bims-celmim 2025-07-13 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2025–07–13
twenty-six papers selected by
Marc Segarra Mondejar

Adaptations of lipid metabolism in low-grade clear cell renal cell carcinoma are linked to cholesteryl ester accumulation.
ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.
Delineating the Metabolic Phenotype of Biopsy-Derived Kidney Cells.
Nondisruptive inducible labeling of ER-membrane contact sites using the Lamin B receptor.
PTEN deficiency in postnatally developing Purkinje cells disrupts metabolic signaling, leading to dendritic abnormalities and sex-specific behavioral deficits.
Acetyl-CoA subcellular compartmentalization regulates T cell adaptation.
Clu1/Clu form mitochondria-associated granules upon metabolic transitions and regulate mitochondrial protein translation via ribosome interactions.
Homocysteine interferes with Ndufa1 leading to mitochondrial dysfunction through repression of the NAD+/Sirt1 pathway in the brain: a possible link between hyperhomocysteinemia and neurodegeneration.
The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence.
PINK1 Loss of Function Selectively Alters the Mitochondrial-Derived Vesicle Pathway.
Mid-Infrared Photothermal Imaging of Fatty Acid Desaturation Reaction in Cancer Cells.
ANGPTL3 orchestrates hepatic fructose sensing and metabolism.
MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.
Extremely low-frequency electromagnetic field (ELF-EMF) enhances mitochondrial energy production in NARP cybrids.
The HIF axes in cancer: angiogenesis, metabolism, and immune-modulation.
Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review).
A photoactivatable chemical lipidomics approach for local sphingolipid metabolic analysis.
Sensing of extracellular l-proline availability by the integrated stress response determines the outcome of cell competition.
Circ0515 reprogramming mitochondrial succinate metabolism and promotes lung adenocarcinoma progression through regulating SDHB.
A guide to characterizing the dynamic mitochondria-endoplasmic reticulum contact sites.
Guanosine enhances thermogenesis and impairs KEAP1-mediated NRF2 degradation to resist ferroptosis in brown adipose tissue.
Glycogen supports glycolytic plasticity in neurons.
Baculovirus enhances arginine uptake and induces mitochondrial autophagy to promote viral proliferation.
Mitochondrial Calcium Uniporter-Mediated Regulation of the SIRT3/GSK3β/β-Catenin Signaling Pathway in Vascular Remodeling.
HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise.
Polyamines buffer labile iron to suppress ferroptosis.

Sci Rep. 2025 Jul 09. 15(1): 24762

Adaptations of lipid metabolism in low-grade clear cell renal cell carcinoma are linked to cholesteryl ester accumulation.

Olatz Fresnedo, Jose Antonio Lopez-Gomez, Carlos Ceniceros, Gorka Larrinaga, Alberto Saiz, Lorena Mosteiro, Hiart Navarro-Imaz, Yuri Rueda.

  Clear cell renal cell carcinoma (ccRCC) is characterized by the accumulation of high quantities of lipids in cytoplasmic lipid droplets. Owing to the tissue heterogeneity of ccRCC, adjacent biopsies from a tumor can diverge substantially in molecular characteristics. To elucidate metabolic alterations leading to extensive lipidomic changes in grade 2 human nephrectomies, we applied a dual lipidome-transcriptome analytical procedure that allows performing correlational studies of the two datasets. Linked to the mean 100 fold increase of esterified cholesterol (ChE) in ccRCC we found multiple significant correlations between ChE and the main membrane lipids that might be mediated by an increased capacity for lipid hydrolysis linked to lysosomes and the endoplasmic reticulum.Our results suggest that the accumulation of ChE from extracellular sources might be a determinant metabolic flux in low-grade ccRCC. ChE mobilization by non-canonical hydrolytic systems might confer increased metabolic flexibility to obtain free cholesterol and fatty acids. Based on correlations between lipidome and lipometabolic transcriptome, this study provides new perspectives for evaluating pharmacological lipid management as a future therapeutic approach for low-grade ccRCC treatment.

Keywords:  AADAC; Cholesteryl ester accumulation; Kidney; Lipidomics; Lysosomal acid lipase; ccRCC

DOI:  https://doi.org/10.1038/s41598-025-09664-x
Science. 2025 Jul 10. 389(6756): 157-162

ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.

Laura F DiGiovanni, Prabhsimran K Khroud, Ruth E Carmichael, Tina A Schrader, Shivneet K Gill, Kyla Germain, Robert Y Jomphe, Christoph Wiesinger, Maxime Boutry, Maki Kamoshita, Daniel Snider, Garret Stubbings, Rong Hua, Noel Garber, Christian Hacker, Andrew D Rutenberg, Roman A Melnyk, Johannes Berger, Michael Schrader, Brian Raught, Peter K Kim.

Maintenance of mitochondrial redox homeostasis is of fundamental importance to cellular health. Mitochondria harbor a host of intrinsic antioxidant defenses, but the contribution of extrinsic, nonmitochondrial antioxidant mechanisms is less well understood. We found a direct role for peroxisomes in maintaining mitochondrial redox homeostasis through contact-mediated reactive oxygen species (ROS) transfer. We found that ACBD5 and PTPIP51 form a contact between peroxisomes and mitochondria. The percentage of these contacts increased during mitochondrial oxidative stress and helped to maintain mitochondrial health through the transfer of mitochondrial ROS to the peroxisome lumen. Our findings reveal a multiorganelle layer of mitochondrial antioxidant defense-suggesting a direct mechanism by which peroxisomes contribute to mitochondrial health-and broaden the scope of known membrane contact site functions.

