bims-celmim 2026-02-01 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2026–02–01
twelve papers selected by
Marc Segarra Mondejar, AINA

Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
Coordination of cell organelles to promote metabolon formation.
Lactylation in cancer: mechanistic insights, tumor microenvironment, and therapeutic horizons.
Silicon Rhodamine-Based Fluorescence Lifetime Probe for Dynamics Mapping Lysosomal Oxidative Stress.
Lysosomes as hubs of metabolic sensing and cellular homeostasis.
Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.
ER proteostasis meets mitochondrial function: contact sites as hubs of communication and therapeutic targets.
Mitochondria as sources and targets of cellular signaling.
Mitochondria in T‑cell tumor immunity and tumor therapies targeting mitochondria (Review).
Hyperammonemia increases the release of pathological extracellular vesicles from monocytes by impairing lysosomal function and autophagy through the TNFα-cAMP-PKA-LC3 pathway.
Ferroptosis in Alzheimer's disease: molecular mechanisms and advances in therapeutic strategies.
TUFT1 stabilizes TGF-β receptor II protein and facilitates activation of hepatic stellate cells into metastasis-promoting myofibroblasts.

J Cell Biol. 2026 Apr 06. pii: e202501023. [Epub ahead of print]225(4):

Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.

Jill E Falk, Tobias Henke, Sindhuja Gowrisankaran, Simone Wanderoy, Himanish Basu, Sinead Greally, Judith Steen, Thomas L Schwarz.

Neuronal signaling requires large amounts of ATP, making neurons particularly sensitive to defects in energy homeostasis. Mitochondrial movement and energy production are therefore regulated to align local demands with mitochondrial output. Here, we report a pathway that arrests mitochondria in response to decreases in the ATP-to-AMP ratio, an indication that ATP consumption exceeds supply. In neurons and cell lines, low concentrations of the electron transport chain inhibitor antimycin A decrease the production of ATP and concomitantly arrest mitochondrial movement without triggering mitophagy. This arrest is accompanied by the accumulation of actin fibers adjacent to the mitochondria, which serve as an anchor that resists the associated motors. This arrest is mediated by activation of the energy-sensing kinase AMPK, which phosphorylates TRAK1. This mechanism likely helps maintain cellular energy homeostasis by anchoring energy-producing mitochondria in places where they are most needed.

DOI: https://doi.org/10.1083/jcb.202501023
Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2532504123

Coordination of cell organelles to promote metabolon formation.

Zhou Sha, Anthony M Pedley, Timothy D Iles, Shaoqing Zhang, Jack R Staub, Ruobo Zhou, Stephen J Benkovic.

  The spatial coordination between cellular organelles and metabolic enzyme assemblies represents a fundamental mechanism for maintaining metabolic efficiency under stress. While previous work has shown that membrane-bound organelles regulate metabolic activities and that membrane-less condensates conduct metabolic reactions, the coordination between these two organizations remains unaddressed. By using a combination of proximity labeling, superresolution fluorescence microscopy, and metabolite analyses using isotopic tracing, we investigated the relationships between these metabolic hotspots. Here, we show that nutrient deficiency elongates mitochondria and transforms the ER from a tubular to sheet-like morphology, coinciding with increased mitochondrial respiration and inosine 5'-monophosphate levels. These structural changes promote the colocalization of purinosomes with these organelles, enhancing metabolic channeling. Disruption of ER sheet formation via MTM1 knockout destabilizes purinosomes, impairs substrate channeling, and reduces intracellular purine nucleotide pools without altering enzyme expression. Our findings reveal that organelle morphology and interorganelle contacts dynamically regulate the assembly and function of metabolic condensates, providing a structural basis for coordinated metabolic control in response to nutrient availability.

Keywords:  biomolecular condensates; cell metabolism; de novo purine biosynthesis; metabolon; purine

DOI:  https://doi.org/10.1073/pnas.2532504123
Front Immunol. 2025 ;16 1697008

Lactylation in cancer: mechanistic insights, tumor microenvironment, and therapeutic horizons.

Qiang Yang, Zhibo Yang, Hai Zhao.

