bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2025–03–30
25 papers selected by
Marc Segarra Mondejar
  1. The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease.
  2. Ubiquitination regulation of mitochondrial homeostasis: a new sight for the treatment of gastrointestinal tumors.
  3. Mfn2 regulates calcium homeostasis and suppresses PASMCs proliferation via interaction with IP3R3 to mitigate pulmonary arterial hypertension.
  4. The influence of fatty acid metabolism on T cell function in lung cancer.
  5. Pyruvate kinase modulates the link between β-cell fructose metabolism and insulin secretion.
  6. Label-free metabolic fingerprinting of motile mammalian spermatozoa with subcellular resolution.
  7. MAM kinases: physiological roles, related diseases, and therapeutic perspectives-a systematic review.
  8. Phospholipid Biosynthesis: An Unforeseen Modulator of Nuclear Metabolism.
  9. A map of mitochondrial biology reveals the energy landscape of the human brain.
  10. Xenotopic synthetic biology: Prospective tools for delaying aging and age-related diseases.
  11. Unveiling Xenobiotic Transport and Effects in Isolated Mitochondria: Insights from Respirometric and Enzymatic Assays.
  12. Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
  13. Non-canonical functions of BCL-2 family members in energy metabolism and necrotic cell death regulation.
  14. A cellular assay to determine the fusion capacity of MFN2 variants linked to Charcot-Marie-Tooth disease of type 2 A.
  15. Running a genetic stop sign accelerates oxygen metabolism and energy production in horses.
  16. H2S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes.
  17. The fate of mitochondrial respiratory complexes in aging.
  18. Deletion of ENO1 sensitizes pancreatic cancer cells to gemcitabine via MYC/RRM1-mediated glycolysis.
  19. LYPLAL1 enzyme activity is linked to hepatic glucose metabolism.
  20. ATP6AP1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy.
  21. The ER-phagy receptor FAM134B is targeted by Salmonella Typhimurium to promote infection.
  22. Control of circadian muscle glucose metabolism through the BMAL1-HIF axis in obesity.
  23. Tracking spatiotemporal distribution of organelle contacts in vivo with SPLICS reporters.
  24. Lysosomal PIP3 revealed by genetically encoded lipid biosensors.
  25. mitoXplorer 3.0, A Web Tool for Exploring Mitochondrial Dynamics in Single-cell RNA-seq Data.
  1. Biomolecules. 2025 Mar 18. pii: 433. [Epub ahead of print]15(3):
    The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease.
    Paola Zanfardino, Alessandro Amati, Mirko Perrone, Vittoria Petruzzella.
      Mitochondrial dynamics, governed by fusion and fission, are crucial for maintaining cellular homeostasis, energy production, and stress adaptation. MFN2 and OPA1, key regulators of mitochondrial fusion, play essential roles beyond their structural functions, influencing bioenergetics, intracellular signaling, and quality control mechanisms such as mitophagy. Disruptions in these processes, often caused by MFN2 or OPA1 mutations, are linked to neurodegenerative diseases like Charcot-Marie-Tooth disease type 2A (CMT2A) and autosomal dominant optic atrophy (ADOA). This review explores the molecular mechanisms underlying mitochondrial fusion, the impact of MFN2 and OPA1 dysfunction on oxidative phosphorylation and autophagy, and their role in disease progression. Additionally, we discuss the divergent cellular responses to MFN2 and OPA1 mutations, particularly in terms of proliferation, senescence, and metabolic signaling. Finally, we highlight emerging therapeutic strategies to restore mitochondrial integrity, including mTOR modulation and autophagy-targeted approaches, with potential implications for neurodegenerative disorders.
    Keywords:  autophagy; mTOR signaling; mitochondria; mitochondrial dynamics; mitophagy; neurodegenerative diseases; oxidative phosphorylation; proliferation; senescence
    DOI:  https://doi.org/10.3390/biom15030433
  2. Front Immunol. 2025 ;16 1533007
    Ubiquitination regulation of mitochondrial homeostasis: a new sight for the treatment of gastrointestinal tumors.
    Bingqian Huang, Yulin Yang, Jinming Liu, Biao Zhang, Nengming Lin.
      Mitochondrial homeostasis (MH) refers to the dynamic balance of mitochondrial number, function, and quality within cells. Maintaining MH is significant in the occurrence, development, and clinical treatment of Gastrointestinal (GI) tumors. Ubiquitination, as an important post-translational modification mechanism of proteins, plays a central role in the regulation of MH. Over the past decade, research on the regulation of MH by ubiquitination has focused on mitochondrial biogenesis, mitochondrial dynamics, Mitophagy, and mitochondrial metabolism during these processes. This review summarizes the mechanism and potential therapeutic targets of ubiquitin (Ub)-regulated MH intervention in GI tumors.
    Keywords:  gastrointestinal tumors; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial homeostasis; mitochondrial metabolism; mitophagy; ubiquitination
    DOI:  https://doi.org/10.3389/fimmu.2025.1533007
  3. J Transl Med. 2025 Mar 24. 23(1): 366
    Mfn2 regulates calcium homeostasis and suppresses PASMCs proliferation via interaction with IP3R3 to mitigate pulmonary arterial hypertension.