DOI: https://doi.org/10.1126/science.adn2804
J Vis Exp. 2025 Jun 17.

Delineating the Metabolic Phenotype of Biopsy-Derived Kidney Cells.

Masataka Kawamura, Catherine Parmentier, Lisa A Robinson, Markus Selzner, Caitriona M McEvoy, Julia M Murphy, Maya G Bozzo-Rey, Sarah Q Crome, Ana Konvalinka, Sergi Clotet-Freixas.

Kidney transplantation is the optimal treatment for end-stage kidney disease; however, transplanted kidneys are often lost prematurely, with up to 50% graft loss at 10 years post-transplant. One of the major causes of premature graft loss is the injury sustained by the graft at the time of transplantation, known as ischemia-reperfusion injury (IRI). Delayed graft function (DGF), defined as the need for dialysis in the first week post-transplant, is a manifestation of severe IRI that shows functional and histologic features of acute kidney injury (AKI). While the mechanisms driving AKI remain unclear, accumulating evidence suggests that altered metabolic function in the allograft mediates AKI and may be the reason for DGF. Thus, deciphering and monitoring the metabolic underpinnings of IRI will improve our capacity to diagnose and prevent AKI. This article describes a unique method to assess mitochondrial respiration (by means of oxygen consumption rate), glycolysis (extracellular acidification rate), and intracellular ATP levels in needle biopsy-derived kidney cell suspensions. The methodology has been optimized in healthy adult male pigs and validated in a porcine model of auto-transplantation. The approach presented has the potential to enhance the real-time assessment of kidney allograft viability in the clinic. Profiling metabolism in patient-derived biopsies may also uncover new biology in other metabolism-based kidney diseases.

DOI: https://doi.org/10.3791/65457
PLoS Biol. 2025 Jul;23(7): e3003249

Nondisruptive inducible labeling of ER-membrane contact sites using the Lamin B receptor.

Laura Downie, Nuria Ferrandiz, Elizabeth Courthold, Megan Jones, Stephen J Royle.

Membrane contact sites (MCSs) are areas of close proximity between organelles that allow the exchange of material, among other roles. The endoplasmic reticulum (ER) has MCSs with a variety of organelles in the cell. MCSs are dynamic, responding to changes in cell state, and are, therefore, best visualized through inducible labeling methods. However, existing methods typically distort ER-MCSs, by expanding contacts or creating artificial ones. Here, we describe a new method for inducible labeling of ER-MCSs using the Lamin B receptor (LBR) and a generic anchor protein on the partner organelle. Termed LaBeRling, this versatile, one-to-many approach allows labeling of different types of ER-MCSs (mitochondria, plasma membrane, lysosomes, early endosomes, lipid droplets, and Golgi), on-demand, in interphase or mitotic human cells. LaBeRling is nondisruptive and does not change ER-MCSs in terms of the contact number, extent or distance measured; as determined by light microscopy or a deep-learning volume electron microscopy approach. We applied this method to study the changes in ER-MCSs during mitosis and to label novel ER-Golgi contact sites at different mitotic stages in live cells.

DOI: https://doi.org/10.1371/journal.pbio.3003249
Sci Rep. 2025 Jul 08. 15(1): 24460

PTEN deficiency in postnatally developing Purkinje cells disrupts metabolic signaling, leading to dendritic abnormalities and sex-specific behavioral deficits.

Lindsay J Walsh, Izabella M Espinal-San Miguel, Ana V Rodriguez, Ursula M Peña, Kiley E Flynn, Will C Remillard, Siena R Brazier, Natalia I Anderson, Aidan J Clark, Tiffany A De Varona, Ileana Soto.

  Conditional deletion of the Pten gene in cerebellar Purkinje cells (PCs) results in cellular hypertrophy, neurodegeneration, and autism-like behaviors in adult mice. Here, we investigated the effects of PTEN conditional deficiency on PC dendritic development and early postnatal motor, spontaneous, and social behaviors. We found that Pten loss disrupts dendritic growth by altering mTOR signaling and reducing AMPK phosphorylation, leading to early motor deficits and sex-specific behavioral alterations. In vivo analysis revealed significant reductions in mitochondrial and lysosomal volume in developing dendrites. Notably, ex vivo treatment with AICAR (an AMPK activator) or Torin1 (an mTOR inhibitor) partially restored dendritic organelle content in Pten-deficient PCs. These findings suggest that PTEN is critical for maintaining metabolic balance during postnatal dendritic maturation, and its loss leads to structural and functional impairments in PCs that contribute to behavioral phenotypes in a sex- and age-dependent manner.

Keywords:  AICAR; AMPK; Lysosomes; Mitochondria; PTEN; Purkinje cells; Torin1; mTORC1

DOI:  https://doi.org/10.1038/s41598-025-09059-y
Cell Immunol. 2025 Jun 28. pii: S0008-8749(25)00086-3. [Epub ahead of print]414 105000

Acetyl-CoA subcellular compartmentalization regulates T cell adaptation.