  The discovery of lactylation, a post-translational modification derived from lactate, has fundamentally altered the perception of cancer metabolism. Once regarded as a metabolic waste product, lactate is now recognized as a central fuel source, a signaling molecule, and an epigenetic substrate capable of reprogramming gene expression and cellular function. Lactylation integrates metabolic reprogramming, tumor plasticity, and immune suppression, thereby orchestrating cancer initiation, progression, and resistance to therapy. This review provides a critical and integrative commentary on recent advances in lactylation biology, drawing from biochemical, epigenetic, and immunological perspectives. It synthesizes mechanistic insights into lactylation, highlights its role in tumorigenesis and the tumor microenvironment (TME), and evaluates therapeutic strategies that target lactate production, transport, and lactylation machinery. By dissecting consensus, controversies, and unresolved questions, we argue that lactylation represents both a hallmark of tumor adaptation and a potential Achilles' heel for intervention. We further discuss future research directions, including comprehensive lactylome mapping, structural biology of lactylated proteins, microbiome-derived lactate, and clinical translation. Ultimately, lactylation is not merely a byproduct of glycolysis but a metabolic language that tumors employ to communicate, adapt, and thrive. Decoding this language may open new frontiers in cancer therapy.

Keywords:  cancer immunotherapy; epigenetic regulation; histone modi7ication; immunometabolism; lactylation; therapeutic targets; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1697008
Chem Biomed Imaging. 2026 Jan 26. 4(1): 105-112

Silicon Rhodamine-Based Fluorescence Lifetime Probe for Dynamics Mapping Lysosomal Oxidative Stress.

Qingshuang Xu, Yiyan Zhang, Yuxun Tang, Senqiang Lv, Lianfeng Su, Pengfeng Mao, Pengqi Liu, Yutao Zhang, Chenxu Yan, Zhiqian Guo.

  Lysosomes are organelles responsible for cellular degradation and recycling. The detection of changes in the lysosomal microenvironment, such as viscosity, oxidative stress, and pH value, as well as their interactions among dynamic organelles, remains an intriguing field that contributes to elucidating intracellular homeostasis. Here, we describe the development of a fluorescent probe tool for uniting fluorescence lifetime imaging microscopy (FLIM) and dual-channel near-infrared (NIR) fluorescence signals, which can simultaneously monitor viscosity and reactive oxygen species (ROS) in lysosomes. SiR-Eda exhibits a viscosity-dependent fluorescence lifetime and ROS-sensitive fluorescence emission, allowing for real-time tracking of lysosomal oxidative stress and viscosity within living cells. We demonstrate the utility of SiR-Eda in detecting changes in lysosomal viscosity and ROS in response to various stimuli including oxidative stress and lysosomal dysfunction. Our probe provides a convenient wash-free multifunctional tool for investigating lysosomal biology and has potential applications in the diagnosis and treatment of lysosome-related diseases.

Keywords:  dual-mode imaging; fluorescence lifetime; lysosomes; probe; viscosity

DOI:  https://doi.org/10.1021/cbmi.5c00085
Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00031-6. [Epub ahead of print]

Lysosomes as hubs of metabolic sensing and cellular homeostasis.

Aakriti Jain, Roberto Zoncu.

  Lysosomes are hubs that couple macromolecular breakdown to cell-wide signaling by sensing metabolic, damage-associated, and environmental cues. Nutrients liberated in the lysosomal lumen as end-products of macromolecular degradation, including amino acids, lipids, and iron, are exported by dedicated transporters for utilization in the cytoplasm. Nutrient transport across the lysosomal membrane is coupled to its sensing by specialized signaling complexes on the cytoplasmic face, which, in response, mediate communication with other organelles and control cell-wide programs for growth, catabolism, and stress response. Lysosomes acquire specialized sensing-signaling features in immune cells, where they shape antigen processing, innate immune signaling, and inflammatory cell death, and in neurons, where they act as sentinels of proteostatic and mitochondrial stress, supporting local translation, organelle quality control, and neuroimmune crosstalk. We highlight recently identified pathways and players that position lysosomes as integrators of nutrient status and organelle health to drive tissue-specific physiology.

Keywords:  amyloid; autophagy; inflammation; lysosome; mTORC1; metabolites; neurodegeneration; organelle contacts; signaling

DOI:  https://doi.org/10.1016/j.molcel.2026.01.011
Elife. 2026 Jan 26. pii: RP95576. [Epub ahead of print]13

Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.

Kanako Shinno, Yuri Miura, Koichi M Iijima, Emiko Suzuki, Kanae Ando.

  Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while the cellular factors that trigger it have not been identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of protein degradation. Axons with mitochondrial depletion showed abnormal protein accumulation and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution. We found that eIF2β was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2α, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2β phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2β expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underlie the onset and progression of age-related neurodegenerative diseases.

Keywords:  D. melanogaster; aging; autophagy; cell biology; mitochondria; neuronal proteostasis; protein aggregation; proteome

DOI:  https://doi.org/10.7554/eLife.95576
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
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
Oncol Rep. 2026 Apr;pii: 59. [Epub ahead of print]55(4):

Mitochondria in T‑cell tumor immunity and tumor therapies targeting mitochondria (Review).