    Rui Wang, Jie Wang, Jing Yu, Zhiqiang Li, Minfang Zhang, Yuhu Chen, Fen Liu, Dongmei Jiang, Jingfei Guo, Xiaomei Li, Yun Wu.
       BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). Recent studies indicate that Mitochondrial fusion protein 2 (Mfn2) maintains intracellular calcium (Ca2+) homeostasis via the mitochondria-associated endoplasmic reticulum membranes (MAMs) pathway, thereby inhibiting PASMCs proliferation and reducing pulmonary artery pressure. However, the precise mechanisms remain unclear.
    METHODS: This study explored the roles of Mfn2 and IP3R3 in PAH progression by assessing their expression in lung tissues of a monocrotaline (MCT)-induced PAH rat model. Immunoprecipitation assays were performed to confirm the interaction between Mfn2 and IP3R3. PASMCs were treated with either silenced or overexpressed Mfn2 and exposed to TNF-ɑ to observe effects on ER stress, IP3R3 expression, mitochondrial Ca2+ transport, and mitochondrial integrity. We also evaluated the effects of 4-phenylbutyric acid (4-PBA) and cistanche phenylethanol glycosides (CPGs) on the Mfn2-IP3R3 interaction in a TNF-α-induced PAH cell model, focusing on Ca2+ transport and mitochondrial structure.
    RESULTS: Mfn2 expression was significantly down-regulated in the MCT-induced PAH rat model. Inhibition of ER stress upregulated Mfn2 expression, downregulated IP3R3 expression, increased mitochondrial Ca2+ concentration, and reduced autophagy, improving pulmonary hemodynamics and vascular remodeling. Overexpression of Mfn2 reduced ER stress, decreased IP3R3 expression, decreased mitochondrial Ca2+ transport, and restored mitochondrial integrity. Immunoprecipitation assays confirmed the interaction between Mfn2 and IP3R3. Inhibition of IP3R3 elevated Mfn2 levels, yielding similar beneficial effects as Mfn2 overexpression. 4-PBA and CPGs modulated the Mfn2-IP3R3 signaling axis, effectively inhibiting PAH progression.
    CONCLUSIONS: Mfn2 mediates mitochondrial Ca2+ transport via IP3R3, suppressing PASMCs proliferation and pulmonary vascular remodeling, underscoring Mfn2's potential in regulating metabolic processes and vascular remodeling in PAH. These findings provide new insights for developing PAH-targeted therapeutics and establish a theoretical basis for traditional Chinese medicine in PAH prevention and treatment.
    Keywords:  Ca2+ homeostasis; Endoplasmic reticulum stress; Mfn2 interact with IP3R3; Mitochondrial autophagy; Pulmonary artery hypertension
    DOI:  https://doi.org/10.1186/s12967-025-06384-8
  4. FEBS J. 2025 Mar 25.
    The influence of fatty acid metabolism on T cell function in lung cancer.
    Jessica Petiti, Ludovica Arpinati, Alessio Menga, Giovanna Carrà.
      The tumor microenvironment (TME) is a complex ecosystem, encompassing a variety of cellular and non-cellular elements surrounding and interacting with cancer cells, overall promoting tumor growth, immune evasion, and therapy resistance. In the context of solid tumors, factors, such as hypoxia, nutritional competition, increased stress responses, glucose demand, and PD-1 signals strongly influence metabolic alterations in the TME, highly contributing to the maintenance of a tumor-supportive and immune-suppressive milieu. Cancer cell-induced metabolic alterations partly result in an increased fatty acid (FA) metabolism within the TME, which strongly favors the recruitment of immune-suppressive M2 macrophages and myeloid-derived suppressor cells, crucial contributors to T-cell exhaustion, tumor exclusion, and decreased effector functions. The drastic pro-tumoral changes induced by the tumor metabolic rewiring result in signaling loops that support tumor progression and metastatic spreading, and negatively impact therapy efficacy. As tumor- and immune metabolism are increasingly gaining attention due to their potential therapeutic implications, we discuss the effects of altered lipid metabolism on tumor progression, immune response, and therapeutic efficacy in the context of lung cancer. In particular, we focus our analysis on the tumor-induced metabolic alterations experienced by T lymphocytes and the possible strategies to overcome immunotherapy resistance by targeting specific metabolic pathways in T cells.
    Keywords:  T‐cell function; cancer metabolism; fatty acid metabolism; lung cancer
    DOI:  https://doi.org/10.1111/febs.70081
  5. FASEB J. 2025 Apr 15. 39(7): e70500
    Pyruvate kinase modulates the link between β-cell fructose metabolism and insulin secretion.
    Naoya Murao, Risa Morikawa, Yusuke Seino, Kenju Shimomura, Yuko Maejima, Tamio Ohno, Norihide Yokoi, Yuichiro Yamada, Atsushi Suzuki.