Annefien Tiggeler, Paul J Coffer.

  Upon activation, naïve T cells undergo rapid proliferation and differentiation, giving rise to clonally expanded populations specifically tailored for an effective immune response. To meet the heightened bioenergetic and biosynthetic demands associated with activation, T cells adapt and reprogram both their metabolism and transcriptome. Beyond this, T cells are also able to dynamically adapt to fluctuations in the microenvironmental nutrient levels. While the adaptability of T cells is a well-established hallmark of their functionality, the molecular mechanisms by which metabolic responses underpin this flexibility remain incompletely defined. Acetyl-CoA, with its role as a central metabolite in mitochondrial ATP production, and a substrate for nuclear histone acetylation reactions, emerges as a key player in a metabolic-epigenetic axis. Recent evidence indicates that enzymes responsible for generating acetyl-CoA can translocate to the nucleus, supporting sub-cellular local acetyl-CoA production. Here, we explore the impact of acetyl-CoA metabolism on T cell functionality within different subcellular compartments and highlight the potential for intervention in acetyl-CoA metabolic pathways in T cell-driven autoimmune diseases and cancers.

Keywords:  Acetyl-CoA; Epigenetic remodelling; Metabolic reprogramming; Nuclear metabolism; T cells

DOI:  https://doi.org/10.1016/j.cellimm.2025.105000
PLoS Genet. 2025 Jul 07. 21(7): e1011773

Clu1/Clu form mitochondria-associated granules upon metabolic transitions and regulate mitochondrial protein translation via ribosome interactions.

Leonor Miller-Fleming, Wing Hei Au, Laura Raik, Pedro Rebelo-Guiomar, Jasper Schmitz, Ha Yoon Cho, Aron Czako, Alexander J Whitworth.

Mitochondria perform essential metabolic functions and respond rapidly to changes in metabolic and stress conditions. As the majority of mitochondrial proteins are nuclear-encoded, intricate post-transcriptional regulation is crucial to enable mitochondria to adapt to changing cellular demands. The eukaryotic Clustered mitochondria protein family has emerged as an important regulator of mitochondrial function during metabolic shifts. Here, we show that the Drosophila melanogaster and Saccharomyces cerevisiae Clu/Clu1 proteins form dynamic, membraneless, mRNA-containing granules adjacent to mitochondria in response to metabolic changes. Yeast Clu1 regulates the translation of a subset of nuclear-encoded mitochondrial proteins by interacting with their mRNAs while these are engaged in translation. We further show that Clu1 regulates translation by interacting with polysomes, independently of whether it is in a diffuse or granular state. Our results demonstrate remarkable functional conservation with other members of the Clustered mitochondria protein family and suggest that Clu/Clu1 granules isolate and concentrate ribosomes engaged in translating their mRNA targets, thus, integrating metabolic signals with the regulation of mitochondrial protein synthesis.

DOI: https://doi.org/10.1371/journal.pgen.1011773
Cell Death Dis. 2025 Jul 07. 16(1): 499

Homocysteine interferes with Ndufa1 leading to mitochondrial dysfunction through repression of the NAD+/Sirt1 pathway in the brain: a possible link between hyperhomocysteinemia and neurodegeneration.

Gaoshang Chai, Yuming Mao, Juan Gong, Shuguang Bi, Yuqi Zhang, Jiajun Wu, Liu Yang, Tianlong Gao, Haitian Fu, Chunjing Yu, Caili Ren, Guofu Zhang, Xuming Zhu, Xin Guan, Haoting Yu, Caijing Tang, Yunjuan Nie, Haitao Yu.

Mitochondrial defects are early pathological changes in neurodegenerative disease (ND). Homocysteine (Hcy) is an independent risk factor for ND. However, whether and how Hcy induces mitochondrial defects during the process of neurodegeneration is unclear. Here, we revealed that Hcy interfered with mitochondrial oxidative phosphorylation (OXPHOS) by inhibiting the mitochondrial electron transport chain (ETC) complex I, resulting in increased levels of reactive oxygen species (ROS) in the hippocampus of rats. Specifically, Hcy suppressed Ndufa1 expression, which is essential for complex I assembly and activation, by interfering with its transcription factor Creb1. Moreover, we found that Hcy induced neurodegeneration-like pathological changes in mitochondria in the brain via the inhibition of the NAD+/Sirt1 pathway, including defects in mitochondrial morphology, mitochondrial biogenesis, and mitophagy, ultimately leading to impairments in synapses and cognition, all of which were reversed by Ndufa1 upregulation. Thus, Ndufa1 is a key molecular switch of Hcy-induced mitochondrial damage, and appropriately targeting Ndufa1 or NAD+ replenishment may serve as a novel therapeutic strategy for Hcy-induced neurodegeneration and cognitive impairment.

DOI: https://doi.org/10.1038/s41419-025-07834-3
Elife. 2025 Jul 07. pii: RP101984. [Epub ahead of print]13

The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence.

Fan Zhang, Yuan Wang, Luyang Zhang, Chunjie Wang, Deping Chen, Haibo Liu, Ren Xu, Cole M Haynes, Jae-Hyuck Shim, Xianpeng Ge.

