bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2025–02–09
fifteen papers selected by
Marc Segarra Mondejar
  1. THE REGULATION OF CELL METABOLISM BY HYPOXIA AND HYPERCAPNIA.
  2. Harmine promotes axon regeneration through enhancing glucose metabolism.
  3. The emerging role of dysregulated propionate metabolism and methylmalonic acid in metabolic disease, aging, and cancer.
  4. CaMKIIβ Ca2+ptures ER signals to initiate autophagosome biogenesis.
  5. Research progress of cysteine transporter SLC7A11 in endocrine and metabolic diseases.
  6. Optical imaging provides flow-cytometry-like single-cell level analysis of HIF-1α-mediated metabolic changes in radioresistant head and neck squamous carcinoma cells.
  7. A new player in the mammalian electron transport chain.
  8. Imaging and Quantifying Mitochondrial Morphology in C. elegans During Aging.
  9. Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
  10. Transmembrane Parkinson's Disease mutation of PINK1 leads to altered mitochondrial anchoring.
  11. MCU expression in hippocampal CA2 neurons modulates dendritic mitochondrial morphology and synaptic plasticity.
  12. Activating AMPK improves pathological phenotypes due to mtDNA depletion.
  13. VPS41 recruits biosynthetic LAMP-positive vesicles through interaction with Arl8b.
  14. Arginine: at the crossroads of nitrogen metabolism.
  15. The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism.
  1. J Biol Chem. 2025 Feb 04. pii: S0021-9258(25)00099-7. [Epub ahead of print] 108252
    THE REGULATION OF CELL METABOLISM BY HYPOXIA AND HYPERCAPNIA.
    Ben Reddan, Eoin P Cummins.
      Every cell in the body is exposed to a certain level of CO2 and O2. Hypercapnia and hypoxia elicit stress signals to influence cellular metabolism and function. Both conditions exert profound yet distinct effects on metabolic pathways and mitochondrial dynamics, highlighting the need for cells to adapt to changes in the gaseous microenvironment. The interplay between hypercapnia and hypoxia signalling is key for dictating cellular homeostasis as microenvironmental CO2 and O2 levels are inextricably linked. Hypercapnia, characterized by elevated pCO₂, introduces metabolic adaptations within the aerobic metabolism pathways, affecting TCA cycle flux, lipid, and amino acid metabolism, OXPHOS and the ETC. Hypoxia, defined by reduced oxygen availability, necessitates a shift from OXPHOS to anaerobic glycolysis to sustain ATP production, a process orchestrated by the stabilisation of HIF-1α. Given that hypoxia and hypercapnia are present in both physiological and cancerous microenvironments, how might the coexistence of hypercapnia and hypoxia influence metabolic pathways and cellular function in physiological niches and the tumor microenvironment?
    DOI:  https://doi.org/10.1016/j.jbc.2025.108252
  2. J Biol Chem. 2025 Feb 02. pii: S0021-9258(25)00101-2. [Epub ahead of print] 108254
    Harmine promotes axon regeneration through enhancing glucose metabolism.
    Ruixuan Liu, Bing Zhou.
      Axon regeneration requires a substantial mitochondrial energy supply. However, injured mature neurons often fail to regenerate due to their inability to meet these elevated energy demands. Our findings indicate that harmine compensates for the energy deficit following axonal injury by enhancing the coupling between glucose metabolism and mitochondrial homeostasis, thereby promoting axon regeneration. Notably, harmine facilitates mitochondrial biogenesis and enhances mitophagy, ensuring efficient mitochondrial turnover and energy supply. Thus, harmine plays a crucial role in enhancing glucose metabolism to maintain mitochondrial function, demonstrating significant potential in treating mature neuronal axon injuries and sciatic nerve injuries.
    Keywords:  axon regeneration; energy supply; glucose metabolism; harmine; metabolic coupling; mitochondrial function; neuron
    DOI:  https://doi.org/10.1016/j.jbc.2025.108254
  3. Cell Metab. 2025 Feb 04. pii: S1550-4131(25)00005-1. [Epub ahead of print]37(2): 316-329
    The emerging role of dysregulated propionate metabolism and methylmalonic acid in metabolic disease, aging, and cancer.