      The intricate link between glucose metabolism, ATP production, and glucose-stimulated insulin secretion (GIIS) in pancreatic β-cells has been well established. However, the effects of other digestible monosaccharides on this mechanism remain unclear. This study examined the interaction between intracellular fructose metabolism and GIIS using MIN6-K8 β-cell lines and mouse pancreatic islets. Fructose at millimolar concentrations potentiated insulin secretion in the presence of stimulatory levels (8.8 mM) of glucose. This potentiation was dependent on sweet taste receptor-activated phospholipase Cβ2 (PLCβ2) signaling. Concurrently, metabolic tracing using 13C-labeled fructose and glucose in conjunction with biochemical analyses demonstrated that fructose blunted the glucose-induced increase in the ATP/ADP ratio. Mechanistically, fructose is substantially converted to fructose 1-phosphate (F1P) at the expense of ATP. F1P directly inhibited PKM2 (pyruvate kinase M2), thereby reducing the later glycolytic flux used for ATP production. Remarkably, F1P-mediated PKM2 inhibition was counteracted by TEPP-46, a small-molecule PKM2 activator. TEPP-46 restored glycolytic flux and the ATP/ADP ratio, leading to the enhancement of fructose-potentiated GIIS in MIN6-K8 cells, normal mouse islets, and fructose-unresponsive diabetic mouse islets. These findings reveal an antagonistic interplay between glucose and fructose metabolism in β-cells, highlighting PKM2 as a crucial regulator and broadening our understanding of the relationship between β-cell fuel metabolism and insulin secretion.
    Keywords:  diabetes mellitus; fructose; glycolysis; insulin secretion; pancreatic beta cells; pyruvate kinase
    DOI:  https://doi.org/10.1096/fj.202401912RR
  6. BMC Biol. 2025 Mar 24. 23(1): 85
    Label-free metabolic fingerprinting of motile mammalian spermatozoa with subcellular resolution.
    Fitore Kusari, Lenka Backova, Dalibor Panek, Ales Benda, Zdenek Trachtulec.
       BACKGROUND: Sperm metabolic pathways that generate energy for motility are compartmentalized within the flagellum. Dysfunctions in metabolic compartments, namely mitochondrial respiration and glycolysis, can compromise motility and male fertility. Studying these compartments is thus required for fertility treatment. However, it is very challenging to capture images of metabolic compartments in motile spermatozoa because the fast beating of the flagellum introduces motion blur. Therefore, most approaches immobilize spermatozoa prior to imaging.
    RESULTS: Our findings indicate that immobilizing sperm alters their metabolic profile, highlighting the necessity for measuring metabolism in spermatozoa during movement. We achieved this by encapsulating mouse epididymis in a hydrogel followed by two-photon fluorescence lifetime imaging microscopy for imaging motile sperm in situ. The autofluorescence of endogenous metabolites-FAD, NADH, and NADPH-enabled us to visualize sperm metabolic compartments without staining. We trained machine learning for automated image segmentation and generated metabolic fingerprints using object-based phasor analysis. We show that metabolic fingerprints of spermatozoa and the mitochondrial compartment (1) can distinguish individual males by genetic background, age, or fecundity status, (2) correlate with fertility, and (3) change with age likely due to increased oxidative metabolism.
    CONCLUSIONS: Our approach eliminates the need for sperm immobilization and labeling and captures the native state of sperm metabolism. This technique could be adapted for metabolism-based sperm selection for assisted reproduction.
    Keywords:  Artificial intelligence; FLIM; Fertility; Metabolism; NADH; NADPH; Sperm
    DOI:  https://doi.org/10.1186/s12915-025-02167-1
  7. Cell Mol Biol Lett. 2025 Mar 28. 30(1): 35
    MAM kinases: physiological roles, related diseases, and therapeutic perspectives-a systematic review.
    A Anjana Mohan, Priti Talwar.
      Mitochondria-associated membranes (MAMs) are tethering regions amid the membranes of the endoplasmic reticulum (ER) and mitochondria. They are a lipid raft-like structure occupied by various proteins that facilitates signal transduction between the two organelles. The MAM proteome participates in cellular functions such as calcium (Ca2+) homeostasis, lipid synthesis, ER stress, inflammation, autophagy, mitophagy, and apoptosis. The human kinome is a superfamily of homologous proteins consisting of 538 kinases. MAM-associated kinases participate in the aforementioned cellular functions and act as cell fate executors. Studies have proved the dysregulated kinase interactions in MAM as an etiology for various diseases including cancer, diabetes mellitus, neurodegenerative diseases, cardiovascular diseases (CVDs), and obesity. Several small kinase inhibitory molecules have been well explored as promising drug candidates in clinical trials with an accelerating impact in the field of precision medicine. This review narrates the physiological actions, pathophysiology, and therapeutic potential of MAM-associated kinases with recent updates in the field.
    Keywords:  Cancer; Diabetes; ER stress; Kinases; MAM; Mitophagy; Neurodegenerative disease; Therapeutics
    DOI:  https://doi.org/10.1186/s11658-025-00714-w
  8. Biol Cell. 2025 Mar;117(3): e70002
    Phospholipid Biosynthesis: An Unforeseen Modulator of Nuclear Metabolism.
    Hong Qiu, Cunqi Ye.