Minjie Zhou, Yijie Xie, Zhipeng Liu, Yi He, Yibing Yin, Keyu Chen, Zhengyu Zhao, Chengshun Zhang, Dingjun Cai.

  Mitochondria are central to cellular metabolic reprogramming, and their energy metabolism pathways are indispensable for T‑cell activation, proliferation and differentiation. Mitochondrial metabolic reprogramming enhances T‑cell activity and antitumor function. Mitochondrial dynamics, including fusion, fission and transfer, regulate T‑cell tumor immune function by modulating the number, morphology and distribution of mitochondria, which is vital for the antitumor effects of T cells. The release of mitochondrial DNA can activate multiple innate immune signaling pathways, such as cyclic GMP‑AMP synthase‑stimulator of interferon genes, Toll‑like receptor 9, and NOD‑, LRR‑, and pyrin domain‑containing protein 3, serving a complex regulatory role in shaping the tumor immunosuppressive microenvironment and T‑cell antitumor immune responses. Notably, mitochondrial dysfunction is a major driver of tumor initiation and progression. T‑cell mitochondrial metabolic reprogramming, dynamic changes and mitochondrial DNA release all affect the antitumor immunity of tumor‑infiltrating T cells. The present review focuses on the relationship between mitochondria and T‑cell antitumor immune responses, exploring the core role of mitochondria in T‑cell tumor immunity from multiple aspects, including mitochondrial energy metabolism, mitochondrial dynamics and mitochondrial DNA. In addition, the present review examines state‑of‑the‑art research on antitumor therapies targeting mitochondria from multiple perspectives, with the aim of providing a reference for developing mitochondria‑targeted antitumor immunotherapy strategies.

Keywords:  T cell; mitochondria; mitochondrial DNA; mitochondrial dynamics; mitochondrial metabolism; tumor immunity

DOI:  https://doi.org/10.3892/or.2026.9064
Front Immunol. 2025 ;16 1724800

Hyperammonemia increases the release of pathological extracellular vesicles from monocytes by impairing lysosomal function and autophagy through the TNFα-cAMP-PKA-LC3 pathway.

Maria A Pedrosa, Paula Izquierdo-Altarejos, Marta Llansola, Vicente Felipo.

   Background: Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) triggered by a shift in peripheral inflammation. A main mechanism by which peripheral alterations are transmitted to the brain is the infiltration of extracellular vesicles (EV). Hyperammonemic rats are a model of MHE that reproduces cognitive impairment. Injection of EV from plasma or peripheral blood mononuclear cells (PBMC) of hyperammonemic rats to normal rats induces neuroinflammation, alterations in neurotransmission, and cognitive impairment. PBMC contain different cell types. The aims were 1) to identify which cell type produces the pathological EV in hyperammonemic rats; 2) to identify the mechanisms by which hyperammonemia increases EV release from monocytes and induces the formation of pathological EV; and 3) to analyze the role of TNFα and PKA in these mechanisms.
Methods: EV were isolated from primary cultures of CD4+ lymphocytes or monocytes from control or hyperammonemic rats and added to hippocampal slices from control rats to assess induction of neuroinflammation and changes in neurotransmission. To assess the role of TNFα and protein kinase A (PKA) in the production of pathological EV by monocytes from hyperammonemic rats, we blocked TNFα with anti-TNFα or inhibited PKA. Lysosomal-autophagy dysfunction was assessed with LysoTracker and by analyzing cathepsin L, LAMP2, and LC3.
Results: In hyperammonemic rats, monocytes but not CD4+ lymphocytes release pathological EV. Hyperammonemia increases the EV release by monocytes and their content of TNFR1 and TNFα. These EV induce activation of glia and of the TNFα-TNFR1-S1PR2-IL-1β-CCL2-BDNF-TrkB pathway and alterations in membrane expression of NMDA and AMPA receptors in hippocampal slices from control rats. Hyperammonemia increases TNFα levels in monocytes, which increases cAMP and PKA activity and reduces LC3 content. This leads to autophagy-lysosome dysfunction, with altered LC3, cathepsin L, and LAMP2 content and pH that increases the release of EV and their TNFR1 and TNFα content. All these changes are reversed by blocking TNFα with anti-TNFα or inhibiting PKA with an inhibitor.
Conclusions: These data unveil that monocytes produce the pathological EV in hyperammonemia and the underlying mechanisms and provide the bases for new treatments to improve cognitive and motor function in hyperammonemia and MHE.