  The dysfunction of the cellular endolysosomal pathway, such as in lysosomal storage diseases, can cause severe musculoskeletal disorders. However, how endolysosomal dysfunction causes musculoskeletal abnormalities remains poorly understood, limiting therapeutic options. Here, we report that CHMP5, a member of the endosomal sorting complex required for transport (ESCRT)-III protein family, is essential to maintain the endolysosomal pathway and regulate bone formation in osteogenic lineage cells. Genetic ablation of Chmp5 in mouse osteogenic cells increases bone formation in vivo and in vitro. Mechanistically, Chmp5 deletion causes endolysosomal dysfunction by decreasing the VPS4A protein, and CHMP5 overexpression is sufficient to increase the VPS4A protein. Subsequently, endolysosomal dysfunction disturbs mitochondrial functions and increases mitochondrial ROS, ultimately resulting in skeletal cell senescence. Senescent skeletal cells cause abnormal bone formation by combining cell-autonomous and paracrine actions. Importantly, the elimination of senescent cells using senolytic drugs can alleviate musculoskeletal abnormalities in Chmp5 conditional knockout mice. Therefore, our results show that cell senescence represents an underpinning mechanism and a therapeutic target for musculoskeletal disorders caused by the aberrant endolysosomal pathway, such as in lysosomal storage diseases. These results also uncover the function and mechanism of CHMP5 in the regulation of cell senescence by affecting the endolysosomal-mitochondrial pathway.

Keywords:  CHMP5; bone; cell biology; cell senescence; endolysosomal pathway; medicine; mouse; musculoskeletal disease; skeletal stem cell

DOI:  https://doi.org/10.7554/eLife.101984
FASEB Bioadv. 2025 Jul;7(7): e70030

PINK1 Loss of Function Selectively Alters the Mitochondrial-Derived Vesicle Pathway.

Charlotte L Collier, Colleen Ruedi, Naomi J Thorne, David A Tumbarello.

  Cell homeostasis and metabolic control require the efficient function of mitochondria and implementation of quality control pathways following damage. Cells have various discrete pathways of mitochondrial quality control (mitoQC) to maintain the healthy network. PINK1 and Parkin are two key players in mitoQC, most highly associated with the ubiquitin-dependent capture and degradation of whole mitochondria by autophagy. However, these proteins have alternative roles in repair routes directing locally damaged cargo to the lysosome, such as the mitochondrial-derived vesicle (MDV) pathway. We aimed to clarify the role of PINK1 and determine how its loss of function impacts mitochondrial dynamics and quality control. Results indicate PINK1 knockout (KO) has little impact on whole mitochondrial turnover in response to damage in SH-SY5Y cells, whereas both PINK1 and Parkin KO cells have healthy mitochondrial networks with efficient ATP production. However, TOM20 positive outer-membrane and damage-induced PDH-positive inner-membrane MDVs are elevated in PINK1 KO cells. Although, in contrast to Parkin KO, this is not due to a defect in trafficking to a LAMP1-positive compartment and may instead indicate increased damage-induced flux. In comparison, loss of Atg5-dependent mitophagy has no effect on whole mitochondrial turnover and only results in a limited elevation in inner-membrane MDVs in response to damage, indicating autophagy-independent mechanisms of whole mitochondrial turnover and a minor compensatory increase in damage-induced MDVs. Therefore, these data suggest PINK1 and Parkin are dispensable for whole mitochondrial turnover, but following their perturbation have disparate effects on the MDV pathway.

Keywords:  Parkinson's; lysosome; membrane trafficking; mitochondria; mitochondrial quality control; vesicle transport

DOI:  https://doi.org/10.1096/fba.2024-00200
bioRxiv. 2025 Jul 05. pii: 2025.07.02.662881. [Epub ahead of print]

Mid-Infrared Photothermal Imaging of Fatty Acid Desaturation Reaction in Cancer Cells.

Xinyan Teng, Tianyu Xia, Jiaze Yin, Mingsheng Li, Jianpeng Ao, Guangrui Ding, Chinmayee V Prabhu Dessai, Ana Maria Isac, Daniela Matei, Hongjian He, Ji-Xin Cheng.

Direct visualization of metabolic conversions within living systems is essential for understanding metabolic activities yet challenging due to the absence of reaction-specific reporters and the limited sensitivity of current imaging modalities. Herein, we report an approach to monitor fatty acids (FAs) desaturation, primarily catalyzed by stearoyl-CoA desaturase, in cancer cells using deuterium (D)-labeled palmitic acid (PA-d31) as the reaction-specific reporter and mid-infrared photothermal (MIP) microscopy as the bond-selective imaging modality. The desaturation of PA-d31 produced a peak at 2246 cm-1 in the cell-silent region, corresponding to the stretching vibration of unsaturated C-D bonds (D-C=C-D) in unsaturated fatty acids. Penalized least squares fitting was employed to remove water background for enhancing the visibility of this peak. Our study revealed heterogeneous spatial distributions of both saturated FAs and their desaturated metabolites within lipid droplet pools in cancer cells. Furthermore, we observed an increase in fatty acid unsaturation level in OVCAR5 cells under cisplatin-induced stress. By directly visualizing fatty acid desaturation, this study offers new insights into fatty acid metabolism and opens avenues for evaluating new therapeutic strategies targeting fatty acid metabolism.