      Glycerophospholipid biosynthesis is crucial not only for providing structural components required for membrane biogenesis during cell proliferation but also for facilitating membrane remodeling under stress conditions. The biosynthetic pathways for glycerophospholipid tails, glycerol backbones, and diverse head group classes intersect with various other metabolic processes, sharing intermediary metabolites. Recent studies have revealed intricate connections between glycerophospholipid synthesis and nuclear metabolism, including metabolite-mediated crosstalk with the epigenome, signaling pathways that govern genome integrity, and CTP-involved regulation of nucleotide and antioxidant biosynthesis. This review highlights recent advances in understanding the functional roles of glycerophospholipid biosynthesis beyond their structural functions in budding yeast and mammalian cells. We propose that glycerophospholipid biosynthesis plays an integrative role in metabolic regulation, providing a new perspective on lipid biology.
    DOI:  https://doi.org/10.1111/boc.70002
  9. Nature. 2025 Mar 26.
    A map of mitochondrial biology reveals the energy landscape of the human brain.
      
    Keywords:  Brain; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00872-z
  10. Sci Adv. 2025 Mar 28. 11(13): eadu1710
    Xenotopic synthetic biology: Prospective tools for delaying aging and age-related diseases.
    Andrey A Parkhitko, Valentin Cracan.
      Metabolic dysregulation represents one of the major driving forces in aging. Although multiple genetic and pharmacological manipulations are known to extend longevity in model organisms, aging is a complex trait, and targeting one's own genes may be insufficient to prevent age-dependent deterioration. An alternative strategy could be to use enzymes from other species to reverse age-associated metabolic changes. In this review, we discuss a set of enzymes from lower organisms that have been shown to affect various metabolic parameters linked to age-related processes. These enzymes include modulators of steady-state levels of amino acids (METase, ASNase, and ADI), NADPH/NADP+ and/or reduced form of coenzyme Q (CoQH2)/CoQ redox potentials (NDI1, AOX, LbNOX, TPNOX, EcSTH, RquA, LOXCAT, Grubraw, and ScURA), GSH (StGshF), mitochondrial membrane potential (mtON and mito-dR), or reactive oxygen species (DAAO and KillerRed-SOD1). We propose that leveraging non-mammalian enzymes represents an untapped resource that can be used to delay aging and age-related diseases.
    DOI:  https://doi.org/10.1126/sciadv.adu1710
  11. J Vis Exp. 2025 Mar 07.
    Unveiling Xenobiotic Transport and Effects in Isolated Mitochondria: Insights from Respirometric and Enzymatic Assays.
    Luis C Vesga, Jonny E Duque Luna, Stelia C Mendez-Sanchez.
      Mitochondria are often referred to as the cell's powerhouse due to their crucial role in energy production through the electron transport chain (ETC). However, their significance extends far beyond energy production. Dysregulation of mitochondrial bioenergetics can trigger intracellular cascades that impact health and cellular function. Given their physiological importance, there is growing interest in exploring the pharmacological potential of mitochondrial function for developing new therapies and bioproducts. Modulating mitochondrial bioenergetics could provide innovative approaches to address challenges such as neurodegenerative disorders, metabolic diseases, and cancer, as well as to develop bioproducts for controlling pests and vector-borne diseases. This work presents a method for assessing the effects of xenobiotics on the electron transport chain (ETC) using various substrates, including glutamate and NADH for complex I, succinate for complex II, and cytochrome c (both oxidized and reduced) for complexes III and IV. This methodology allows the activation or inhibition of electron transport through mitochondrial complexes to be evaluated using a respirometer and spectrophotometer. The mitochondria can be sourced from isolated mitochondria, fragmented cells, or homogenized tissue from various species. In the laboratory, mitochondrial function has been analyzed in Aedes aegypti and Wistar rats, but this method is also applicable to other species, such as Rhipicephalus microplus and Rhodnius prolixus. This approach provides the basis for theorizing about the existence of uncoupler proteins and species-specific oxidizable substrate preferences influenced by their unique energetic demands. Recent findings offer valuable insights into innovative bioinsecticide design strategies that target mitochondrial function, holding significant potential for effectively controlling vector-borne diseases and pest infestations.
    DOI:  https://doi.org/10.3791/67146
  12. Nat Commun. 2025 Mar 21. 16(1): 2810
    Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
    Donato D'Angelo, Víctor H Sánchez-Vázquez, Benjamín Cartes-Saavedra, Denis Vecellio Reane, Ryan R Cupo, Hilda Delgado de la Herran, Giorgia Ghirardo, James Shorter, Ron A Wevers, Saskia B Wortmann, Fabiana Perocchi, Rosario Rizzuto, Anna Raffaello, György Hajnóczky.
      Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. Additionally, OPA1 decreases, and aggregation occurs, accompanied by mitochondrial fragmentation. Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes. Thus, mtCU and fusion activity are dependent on CLPB, and their impairments might contribute to the disease caused by CLPB variants.
    DOI:  https://doi.org/10.1038/s41467-025-57641-9
  13. Cell Cycle. 2025 Mar 27. 1-18
    Non-canonical functions of BCL-2 family members in energy metabolism and necrotic cell death regulation.
    Mohamed El-Mesery, Franziska Rudolf, Yannick Heimann, Georg Häcker, Thomas Brunner.