    Moniquetta Shafer, Vivien Low, Zhongchi Li, John Blenis.
      Propionate metabolism dysregulation has emerged as a source of metabolic health alterations linked to aging, cardiovascular and renal diseases, obesity and diabetes, and cancer. This is supported by several large cohort population studies and recent work revealing its role in cancer progression. Mutations in several enzymes of this metabolic pathway are associated with devastating inborn errors of metabolism, resulting in severe methylmalonic and propionic acidemias. Beyond these rare diseases, however, the broader pathological significance of propionate metabolism and its metabolites has been largely overlooked. Here, we summarize earlier studies and new evidence that the alteration of this pathway and associated metabolites are involved in the development of various metabolic diseases and link aging to cancer progression and metastasis.
    Keywords:  BCAA metabolism; BCAAs; MMA; aging; branched-chain amino acids; cancer metabolism; metabolic disorders; methylmalonic acid; methylmalonyl-CoA; propionate; propionyl-CoA
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.005
  4. Mol Cell. 2025 Feb 06. pii: S1097-2765(25)00045-0. [Epub ahead of print]85(3): 464-465
    CaMKIIβ Ca2+ptures ER signals to initiate autophagosome biogenesis.
    Leonardo Luís Artico, Ana Paula Arruda.
      Cytosolic Ca2+ transients are critical signals for autophagy regulation; however, how they translate into functional autophagic events remains unclear. In this issue of Molecular Cell, Zheng et al.1 identify CaMKIIβ as a key player decoding Ca2+ transients at the ER surface to initiate autophagosome formation through the FIP200 complex.
    DOI:  https://doi.org/10.1016/j.molcel.2025.01.011
  5. Mol Biol Rep. 2025 Feb 03. 52(1): 185
    Research progress of cysteine transporter SLC7A11 in endocrine and metabolic diseases.
    Jiaqi Chen, Mengzhu Yuan, Jianping Wang.
      SLC7A11, often called xCT, belongs to the SLC family of transporters, which mediates the cellular influx of cystine and the efflux of glutamate. These transport processes are crucial for synthesizing GSH, enhancing the cell's ability to mitigate oxidative stress (OS). Emerging studies highlight the pivotal role of OS in triggering and exacerbating various metabolic and endocrine disorders, underlining the critical importance of regulating SLC7A11 expression levels. This study reviews the diverse roles of SLC7A11 in endocrine and metabolic diseases, examining its relationship with the metabolism of three key nutrients: proteins and amino acids, carbohydrates, and lipids. Additionally, the involvement of SLC7A11 in the onset and development of various common endocrine and metabolic disorders is analyzed. Additionally, it provides an overview of the current clinical and experimental use of SLC7A11 inhibitors and agonists. This review aims to offer insightful perspectives into the involvement of SLC7A11 in endocrine and metabolic pathologies and to foster the development of innovative therapeutic strategies that target SLC7A11.
    Keywords:  Endocrine and metabolic diseases; Ferroptosis; Oxidative stress; SLC7A11
    DOI:  https://doi.org/10.1007/s11033-024-10193-5
  6. Biophotonics Discov. 2025 Jan;pii: 012702. [Epub ahead of print]2(1):
    Optical imaging provides flow-cytometry-like single-cell level analysis of HIF-1α-mediated metabolic changes in radioresistant head and neck squamous carcinoma cells.
    Jing Yan, Carlos Frederico Lima Goncalves, Pranto Soumik Saha, Cristina M Furdui, Caigang Zhu.
       Significance: Radioresistance remains a significant problem for head and neck squamous cell carcinoma (HNSCC) patients. To mitigate this, the cellular and molecular pathways used by radioresistant HNSCC that drive recurrence must be studied.
    Aim: We aim to demonstrate optical imaging strategies to provide flow cytometry-like single-cell level analysis of hypoxia-inducible factor 1-alpha (HIF-1α)-mediated metabolic changes in the radioresistant and radiosensitive HNSCC cells but in a more efficient, cost-effective, and non-destructive manner. Through both optical imaging and flow cytometry studies, we will reveal the role of radiation-induced HIF-1α overexpression and the following metabolic changes in the radioresistance development for HNSCC.