DOI: https://doi.org/10.1101/2025.07.02.662881
Cell Rep. 2025 Jul 09. pii: S2211-1247(25)00733-8. [Epub ahead of print]44(7): 115962

ANGPTL3 orchestrates hepatic fructose sensing and metabolism.

Meng Zhao, Karen Y Linde-Garelli, Zeyuan Zhang, David Toomer, Saranya C Reghupaty, John Isaiah Jimenez, Laetitia Coassolo, Lianna W Wat, Daniel Fernandez, Katrin J Svensson.

  Fructose metabolism is linked to metabolic dysfunction-associated steatotic liver disease (MASLD), but the regulatory mechanisms governing fructose uptake remain poorly understood. Here, we demonstrate that MASLD livers exhibit increased uptake of fructose-derived carbons compared to healthy livers and identify that the MASLD hepatocyte secretome can increase fructose metabolism. By performing fractionation and untargeted proteomics, we uncover a role for Angiopoietin-like 3 (ANGPTL3) as a regulator of hepatic fructose metabolism, independent of its role as a lipoprotein lipase (LPL) inhibitor. Circulating ANGPTL3 levels increase in response to fructose exposure, consistent with an action as a fructose sensor. Angptl3 knockdown in the liver resulted in a significant reduction in the uptake of hepatic fructose metabolites in vivo and downregulation of the facilitative hepatic fructose transporter slc2a8 (GLUT8) and fructolysis enzymes. This work demonstrates the existence of extracellular control of hepatic fructose metabolism through ANGPTL3.

Keywords:  ANGPTL3; CP: Metabolism; MASLD; fructolysis; fructose

DOI:  https://doi.org/10.1016/j.celrep.2025.115962
J Cell Sci. 2025 Jul 01. pii: jcs263701. [Epub ahead of print]138(13):

MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.

Michal Wasilewski, Karthik Mohanraj, Maciej Zakrzewski, Remigiusz A Serwa, Agnieszka Chacinska.

  Most mitochondrial proteins are imported through the actions of the presequence translocase of the inner membrane, the TIM23 complex, which requires energy in the form of the electrochemical potential of the inner membrane and ATP. Conversions of energy in mitochondria are disturbed in mitochondrial disorders that affect oxidative phosphorylation. Despite the widely accepted dependence of protein import into mitochondria on mitochondrial bioenergetics, effects of mitochondrial disorders on biogenesis of the mitochondrial proteome are poorly characterized. Here, we describe molecular tools that can be used to explore mitochondrial protein import in intact cells, the mitoRUSH assay, and a novel method based on labeling of nascent proteins with an amino acid analog and click chemistry. Using these orthogonal approaches, we discovered that defects in the electron transport chain and manipulating the expression of TIMM23, as well as the TIMM17A or TIMM17B paralogs, in human cells are associated with a decrease in protein import into mitochondria. We postulate that in the absence of a functional electron transfer chain, the mechanisms that support electrochemical potential of the inner membrane and ATP production are insufficient to sustain the import of proteins to mitochondria.

Keywords:  Bioenergetics; Mitochondria; Mitochondrial diseases; Protein import; TIM23; Translocase; mitoRUSH

DOI:  https://doi.org/10.1242/jcs.263701
Sci Rep. 2025 Jul 08. 15(1): 24369

Extremely low-frequency electromagnetic field (ELF-EMF) enhances mitochondrial energy production in NARP cybrids.

Mikako Ito, Zhizhou Huang, Kosaku Nomura, Masaki Teranishi, Fei Zhao, Hiroyuki Mino, Makoto Yoneda, Masashi Tanaka, Kinji Ohno.

  A mutation (m.8993T > G) in MT-ATP6 in mitochondrial DNA (mtDNA) causes the neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome by impairing mitochondrial energy production. Extremely low-frequency electromagnetic field (ELF-EMF) suppresses mitochondrial oxidative phosphorylation (OXPHOS) Complex II and induces mitohormetic activation of mitochondrial OXPHOS activities. We examined the effects of ELF-EMF on normal cybrids carrying 100% wild-type mtDNA (2SA cybrids) and NARP cybrids carrying 40% wild-type and 60% mutant mtDNA (NARP3-2 cybrids). We found that ELF-EMF had no effect on the copy number of mtDNA either in 2SA or NARP3-2 cybrids, or the ratio of wild-type-to-mutant mtDNA in NARP3-2 cybrids. Instead, ELF-EMF increased the transcription of mtDNA and the transcription ratio of wild-type-to-mutant mtDNA in NARP3-2 cybrids. In addition, ELF-EMF increased the expression of mitochondrial OXPHOS proteins and the mitochondrial OXPHOS Complex V activity in NARP3-2 cybrids. ELF-EMF upregulated fission-promoting phosphorylation of DRP1, as well as the expression of fusion-promoting MFN1 and MFN2, in NARP3-2 cybrids. ELF-EMF also increased ATP production estimated by oxygen consumption rates (OCR) and by a biochemical assay in NARP3-2 cybrids. Hormetic activation of mitochondria by ELF-EMF is likely to be effective to ameliorate defective mitochondrial energy production in NARP and other mitochondrial diseases.