      The large family of BCL-2 proteins plays a well-established role in the regulation of mitochondrial apoptosis pathway, and the crosstalk between death receptor signaling and mitochondrial apoptosis. Accumulating evidence suggests, however, that various BCL-2 family members are also involved in the regulation of apoptosis-unrelated necrotic forms of cell death, and even non-cell death processes. In this review, we discuss the emerging role of BCL-2 family members, and in particular BIM, in the regulation of mitochondrial dynamics, morphology and energy metabolism, and associated consequences for drug-inuced necrotic cell death.
    Keywords:  BCL-2; apoptosis; electron transport chain; glycolysis; mitochondria; mitotoxicants
    DOI:  https://doi.org/10.1080/15384101.2025.2484868
  14. Sci Rep. 2025 Mar 22. 15(1): 9971
    A cellular assay to determine the fusion capacity of MFN2 variants linked to Charcot-Marie-Tooth disease of type 2 A.
    Chloe Barsa, Julian Perrin, Claudine David, Arnaud Mourier, Manuel Rojo.
      Charcot-Marie-Tooth Disease (CMT) is an inherited peripheral neuropathy with two main forms: demyelinating CMT1 and axonal CMT2. The most frequent subtype of CMT2 (CMT2A) is linked to mutations of MFN2, encoding a ubiquitously expressed GTP-binding protein anchored to the mitochondrial outer membrane and essential for mitochondrial fusion. The use of Next-Generation Sequencing has led to the identification of increasing numbers of MFN2 variants, yet many of them remain of unknown significance, depriving patients of a clear diagnosis. In this work, we establish a cellular assay allowing to assess the impact of 12 known MFN2 variants linked to CMT2A on mitochondrial fusion. The functional analysis revealed that out of the 12 selected MFN2 mutations, only six exhibited reduced fusion activity. The classification of MFN2 variants according to the results of the functional assay revealed a correlation between the fusion capacity, the age at onset of CMT2A and computational variant effect predictions relying on the analysis of the protein sequence. The functional assay and the results obtained will assist and improve the classification of novel MFN2 variants identified in patients.
    Keywords:  CMT2A; Charcot–Marie-Tooth disease; MFN2; Mitochondrial dynamics; Mitochondrial fusion; Single nucleotide variants; Variant effect predictor; Variants of unknown significance
    DOI:  https://doi.org/10.1038/s41598-025-93702-1
  15. Science. 2025 Mar 28. 387(6741): eadr8589
    Running a genetic stop sign accelerates oxygen metabolism and energy production in horses.
    Gianni M Castiglione, Xin Chen, Zhenhua Xu, Nadir H Dbouk, Anamika A Bose, David Carmona-Berrio, Emiliana E Chi, Lingli Zhou, Tatiana N Boronina, Robert N Cole, Shirley Wu, Abby D Liu, Thalia D Liu, Haining Lu, Ted Kalbfleisch, David Rinker, Antonis Rokas, Kyla Ortved, Elia J Duh.
      Horses are among nature's greatest athletes, yet the ancestral molecular adaptations fueling their energy demands are poorly understood. Within a clinically important pathway regulating redox and metabolic homeostasis (NRF2/KEAP1), we discovered an ancient mutation-conserved in all extant equids-that increases mitochondrial respiration while decreasing tissue-damaging oxidative stress. This mutation is a de novo premature opal stop codon in KEAP1 that is translationally recoded into a cysteine through previously unknown mechanisms, producing an R15C mutation in KEAP1 that is more sensitive to electrophiles and reactive oxygen species. This recoding enables increased NRF2 activity, which enhances mitochondrial adenosine 5'-triphosphate production and cellular resistance to oxidative damage. Our study illustrates how recoding of a de novo stop codon, a strategy thought restricted to viruses, can facilitate adaptation in vertebrates.
    DOI:  https://doi.org/10.1126/science.adr8589
  16. J Biol Chem. 2025 Mar 20. pii: S0021-9258(25)00282-0. [Epub ahead of print] 108433
    H2S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes.
    David A Hanna, Brandon Chen, Yatrik M Shah, Oleh Khalimonchuk, Brian Cunniff, Ruma Banerjee.
      Mitochondrial form and function are intimately interconnected, responding to cellular stresses and changes in energy demand. Hydrogen sulfide, a product of amino acid metabolism, has dual roles as an electron transport chain substrate and complex IV (CIV) inhibitor, leading to a reductive shift, which has pleiotropic metabolic consequences. Luminal sulfide concentration in colon is high due to microbial activity, and in this study, we demonstrate that chronic sulfide exposure of colonocyte-derived cells leads to lower Mic60 and Mic19 expression that is correlated with a profound loss of cristae and lower mitochondrial networking. Sulfide-induced depolarization of the inner mitochondrial membrane activates Oma1-dependent cleavage of Opa1 and is associated with a profound loss of CI and CIV activities associated with respirasomes. Our study reveals a potential role for sulfide as an endogenous modulator of mitochondrial dynamics and suggests that this regulation is corrupted in hereditary or acquired diseases associated with elevated sulfide.