    Approach: We optimized the use of two metabolic probes: 2-[N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG) (to report glucose uptake) and Tetramethylrhodamine ethyl ester (TMRE) (to report mitochondrial membrane potential) with both a standard fluorescence microscope and a flow cytometry device, to report the changes in metabolism between radioresistant (rSCC-61) and radiosensitive (SCC-61) HNSCC cell lines under radiation stresses with or without HIF-1α inhibition.
    Results: We found that the matched HNSCC cell lines had different baseline metabolic phenotypes, and their metabolism responded differently to radiation stress along with significantly enhanced HIF-1α expressions in the rSCC-61 cells. HIF-1α inhibition during the radiation treatment modulates the metabolic changes and radio-sensitizes the rSCC-61 cells. Through these studies, we demonstrated that a standard fluorescence microscope along with proper image processing methods can provide flow cytometry-like single-cell level analysis of HIF-1α-mediated metabolic changes in the radioresistant and radiosensitive HNSCC cells.
    Conclusions: Our reported optical imaging strategies may enable one to study the role of metabolism reprogramming in cancer therapeutic resistance development at the single-cell level in a more efficient, cost-effective, and non-destructive manner. Our understanding of radiation resistance mechanisms using our imaging methods will offer opportunities to design targeted radiotherapy for improved treatment outcomes for HNSCC patients.
    Keywords:  fluorescence microscopy; head and neck squamous cell carcinoma; optical metabolic imaging; radiation therapy; tumor metabolism
    DOI:  https://doi.org/10.1117/1.bios.2.1.012702
  7. Cell Metab. 2025 Feb 04. pii: S1550-4131(24)00494-7. [Epub ahead of print]37(2): 310-312
    A new player in the mammalian electron transport chain.
    Judy Hirst.
      In an evolutionary twist to mammalian bioenergetics, Spinelli and coworkers reveal the presence of rhodoquinones in mammalian mitochondria, expanding the established premise that the mammalian respiratory chain relies uniquely on ubiquinones for catalysis.
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.012
  8. J Vis Exp. 2025 Jan 17.
    Imaging and Quantifying Mitochondrial Morphology in C. elegans During Aging.
    Juri Kim, Maxim Averbukh, Athena Alcala, Rebecca Aviles Barahona, Matthew Vega, Gilberto Garcia, Ryo Higuchi-Sanabria, Naibedya Dutta.
      Mitochondria, important cellular organelles found in most eukaryotic cells, are major sites of energy production through aerobic respiration. Beyond this well-known role as the 'cellular powerhouse,' mitochondria are also involved in many other essential cellular processes, including the regulation of cellular metabolism, proliferation, immune signaling, and hormonal signaling. Deterioration in mitochondrial function during aging or under mitochondrial stress is often characterized by distinct changes in mitochondrial morphology and volume. The nematode C. elegans is an ideal model for studying these changes due to its transparent body and short lifespan, which facilitate live microscopy throughout its lifetime. However, even within the C. elegans field, numerous transgenic constructs and methods for mitochondrial imaging are available, each with its own limitations. Here, single-copy, matrix-localized GFP constructs are presented as a robust and reliable method for imaging mitochondrial morphology in C. elegans. This study specifically focuses on experimentally controllable factors to minimize errors and reduce variability between replicates and across studies when performing mitochondrial imaging during the aging process. Additionally, mitoMAPR is recommended as a robust method to quantify changes in mitochondrial morphology across tissue types during aging.
    DOI:  https://doi.org/10.3791/67610
  9. Cell Metab. 2025 Jan 29. pii: S1550-4131(24)00491-1. [Epub ahead of print]
    Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
    Won Dong Lee, Daniel R Weilandt, Lingfan Liang, Michael R MacArthur, Natasha Jaiswal, Olivia Ong, Charlotte G Mann, Qingwei Chu, Craig J Hunter, Rolf-Peter Ryseck, Wenyun Lu, Anna M Oschmann, Alexis J Cowan, Tara A TeSlaa, Caroline R Bartman, Cholsoon Jang, Joseph A Baur, Paul M Titchenell, Joshua D Rabinowitz.