Keywords:  And mitohormesis; Extremely low-frequency electromagnetic field (ELF-EMF); Mitochondrial DNA; Mitochondrial biogenesis; Mitophagy; Neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome

DOI:  https://doi.org/10.1038/s41598-025-10536-7
Trends Biochem Sci. 2025 Jul 09. pii: S0968-0004(25)00135-5. [Epub ahead of print]

The HIF axes in cancer: angiogenesis, metabolism, and immune-modulation.

Karen Acuña-Pilarte, Mei Yee Koh.

  The hypoxia-inducible factors (HIFs) are central transcriptional mediators of the cellular response to hypoxia. HIF activation typically drives a physiologically beneficial adaptive response to hypoxia. However, within solid tumors, the HIF-driven adaptation to hypoxia results in alterations within major cancer cell signaling axes, including those regulating angiogenesis, metabolism, and immune modulation, which profoundly impact tumor progression. This review describes established and recent findings of the role of HIFs in the regulation of these major axes, and the impact of the 'HIF axes' on tumor progression and response to therapy. Current and emerging therapies targeting these axes will also be discussed.

Keywords:  hypoxia; hypoxia-inducible factor (HIF); metabolic reprogramming; solid tumors; therapeutics targeting; tumor microenvironment

DOI:  https://doi.org/10.1016/j.tibs.2025.06.005
Int J Mol Med. 2025 Sep;pii: 139. [Epub ahead of print]56(3):

Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review).

Yunlong Sun, Kaifang Wei, Xudong Liao, Jian'an Wang, Li'na Gao, Bo Pang.

  Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and neuroinflammation, with microglial dysfunction emerging as a central driver of pathogenesis. Microglia, the central nervous system‑resident immune cells, exhibit dual pro‑inflammatory and anti‑inflammatory phenotypes, dynamically regulated by lipid metabolic reprogramming. Chronic activation of M1 microglia exacerbates neuronal damage, while M2 microglia promote tissue repair via phagocytic clearance and neurotrophic factor secretion. Lipid dysregulation‑marked by ceramide accumulation, cholesterol esterification defects and oxidized lipid‑driven neuroinflammation‑critically modulates microglial polarization. Mechanistic studies reveal that mitochondrial dysfunction, lysosomal stress and ferroptosis intersect with lipid metabolic pathways to amplify neurotoxicity. Therapeutic strategies targeting lipid homeostasis, such as TREM2 agonism, demonstrate efficacy in preclinical models by restoring microglial function and mitigating pathology. This review synthesizes emerging evidence linking microglial lipid metabolism to NDD progression, highlighting novel biomarkers and therapeutic avenues to disrupt the lipid‑neuroinflammation axis in neurodegeneration.

Keywords:  ferroptosis; lipid metabolism; microglia; neurodegeneration

DOI:  https://doi.org/10.3892/ijmm.2025.5580
Methods. 2025 Jul 08. pii: S1046-2023(25)00149-5. [Epub ahead of print]

A photoactivatable chemical lipidomics approach for local sphingolipid metabolic analysis.

Xiaoxue Wang, Zhiyi Zhang, Shuwei Tian, Suihan Feng.

  In eukaryotic cells, lipid metabolism is tightly regulated depending on the subcellular localization, which is essential for maintaining lipid homeostasis. However, understanding compartmentalized lipid metabolism remains challenging due to limited availability of suitable techniques. In this study, we present a chemical lipidomics approach that combines photoactivatable probes with high resolution mass spectrometry and stable-isotope labelling to analyze lipid dynamics at subcellular resolution. We applied this method to analyze the metabolism of 1-deoxysphingolipid (DoxSL), a non-canonical lipid species linked to various metabolic diseases and neuropathy, whose metabolism remains largely unexplored. Using the photoactivatable probes, we selectively delivered 1-deoxysphinganine, a key DoxSL intermediate, to mitochondria upon photo-illumination and subsequently analyzed its local metabolic products over time. Our data show that most 1-deoxysphinganine delivered to mitochondria is rapidly converted into 1-deoxyceramides, while only a small fraction forms oxidized products. Further lipidomic analysis revealed that 1-deoxyceramides are transported to the extracellular space and that DoxSL is also present in mouse and human serum samples. In summary, we developed novel probes to track lipid dynamics with high spatiotemporal resolution in a non-invasive manner and provided new insights into sphingolipid metabolism.

Keywords:  1-Deoxysphingolipid; Chemical lipidomics; Lipid metabolism; Photoactivatable probes

DOI:  https://doi.org/10.1016/j.ymeth.2025.07.002
Sci Adv. 2025 Jul 11. 11(28): eadw1883

Sensing of extracellular l-proline availability by the integrated stress response determines the outcome of cell competition.

Shruthi Krishnan, Ana Lima, Sizhe Tan, Ying Thong Low, Salvador Perez Montero, Aida Di Gregorio, Adrian Perez Barreto, Sarah Bowling, Karen Vousden, Tristan A Rodriguez.