    Keywords:  Cristae; cristae; electron transport chain; hydrogen sulfide; mitochondrial dynamics; respirasome
    DOI:  https://doi.org/10.1016/j.jbc.2025.108433
  17. Trends Cell Biol. 2025 Mar 26. pii: S0962-8924(25)00042-X. [Epub ahead of print]
    The fate of mitochondrial respiratory complexes in aging.
    Hanna Salmonowicz, Karolina Szczepanowska.
      While mitochondrial dysfunction is one of the canonical hallmarks of aging, it remains only vaguely defined. Its core feature embraces defects in energy-producing molecular machinery, the mitochondrial respiratory complexes (MRCs). The causes and consequences of these defects hold research attention. In this review, we assess the lifecycle of respiratory complexes, from biogenesis to degradation, and look closely at the mechanisms that could underpin their dysfunction in aged cells. We discuss how these processes could be altered by aging and expand on the fate of MRCs in age-associated pathologies. Given the complexity behind MRC maintenance and functionality, several traits could contribute to the phenomenon known as age-associated mitochondrial dysfunction. New advances will help us better understand the fate of this machinery in aging and age-related diseases.
    Keywords:  OXPHOS; age-associated diseases; dysfunction; mitochondria; protein complexes, aging hallmarks
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.008
  18. Sci Rep. 2025 Mar 22. 15(1): 9941
    Deletion of ENO1 sensitizes pancreatic cancer cells to gemcitabine via MYC/RRM1-mediated glycolysis.
    Yingpeng Lu, Hongqin Ma, Xiaoxiao Xiong, Yusheng Du, Li Liu, Ji Wang, Wenxing Zhao.
      Glycolysis is a critical metabolic pathway in cancer cells, fulfilling their energy requirements, supporting biosynthesis, maintaining redox balance, and enabling survival in hostile environments. Alpha-enolase (ENO1) has been identified as a key promoter of tumor progression through its involvement in glycolysis. This study aims to elucidate the relationship between ENO1, glycolysis, and gemcitabine sensitivity in pancreatic cancer (PC). The expression levels of ENO1 in PC were analyzed using the GEPIA2 database, Kaplan-Meier survival plots, and immunohistochemistry (IHC). To assess the impact of ENO1 on gemcitabine sensitivity, we manipulated ENO1 expression in PC cell lines through overexpression and silencing techniques. Subsequent analyses included flow cytometry assays, glucose uptake and lactate production measurements, and cytotoxicity assays. The underlying mechanisms by which ENO1 modulates gemcitabine sensitivity were explored using Western blotting (WB). ENO1 was found to be significantly overexpressed in PC tissues, and elevated ENO1 levels were associated with poorer prognosis in PC patients. Overexpression of ENO1 reduced the sensitivity of PC cells to gemcitabine, enhancing cell proliferation, migration, and invasion by altering the cell cycle and inhibiting apoptosis. Conversely, silencing ENO1 decreased glycolysis in PC cells and heightened their sensitivity to gemcitabine. Furthermore, glycolysis inhibition-achieved through ENO1 knockdown, glucose deprivation, or treatment with 2-Deoxy-D-glucose (2-DG)-further enhanced the susceptibility of PC cells to gemcitabine. Mechanistically, ENO1 was found to regulate the expression of gemcitabine resistance-related genes, particularly ribonucleotide reductase catalytic subunit M1 (RRM1), via MYC through the glycolytic pathway, thereby contributing to gemcitabine resistance. This study demonstrates that ENO1 plays a crucial role in PC progression and is closely linked to gemcitabine resistance through its regulation of the glycolytic pathway.
    Keywords:  ENO1; Gemcitabine sensitivity; Glycolysis; PC; RRM1
    DOI:  https://doi.org/10.1038/s41598-025-94319-0
  19. Biochem Biophys Res Commun. 2025 Mar 19. pii: S0006-291X(25)00370-5. [Epub ahead of print]759 151656
    LYPLAL1 enzyme activity is linked to hepatic glucose metabolism.
    Roxana Filip, Étienne Bélanger, Xinhzu Chen, David Lefebvre, Spencer M Uguccioni, John Paul Pezacki.
      The serine hydrolase LYPLAL1 is a poorly characterised enzyme with emerging roles in hepatic metabolism. A multitude of association studies have shown links between variants of this gene locus and metabolic conditions such as obesity and insulin resistance. However, the enzyme's function is still largely unknown. Recent biochemical studies have revealed that it may play a role in hepatic glucose metabolism and that its activity is allosterically regulated. Herein, we use a selective activity-based probe to delineate LYPLAL1's involvement in hepatic metabolism. We show that the enzyme's activity is modulated during metabolic stress, specifically pointing to a putative role in negatively regulating gluconeogenesis and upregulating glycolysis. We also determine that knock-out of the enzyme does not affect liver lipid profiles and bring forth evidence for insulin-mediated control of LYPLAL1 in HepG2 cells. Furthermore, LYPLAL1 activity appears to be largely post-translationally regulated as gene expression levels remain largely constant under insulin and glucagon treatments. Taken together these data point to an enzymatic role in regulating glucose metabolism that may be part of a feedback mechanism of signal transduction.
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151656
  20. Cell Death Dis. 2025 Mar 25. 16(1): 201
    ATP6AP1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy.
