the inner and outer mitochondrial membranes. As organelles of proteobacterial origin, mitochondria harbor danger signals and require protection from the consequences of membrane damage by efficient quality control mechanisms. However, mitochondria have also been co-opted by eukaryotic cells to react to cellular damage and promote effective immune responses. In this review, we provide an overview of our current knowledge of mitochondria as both sources and targets of cellular signaling.

Keywords: ISR; MAVS; NEMO; NF-κB; UPRmt; cGAS/STING; cardiolipin; inflammation; innate immune signaling; membrane contact sites; mitochondria; mtDNA; mtRNA; signaling

DOI: https://doi.org/10.1016/j.molcel.2026.01.008

BMC Microbiol. 2026 Jan 28.

Vacuole and mitochondria patch (vCLAMP) protein Mcp1 reduces the pathogenesis of Candida albicans by impeding the function of Cap1-mediated oxidative stress response.

Yunyun Wei, Xiaolong Mao.

BACKGROUND: Vacuole and mitochondria patch (vCLAMP) is a novel organelle membrane contact site. The vCLAMP protein Mcp1 plays a crucial role in cellular signaling and homeostasis. However, its role in the virulence of Candida albicans remains to be elucidated.
RESULTS: This study explored the function of Mcp1 in the oxidative stress response of C. albicans. Fluorescence co-localization and immune transmission electron microscopy results suggested that Mcp1 was located on vacuolar and mitochondrial membranes. RNA sequencing and Gene Ontology enrichment analyses showed that the deletion of MCP1 inhibited the expression of genes related to the oxidative stress response, such as GLR1, TRR1, and SOD2, in C. albicans. In addition, the deletion of MCP1 diminished the activity of antioxidant enzymes. Further studies found that MCP1 deletion impeded the phosphorylation and nuclear localization of the transcription factor Cap1, leading to an increase in intracellular reactive oxygen species (ROS) levels. The elevated ROS levels impaired mitochondrial function and morphology and reduced hyphal development and biofilm formation. Notably, the continuous expression of phosphorylated Cap1 in MCP1 deletion strains could restore the expression level of GLR1. Furthermore, a mouse model revealed that the deletion of MCP1 reduced the ability of C. albicans to infect the host.
CONCLUSION: This study reveals that the vCLAMP protein Mcp1 plays an essential role in the hyphal development and virulence of C. albicans via the Cap1-mediated oxidative stress response, which provides a promising drug target for the treatment of Candida infections.

Keywords: Candida albicans ; Mcp1; Organelle membranes; Oxidative stress response; vCLAMP

DOI: https://doi.org/10.1186/s12866-026-04767-5

J Cell Mol Med. 2026 Feb;30(3): e71014

TRPM8 Regulates Mitochondrial Ca2+-Dynamics, Temperature and Endoplasmic Reticulum-Mitochondrial Contact Points in T Cell.

Tusar Kanta Acharya, Shamit Kumar, Tejas Pravin Rokade, Parnasree Mahapatra, Young Tae Chang, Chandan Goswami.

TRPM8 is a cold temperature-sensitive and non-selective Ca2+-channel. Previously we have observed that TRPM8 is endogenously expressed and affects T cell activation process. Now, we report that TRPM8 regulates functions of mitochondria and ER, two important sub-cellular compartments. Pharmacological modulation of TRPM8 and/or due to TCR-treatment regulates mitochondrial Ca2+, ATP, membrane potential, cardiolipin level and mitochondrial temperature in a context-dependent manner. In addition, TRPM8 alters the relative temperature of mitochondria and ER, ER-mitochondrial contact points, mainly at the immunological synapse (IS), and thus TRPM8 has the potential to affect the overall cellular functions. Our data suggests both, i.e., the presence and enrichment of TRPM8 in the IS of T cells. We suggest that TRPM8 is a crucial regulator of Ca2+-signalling in T cells and significantly contributes to Ca2+-buffering by modulating cellular and sub-cellular organelle functions. These findings are useful to understand the functions of T cells in different pathological conditions.

Keywords: Ca2+‐buffering; T‐cell activation; immune regulation; immune synapse; metabolism; mitochondria; sub‐cellular organelle temperature

DOI: https://doi.org/10.1111/jcmm.71014