Cell competition is a conserved fitness quality control that eliminates cells that are less fit than their neighbors. How winner cells induce the elimination of losers is poorly understood. We tackle this question by studying the onset of embryonic differentiation in mice, where cell competition eliminates 35% of embryonic cells. These loser cells have mitochondrial dysfunction, which we show causes amino acid deprivation and activation of the integrated stress response (ISR), a pathway essential for their survival. We demonstrate that l-proline is a key amino acid sensed by the ISR and that proline represses the ISR and drives their elimination. These results indicate that cell competition acts as a previously unidentified tissue-sparing mechanism, regulated by the availability of extracellular amino acids, that allows for the elimination of dysfunctional cells when amino acids are plentiful but ensures their survival in nutrient-poor environments.

DOI: https://doi.org/10.1126/sciadv.adw1883
Cell Death Dis. 2025 Jul 05. 16(1): 497

Circ0515 reprogramming mitochondrial succinate metabolism and promotes lung adenocarcinoma progression through regulating SDHB.

Yixiao Yuan, Yue Wu, Chunhong Li, Zuotian Huang, Dadi Peng, Zhongjun Wu, Xiulin Jiang.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide. Its high incidence and poor prognosis are closely associated with complex molecular mechanisms. Circular RNAs (circRNAs), a class of non-coding RNAs, play significant regulatory roles in tumorigenesis and progression. However, their specific functions and mechanisms in lung cancer remain largely unclear. This study aims to elucidate the expression pattern and molecular mechanisms of circ0515 in lung cancer, particularly its roles in tumor proliferation, migration, and metabolism. The study revealed that circ0515 is significantly upregulated in lung cancer tissues and cell lines, specific knockdown of circ0515 using short hairpin RNA (shRNA) or antisense oligonucleotide (ASO) significantly inhibits lung cancer cell proliferation, migration, and xenograft tumor formation. On one hand, circ0515 acts as a molecular sponge for miRNA-328-3p, upregulating its downstream target gene YWHAZ, thereby activating the AKT signaling pathway and significantly promoting lung cancer cell proliferation and migration. On the other hand, circ0515 recruited RNA binding motif protein 45 (RBM45) to stabilize SDHB mRNA, promoting SDHB expression and mitochondrial oxidative phosphorylation and succinate metabolism, leading to increased cisplatin resistance in lung cancer cells. These findings not only advance our understanding of the functional roles of circ0515 in lung cancer but also provide a theoretical basis for considering circ0515 as a potential therapeutic target for NSCLC.

DOI: https://doi.org/10.1038/s41419-025-07830-7
FEBS J. 2025 Jul 07.

A guide to characterizing the dynamic mitochondria-endoplasmic reticulum contact sites.

Antigoni Diokmetzidou, Luca Scorrano.

  Organelles were once regarded as discrete entities, but it is now established that they interact through specialized membrane contacts maintained by protein tethers and lipid interactions. Among these, mitochondria-endoplasmic reticulum contact sites (MERCS) emerged as hubs for calcium signaling, lipid metabolism, and mitochondrial dynamics. Here, we critically appraise current methodologies for MERC visualization and quantification, survey the molecular toolbox for their selective perturbation, and highlight common experimental pitfalls. We also discuss key conceptual issues-defining MERCs on structural and functional grounds, addressing redundancy among tethering factors, and distinguishing primary MERC-mediated effects from secondary cellular responses. Finally, we propose that an integrative strategy combining imaging, precise biochemical isolation, proteomics, and functional assays will be essential to resolve outstanding questions about MERC dynamics in physiology and pathology.

Keywords:  endoplasmic reticulum; imaging; membrane contact sites; mitochondria; mitochondria–ER contact sites

DOI:  https://doi.org/10.1111/febs.70184
Free Radic Biol Med. 2025 Jul 03. pii: S0891-5849(25)00807-X. [Epub ahead of print]238 360-369

Guanosine enhances thermogenesis and impairs KEAP1-mediated NRF2 degradation to resist ferroptosis in brown adipose tissue.

Yiping Tang, Mengfei Zhao, Nannan Wang, Hongyu Nie, Jiangwei Song, Ziyue Zhou, Wenjuan Tang, Jingzi Zhang, Chaojun Li, Lei Fang.

  Brown adipose tissue (BAT) is the primary site of non-shivering thermogenesis, playing a crucial role in the regulation of glucose and lipid metabolism, as well as energy balance. In-depth research on BAT can aid in identifying therapeutic targets for various metabolic diseases. In this study, we conducted transcriptomic analysis and found significant changes in ferroptosis-related genes in BAT of mice following cold exposure. The notable decrease in GPX4 and reduced levels of glutathione, along with increased levels of malondialdehyde and ferrous ions, further suggest that ferroptosis may occur in mouse BAT under cold exposure. Cellular experiments indicated that the thermogenic and lipolytic capacities of brown adipocytes are impaired due to ferroptosis. Additionally, non-targeted metabolomic analysis revealed significant alterations in a group of purine nucleotide metabolites (GMP, guanosine, inosine, xanthine, hypoxanthine, and guanine) in mouse serum after cold exposure. Notably, guanosine was shown to enhance UCP1 expression and lipolytic capacity in brown adipocytes. Furthermore, guanosine can partially rescue ferroptosis of brown adipocytes by competitively binding to KEAP1, thereby activating the KEAP1-NRF2 pathway. Our study demonstrates that ferroptosis may occur in BAT under cold exposure, and guanosine acts as a thermogenic enhancer to resist cold-induced ferroptosis by targeting KEAP1 to disrupt KEAP1-NRF2 interaction.