      Lactate is among the highest flux circulating metabolites. It is made by glycolysis and cleared by both tricarboxylic acid (TCA) cycle oxidation and gluconeogenesis. Severe lactate elevations are life-threatening, and modest elevations predict future diabetes. How lactate homeostasis is maintained, however, remains poorly understood. Here, we identify, in mice, homeostatic circuits regulating lactate production and consumption. Insulin induces lactate production by upregulating glycolysis. We find that hyperlactatemia inhibits insulin-induced glycolysis, thereby suppressing excess lactate production. Unexpectedly, insulin also promotes lactate TCA cycle oxidation. The mechanism involves lowering circulating fatty acids, which compete with lactate for mitochondrial oxidation. Similarly, lactate can promote its own consumption by lowering circulating fatty acids via the adipocyte-expressed G-protein-coupled receptor hydroxycarboxylic acid receptor 1 (HCAR1). Quantitative modeling suggests that these mechanisms suffice to produce lactate homeostasis, with robustness to noise and perturbation of individual regulatory mechanisms. Thus, through regulation of glycolysis and lipolysis, lactate homeostasis is maintained.
    Keywords:  HCAR1 signaling; TCA cycle; competitive catabolism; diabetes mellitus; insulin resistance; insulin signaling; lactate metabolism; metabolic flux; metabolic homeostasis; quantitative modeling
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.009
  10. J Biol Chem. 2025 Feb 03. pii: S0021-9258(25)00100-0. [Epub ahead of print] 108253
    Transmembrane Parkinson's Disease mutation of PINK1 leads to altered mitochondrial anchoring.
    Raelynn Brassard, Elena Arutyunova, Emmanuella Takyi, L Michel Espinoza-Fonseca, Howard Young, Nicolas Touret, M Joanne Lemieux.
      Parkinson's disease (PD) is a devastating neurodegenerative disease resulting from the death of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Familial and sporadic forms of the disease have been linked to mitochondrial dysfunction. Pathology has been identified with mutations in the PARK6 gene encoding PTEN-induced kinase 1 (PINK1), a quality control protein in the mitochondria. Disease-associated mutations at the transmembrane region of PINK1 protein were predicted to disrupt the cleavage of the transmembrane region by the PARL protease at the inner mitochondrial membrane. Here, using microscopy, kinetic analysis and molecular dynamic simulations, we analyzed 3 PD associated TM mutations; PINK1-C92F, PINK1-R98W and PINK1-I111S, and found that mitochondrial localization and cleavage by the PARL protease were not significantly impaired. However, clearance of hydrolyzed PINK1-R98W appears to be compromised due to altered positioning of the protein in the outer mitochondrial membrane, preventing association with TOM complexes and slowing cleavage by PARL. This single amino acid change slows degradation of proteolyzed PINK1, increasing its accumulation at the outer mitochondrial membrane and resulting in increased mitophagy and decreased mitochondrial content among these cells.
    Keywords:  MD Simulation; PARL; Parkinson’s Disease; Proteostasis; Rhomboid Protease
    DOI:  https://doi.org/10.1016/j.jbc.2025.108253
  11. Sci Rep. 2025 Feb 06. 15(1): 4540
    MCU expression in hippocampal CA2 neurons modulates dendritic mitochondrial morphology and synaptic plasticity.
    Katy E Pannoni, Quentin S Fischer, Renesa Tarannum, Mikel L Cawley, Mayd M Alsalman, Nicole Acosta, Chisom Ezigbo, Daniela V Gil, Logan A Campbell, Shannon Farris.