    Zhengwei Yan, Aidi Huang, Dongwen Ma, Chenao Hong, Shengmiao Zhang, Luling He, Hai Rao, Shiwen Luo.
      Autophagy is a highly conserved cellular process essential for maintaining cellular homeostasis and influencing cancer development. Lysosomal acidification and autophagosome-lysosome fusion are two important steps of autophagy degradation that are tightly regulated. Although many key proteins that regulate these two events have been identified, the effector proteins that co-regulate both steps remain to be explored. ATP6AP1, an accessory subunit of V-ATPase, plays a critical role in the assembly and regulation of V-ATPase. However, the function of ATP6AP1 in autophagy remains unknown, and the role of ATP6AP1 in cancer is still poorly understood. In this study, we found that ATP6AP1 is overexpressed in luminal breast cancer tissues and promotes the proliferation and tamoxifen resistance of luminal breast cancer cells both in vitro and in vivo. We also observed that high ATP6AP1 expression correlates with poor overall patient survival. Our research further revealed that ATP6AP1 enhances tamoxifen resistance by activating autophagy. Mechanistically, ATP6AP1 promotes autophagy by regulating both lysosomal acidification and autophagosome-lysosome fusion. Remarkably, ATP6AP1 induces lysosomal acidification through the regulation of V-ATPase assembly and facilitates autophagosome-lysosome fusion by enhancing the interaction between Rab7 and the HOPS complex. Together, our studies identify ATP6AP1 as a crucial regulator of autophagy, potentially serving as a valuable prognostic marker or therapeutic target in human luminal breast cancer.
    DOI:  https://doi.org/10.1038/s41419-025-07534-y
  21. Nat Commun. 2025 Mar 25. 16(1): 2923
    The ER-phagy receptor FAM134B is targeted by Salmonella Typhimurium to promote infection.
    Damián Gatica, Reham M Alsaadi, Rayan El Hamra, Boran Li, Rudolf Mueller, Makoto Miyazaki, Qiming Sun, Subash Sad, Ryan C Russell.
      Macroautophagy/autophagy is a key catabolic-recycling pathway that can selectively target damaged organelles or invading pathogens for degradation. The selective autophagic degradation of the endoplasmic reticulum (hereafter referred to as ER-phagy) is a homeostatic mechanism, controlling ER size, the removal of misfolded protein aggregates, and organelle damage. ER-phagy can also be stimulated by pathogen infection. However, the link between ER-phagy and bacterial infection remains poorly understood, as are the mechanisms evolved by pathogens to escape the effects of ER-phagy. Here, we show that Salmonella enterica serovar Typhimurium inhibits ER-phagy by targeting the ER-phagy receptor FAM134B, leading to a pronounced increase in Salmonella burden after invasion. Salmonella prevents FAM134B oligomerization, which is required for efficient ER-phagy. FAM134B knock-out raises intracellular Salmonella number, while FAM134B activation reduces Salmonella burden. Additionally, we found that Salmonella targets FAM134B through the bacterial effector SopF to enhance intracellular survival through ER-phagy inhibition. Furthermore, FAM134B knock-out mice infected with Salmonella presented severe intestinal damage and increased bacterial burden. These results provide mechanistic insight into the interplay between ER-phagy and bacterial infection, highlighting a key role for FAM134B in innate immunity.
    DOI:  https://doi.org/10.1038/s41467-025-58035-7
  22. Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2424046122
    Control of circadian muscle glucose metabolism through the BMAL1-HIF axis in obesity.
    Claire A Chaikin, Abhishek V Thakkar, Adam W T Steffeck, Eric M Pfrender, Kaitlyn Hung, Pei Zhu, Nathan J Waldeck, Rino Nozawa, Weimin Song, Christopher R Futtner, Mattia Quattrocelli, Joseph Bass, Issam Ben-Sahra, Clara B Peek.
      Disruptions of circadian rhythms are widespread in modern society and lead to accelerated and worsened symptoms of metabolic syndrome. In healthy mice, the circadian clock factor BMAL1 is required for skeletal muscle function and metabolism. However, the importance of muscle BMAL1 in the development of metabolic diseases, such as diet-induced obesity (DIO), remains unclear. Here, we demonstrate that skeletal muscle-specific BMAL1-deficient mice exhibit worsened glucose tolerance upon high-fat diet feeding, despite no evidence of increased weight gain. Metabolite profiling from Bmal1-deficient muscles revealed impaired glucose utilization specifically at early steps in glycolysis that dictate the switch between anabolic and catabolic glucose fate. We provide evidence that this is due to abnormal control of the nutrient stress-responsive hypoxia-inducible factor (HIF) pathway. Genetic HIF1α stabilization in muscle Bmal1-deficient mice restores glucose tolerance and expression of 217/736 dysregulated genes during DIO, including glycolytic enzymes. Together, these data indicate that during DIO, skeletal muscle BMAL1 is an important regulator of HIF-driven glycolysis and metabolic flexibility, which influences the development of high-fat-diet-induced glucose intolerance.