Keywords:  CD4+ T lymphocytes; TNFα; extracellular vesicles; hyperammonemia; lysosomal-autophagy dysfunction; minimal hepatic encephalopathy; monocytes; neuroinflammation

DOI:  https://doi.org/10.3389/fimmu.2025.1724800
Front Neurosci. 2025 ;19 1673315

Ferroptosis in Alzheimer's disease: molecular mechanisms and advances in therapeutic strategies.

Ze Zhou, Yiting Zhang, Siyi Liu, Haixia Tang, Lianhao Yang, Yanming Lu, Jiaobao Liao, Shuowei Zhang, Zukun Chen, Ling Yang.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized primarily by the continuous decline of cognitive functions. Its pathogenesis involves complex, multidimensional interactions among various molecular pathways. In recent years, ferroptosis, a regulated form of iron-dependent cell death, has emerged as a crucial contributor to AD progression. Ferroptosis is defined by the accumulation of lipid peroxides and inactivation of glutathione peroxidase 4 (GPX4), and is typically initiated in the context of disrupted iron homeostasis, aberrant lipid metabolism, and mitochondrial dysfunction in the brain. This review comprehensively delineates the molecular mechanisms underlying dysregulated iron metabolism in AD and proposes an integrative "iron-lipid-energy-inflammation" axis as a pathological framework. Particular attention is given to the GPX4 signaling pathway as a central hub linking lipid peroxidation, mitochondrial damage, and immune responses. Moreover, ferroptosis can propagate through intercellular mechanisms involving the release of damage-associated molecular patterns (DAMPs), dysregulation of immune checkpoints, and exosome-mediated signaling, collectively driving microglial activation, T-cell infiltration, and blood-brain barrier disruption, culminating in systemic immune imbalance. We further evaluate multiple therapeutic strategies targeting ferroptosis, including iron chelators, antioxidants, GPX4 activators, and lipoxygenase inhibitors. Based on emerging evidence, we propose a precision medicine approach that incorporates ferroptosis subtyping, multi-omics analysis, and targeted delivery systems. Ferroptosis represents a promising frontier for early diagnosis and intervention in AD, potentially enabling the development of causality-oriented, mechanism-based therapies.

Keywords:  Alzheimer’s disease; ferroptosis; glutathione peroxidase 4; immune regulation; iron homeostasis; lipid peroxidation; precision medicine

DOI:  https://doi.org/10.3389/fnins.2025.1673315
Cell Death Differ. 2026 Jan 28.

TUFT1 stabilizes TGF-β receptor II protein and facilitates activation of hepatic stellate cells into metastasis-promoting myofibroblasts.

Yue Li, Yu Shi, Yaxin Fu, Lianying Jiao, Hanqi Li, Lu Shao, Xuelian Xiao, Ningling Kang, Liankang Sun, Kangsheng Tu.

Cancer-associated fibroblasts (CAFs) transdifferentiated from hepatic stellate cells (HSCs) are a critical determinant of liver metastasis of colorectal cancer (CRC). However, the mechanisms behind transforming growth factor β (TGF-β)-stimulated activation of HSCs into CAFs remain poorly understood. Immunoprecipitation coupled with mass spectrometry identified tuftelin 1 (TUFT1) as a novel TGF-β receptor II (TβRII) binding protein in primary human HSCs and immortalized LX2 cells. TUFT1 interacts with TβRII via its fragments (amino acids 1-86, 87-157), protecting TβRII from lysosomal degradation to facilitate TGF-β signaling and myofibroblastic activation of HSCs. Mechanistically, TUFT1 competes with caveolin-1 for TβRII binding, retrieving TβRII from the lipid rafts/caveolae-mediated degradation pathway and sorting it into the endosome-mediated trafficking and signaling pathway. Clinically, TUFT1 expression was confirmed in the CAFs of patient-derived colorectal cancer liver metastasis (CRCLM) tissues. Both protein and transcript analyses revealed higher TUFT1 expression in the CAFs of CRCLM than in HSCs. Furthermore, bulk RNA sequencing indicated that knocking down TUFT1 altered the TGF-β transcriptome of HSCs and suppressed HSC expression of tumor-promoting factors. In HSC/CRC co-implantation and portal vein tumor injection mouse models, targeting TUFT1 of HSCs inhibited HSC activation and restricted CRC growth in both subcutaneous and hepatic sites. Taken together, our findings uncover the novel function of TUFT1 in the hepatic tumor microenvironment, highlighting its role as a critical regulator of HSC activation and the pro-metastatic hepatic niche via promoting TβRII protein stability. Targeting TUFT1 in HSCs presents a promising therapeutic approach for combating CRCLM.

DOI: https://doi.org/10.1038/s41418-026-01664-2