      Neuronal mitochondria are diverse across cell types and subcellular compartments in order to meet unique energy demands. While mitochondria are essential for synaptic transmission and synaptic plasticity, the mechanisms regulating mitochondria to support normal synapse function are incompletely understood. The mitochondrial calcium uniporter (MCU) is proposed to couple neuronal activity to mitochondrial ATP production, which would allow neurons to rapidly adapt to changing energy demands. MCU is uniquely enriched in hippocampal CA2 distal dendrites compared to proximal dendrites, however, the functional significance of this layer-specific enrichment is not clear. Synapses onto CA2 distal dendrites readily express plasticity, unlike the plasticity-resistant synapses onto CA2 proximal dendrites, but the mechanisms underlying these different plasticity profiles are unknown. Using a CA2-specific MCU knockout (cKO) mouse, we found that MCU deletion impairs plasticity at distal dendrite synapses. However, mitochondria were more fragmented and spine head area was diminished throughout the dendritic layers of MCU cKO mice versus control mice. Fragmented mitochondria might have functional changes, such as altered ATP production, that could explain the structural and functional deficits at cKO synapses. Differences in MCU expression across cell types and circuits might be a general mechanism to tune mitochondrial function to meet distinct synaptic demands.
    Keywords:  Dendrites; Hippocampal CA2; Mitochondria; Mitochondrial calcium uniporter; Spines; Synaptic plasticity
    DOI:  https://doi.org/10.1038/s41598-025-85958-4
  12. FEBS J. 2025 Feb 07.
    Activating AMPK improves pathological phenotypes due to mtDNA depletion.
    Gustavo Carvalho, Tran V H Nguyen, Bruno Repolês, Josefin M E Forslund, W M Ruchitha Rukmal Wijethunga, Farahnaz Ranjbarian, Isabela C Mendes, Choco Michael Gorospe, Namrata Chaudhari, Micol Falabella, Mara Doimo, Sjoerd Wanrooij, Robert D S Pitceathly, Anders Hofer, Paulina H Wanrooij.
      AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis that also plays a role in preserving mitochondrial function and integrity. Upon a disturbance in the cellular energy state that increases AMP levels, AMPK activity promotes a switch from anabolic to catabolic metabolism to restore energy homeostasis. However, the level of severity of mitochondrial dysfunction required to trigger AMPK activation is currently unclear, as is whether stimulation of AMPK using specific agonists can improve the cellular phenotype following mitochondrial dysfunction. Using a cellular model of mitochondrial disease characterized by progressive mitochondrial DNA (mtDNA) depletion and deteriorating mitochondrial metabolism, we show that mitochondria-associated AMPK becomes activated early in the course of the advancing mitochondrial dysfunction, before any quantifiable decrease in the ATP/(AMP + ADP) ratio or respiratory chain activity. Moreover, stimulation of AMPK activity using the specific small-molecule agonist A-769662 alleviated the mitochondrial phenotypes caused by the mtDNA depletion and restored normal mitochondrial membrane potential. Notably, the agonist treatment was able to partially restore mtDNA levels in cells with severe mtDNA depletion, while it had no impact on mtDNA levels of control cells. The beneficial impact of the agonist on mitochondrial membrane potential was also observed in cells from patients suffering from mtDNA depletion. These findings improve our understanding of the effects of specific small-molecule activators of AMPK on mitochondrial and cellular function and suggest a potential application for these compounds in disease states involving mtDNA depletion.
    Keywords:  AMPK; AMP‐activated protein kinase; mitochondrial DNA depletion; polymerase ɣ
    DOI:  https://doi.org/10.1111/febs.70006
  13. J Cell Biol. 2025 Apr 03. pii: e202405002. [Epub ahead of print]224(4):
    VPS41 recruits biosynthetic LAMP-positive vesicles through interaction with Arl8b.
    Paolo Sanzà, Jan van der Beek, Derk Draper, Cecilia de Heus, Tineke Veenendaal, Corlinda Ten Brink, Ginny G Farías, Nalan Liv, Judith Klumperman.