    Keywords:  circadian rhythm; diet-induced obesity; hypoxia; skeletal muscle
    DOI:  https://doi.org/10.1073/pnas.2424046122
  23. Cell Death Dis. 2025 Mar 27. 16(1): 214
    Tracking spatiotemporal distribution of organelle contacts in vivo with SPLICS reporters.
    Lucia Barazzuol, Tetiana Tykhonenko, Tia L Griffiths, Alessio Vagnoni, Marisa Brini, Tito Calì.
      Organelle contact sites are crucial for cellular function, enabling the exchange of lipids, ions, and other molecules between different organelles. The ability to track these contact sites in vivo has been significantly advanced by the development of SPLICS (Split-GFP-based Contact Site Sensors) reporters, which have provided unprecedented insights into the intricate network of organelle communication. This innovative and powerful tool allows the real-time visualization of different organelle interactions in living cells and in vivo thus unraveling the complexity of their dynamic in the context of cellular homeostasis. Recent studies highlighted the dynamic nature of organelle contact sites either in terms of tethering/untethering and of movement of the contact itself in time and space: whether unique temporal behaviors and contact site-specific dynamics of different organelle interactions exist is currently unknown. In this study, we investigated the spatiotemporal distribution of various organelle contact sites using time-lapse in vitro and in vivo imaging and discovered an evolutionarily conserved dynamic pattern among different contact sites, influenced by the specific partner organelles involved. These findings highlight the importance of spatial and temporal regulation at organelle contact sites, which may underlie their diverse physiological functions. The discovery of contact site-specific dynamics opens new avenues for understanding the regulation of organelle interactions in health and disease, with potential implications for developing targeted therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-025-07511-5
  24. Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2426929122
    Lysosomal PIP3 revealed by genetically encoded lipid biosensors.
    Ayse Z Sahan, Mingyuan Chen, Qi Su, Qingrong Li, Dong Wang, Jin Zhang.
      3-Phosphoinositides (3-PIs), phosphatidylinositol (3,4) bisphosphate [PI(3,4)P2] and phosphatidylinositol (3,4,5) trisphosphate (PIP3), are important lipid second messengers in the Phosphoinositide 3-Kinase (PI3K)/Akt signaling pathway, which is crucial to cell growth and frequently dysregulated in cancer. Emerging evidence suggests these lipid second messengers may be present in membranes beyond the plasma membrane, yet their spatial regulation within other membrane compartments is not well understood. To dissect the spatial regulation of specific 3-PI species, we developed genetically encodable biosensors with selectivity for PIP3 or PI(3,4)P2. Using these biosensors, we showed that PIP3 significantly accumulated at the lysosome upon growth factor stimulation, in contrast to the conventional view that PIP3 is exclusively present in the plasma membrane. Furthermore, we showed that lysosomal PIP3 originates from the plasma membrane and relies on dynamin-dependent endocytosis for lipid internalization. Thus, PIP3 can exploit dynamic trafficking pathways to access subcellular compartments and regulate signaling in a spatially selective manner.
    Keywords:  3-phosphoinositide; cellular signaling; fluorescent biosensor; lysosome; spatiotemporal regulation
    DOI:  https://doi.org/10.1073/pnas.2426929122
  25. J Mol Biol. 2025 Feb 12. pii: S0022-2836(25)00070-1. [Epub ahead of print] 169004
    mitoXplorer 3.0, A Web Tool for Exploring Mitochondrial Dynamics in Single-cell RNA-seq Data.
    Margaux Haering, Andrea Del Bondio, Helene Puccio, Bianca H Habermann.
      Mitochondria are essential eukaryotic organelles, primarily recognized for their roles in ATP production, cellular metabolism and signalling. It is widely accepted that their structure, composition and function differ across cell types. However, little is known about mitochondrial variability within the same cell type. A comprehensive understanding of mitochondrial function and dynamics requires investigation at both, the individual cell type and single-cell resolution. Based on our mitoXplorer 2.0 web tool, we introduce mitoXplorer 3.0 with new features adapted for analysing single-cell sequencing data, focusing only on mitochondria. We developed a formatting script, scXplorer, which generates mitoXplorer 3.0 compatible files for data upload. The script generates pseudo-bulk transcriptomes of cell types from scRNA-seq data, enabling differential expression analysis and subsequent mitochondria-centric analysis with mitoXplorer classical interfaces. It also creates a single-cell expression matrix only containing mitochondria-associated genes (mito-genes), which can be analysed for cell-to-cell variability with novel, interactive interfaces created for mitoXplorer 3.0: these new interfaces help to identify sub-clusters of cell types based only on mito-genes and offer in-depth mitochondria-centric analysis of subpopulations. We demonstrate the usability and predictive power of mitoXplorer 3.0 through analysis of single-cell transcriptome data from a Spinocerebellar Ataxia Type 1 study. Our analysis identified several mitochondrial processes and genes significantly affected in SCA1 Purkinje cells, potentially contributing to mitochondrial dysfunction and subsequent Purkinje cell degeneration in this disease. MitoXplorer 3.0 is freely available at https://mitoxplorer3.ibdm.univ-amu.fr.
    Keywords:  data integration; mitoXplorer; mitochondria; single-nuclei sequencing; visual data mining
    DOI:  https://doi.org/10.1016/j.jmb.2025.169004
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