      Vacuolar protein sorting 41 (VPS41), a component of the homotypic fusion and protein sorting (HOPS) complex for lysosomal fusion, is essential for the trafficking of lysosomal membrane proteins via lysosome-associated membrane protein (LAMP) carriers from the trans-Golgi network (TGN) to endo/lysosomes. However, the molecular mechanisms underlying this pathway and VPS41's role herein remain poorly understood. Here, we investigated the effects of ectopically localizing VPS41 to mitochondria on LAMP distribution. Using electron microscopy, we identified that mitochondrial-localized VPS41 recruited LAMP1- and LAMP2A-positive vesicles resembling LAMP carriers. The retention using selective hooks (RUSH) system further revealed that newly synthesized LAMPs were specifically recruited by mitochondrial VPS41, a function not shared by other HOPS subunits. Notably, we identified the small GTPase Arl8b as a critical factor for LAMP carrier trafficking. Arl8b was present on LAMP carriers and bound to the WD40 domain of VPS41, enabling their recruitment. These findings reveal a unique role of VPS41 in recruiting TGN-derived LAMP carriers and expand our understanding of VPS41-Arl8b interactions beyond endosome-lysosome fusion, providing new insights into lysosomal trafficking mechanisms.
    DOI:  https://doi.org/10.1083/jcb.202405002
  14. EMBO J. 2025 Feb 07.
    Arginine: at the crossroads of nitrogen metabolism.
    Tak Shun Fung, Keun Woo Ryu, Craig B Thompson.
      L-arginine is the most nitrogen-rich amino acid, acting as a key precursor for the synthesis of nitrogen-containing metabolites and an essential intermediate in the clearance of excess nitrogen. Arginine's side chain possesses a guanidino group which has unique biochemical properties, and plays a primary role in nitrogen excretion (urea), cellular signaling (nitric oxide) and energy buffering (phosphocreatine). The post-translational modification of protein-incorporated arginine by guanidino-group methylation also contributes to epigenetic gene control. Most human cells do not synthesize sufficient arginine to meet demand and are dependent on exogenous arginine. Thus, dietary arginine plays an important role in maintaining health, particularly upon physiologic stress. How cells adapt to changes in extracellular arginine availability is unclear, mostly because nearly all tissue culture media are supplemented with supraphysiologic levels of arginine. Evidence is emerging that arginine-deficiency can influence disease progression. Here, we review new insights into the importance of arginine as a metabolite, emphasizing the central role of mitochondria in arginine synthesis/catabolism and the recent discovery that arginine can act as a signaling molecule regulating gene expression and organelle dynamics.
    Keywords:  Arginine Deficiency; Arginine Metabolism; Metabolite Signaling; Mitochondria; Protein Synthesis
    DOI:  https://doi.org/10.1038/s44318-025-00379-3
  15. Mol Cell. 2025 Feb 06. pii: S1097-2765(25)00036-X. [Epub ahead of print]85(3): 638-651.e9
    The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism.
    Wang Jiahui, Yu Xiang, Zhong Youhuan, Ma Xiaomin, Gao Yuanzhu, Zhou Dejian, Wang Jie, Fu Yinkun, Fan Shi, Su Juncheng, Huang Masha, Haigis Marcia, Wang Peiyi, Xu Yingjie, Yang Wen.
      Mitochondrial heat shock proteins and co-chaperones play crucial roles in maintaining proteostasis by regulating unfolded proteins, usually without specific target preferences. In this study, we identify a DNAJC-type co-chaperone: T cell activation inhibitor, mitochondria (TCAIM), and demonstrate its specific binding to α-ketoglutarate dehydrogenase (OGDH), a key rate-limiting enzyme in mitochondrial metabolism. This interaction suppresses OGDH function and subsequently reduces carbohydrate catabolism in both cultured cells and murine models. Using cryoelectron microscopy (cryo-EM), we resolve the human OGDH-TCAIM complex and reveal that TCAIM binds to OGDH without altering its apo structure. Most importantly, we discover that TCAIM facilitates the reduction of functional OGDH through its interaction, which depends on HSPA9 and LONP1. Our findings unveil a role of the mitochondrial proteostasis system in regulating a critical metabolic enzyme and introduce a previously unrecognized post-translational regulatory mechanism.
    Keywords:  DNAJC; OGDH; TCAIM; charperon; metabolism; mitochondria; protein degradation; protein interaction; single-particle cryo-EM; α-ketoglutarate dehydrogenase
    DOI:  https://doi.org/10.1016/j.molcel.2025.01.006
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