Keywords:  Brown adipose tissue; Ferroptosis; Guanosine; KEAP1-NRF2

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.07.003
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2509003122

Glycogen supports glycolytic plasticity in neurons.

Milind Singh, Aaron D Wolfe, Anjali A Vishwanath, Anastasia Tsives, Ian J Gonzalez, Sarah E Emerson, Richard Goodman, Daniel Colón-Ramos.

  Glycogen is the largest energy reserve in the brain, but the specific role of glycogen in supporting neuronal energy metabolism in vivo is not well understood. We established a system in Caenorhabditis elegans to dynamically probe glycolytic states in single cells of living animals via the use of the glycolytic sensor HYlight and determined that neurons can dynamically regulate glycolysis in response to activity or transient hypoxia. We performed an RNAi screen and identified that PYGL-1, an ortholog of the human glycogen phosphorylase, is required in neurons for glycolytic plasticity. We determined that neurons employ at least two mechanisms of glycolytic plasticity: glycogen-dependent glycolytic plasticity (GDGP) and glycogen-independent glycolytic plasticity. We uncover that GDGP is employed under conditions of mitochondrial dysfunction, such as transient hypoxia or in mutants for mitochondrial function. We find that the loss of GDGP impairs glycolytic plasticity and is associated with defects in synaptic vesicle recycling during hypoxia. Together, our study reveals that, in vivo, neurons can directly use glycogen as a fuel source to sustain glycolytic plasticity and synaptic function.

Keywords:  C. elegans; glycogen utilization; glycolytic biosensor; glycolytic plasticity; neuronal metabolism

DOI:  https://doi.org/10.1073/pnas.2509003122
PLoS Pathog. 2025 Jul 08. 21(7): e1013331

Baculovirus enhances arginine uptake and induces mitochondrial autophagy to promote viral proliferation.

Shigang Fei, Junming Xia, Yigui Huang, Minyang Zhou, Biying Xie, Yibing Kong, Luc Swevers, Jingchen Sun, Min Feng.

As obligatory intracellular parasites, viruses must rely on metabolic reprogramming of host cells to meet their replication needs. Baculovirus is an important biopesticide and a vector for the preparation of biological products. In addition, one of its representative species, Bombyx mori nucleopolyhedrovirus (BmNPV-Baculoviridae), also causes huge losses to the insect industry. In our previous study, amino acid metabolism has been found to play a crucial role in the BmNPV infection process. However, the mechanisms by which BmNPV reprograms host amino acid metabolism remains unclear. In fact, current insights in the importance of amino acid metabolism are limited to the impact of glutamine on viral infection. Therefore, unraveling the mechanism of amino acid metabolism reprogramming induced by baculovirus would advance this field of research to a great extent. In this study, targeted metabolomics revealed that the preferred amino acids of BmNPV budded virus (BV) include arginine, lysine, proline, isoleucine, histidine and others. In addition, most of the viral amino acids were found to be increased in the hemolymph of BmNPV infected silkworms at the later stage of infection, especially arginine, valine, phenylalanine and others. Furthermore, the importance of arginine for BmNPV proliferation was validated. Next, we confirmed that the expression of the arginine transporter Slc7a6 was strongly induced by BmNPV infection and that Slc7a6 could promote arginine uptake to support BmNPV proliferation in host cells. Moreover, using Slc7a6 knockout cells which eliminate extracellular arginine uptake, we confirmed that BmNPV could induce mitochondrial autophagy, thereby supplementing intracellular arginine and providing necessary amino acids for BmNPV proliferation. Overall, these findings support a model in which baculovirus (BmNPV) enhances the uptake of exogenous amino acids by inducing the expression of amino acid transporters and activating autophagy of organelles to maintain intracellular amino acid levels, thereby facilitating virus proliferation.

DOI: https://doi.org/10.1371/journal.ppat.1013331
FASEB J. 2025 Jul 15. 39(13): e70761

Mitochondrial Calcium Uniporter-Mediated Regulation of the SIRT3/GSK3β/β-Catenin Signaling Pathway in Vascular Remodeling.

Min Jiang, Lejian Lin, Shuai Yue, Shujin Shi, Haojie Yan, Hui Yi, Fan Han, Shuai Xu, Junjie Su, Ran Zhang.

  Calcium homeostasis plays a crucial role in regulating the phenotype of vascular smooth muscle cells (VSMCs) and vascular remodeling. This study aims to investigate the role of the mitochondrial calcium uniporter (MCU), which facilitates the uptake of Ca2+ into the mitochondria, in vascular remodeling and its underlying regulatory mechanisms. Vascular remodeling in rats was induced through either 21-day hindlimb unloading (HU) or 21-day angiotensin II (Ang II) infusion (0.7 mg/kg/day). Phenotypic switching of VSMCs and vascular remodeling were assessed. To induce phenotypic switching and clarify the underlying regulatory mechanisms, VSMCs were treated with Ang II (100 μmol/L). Gene manipulation was performed using plasmids, lentivirus, and adeno-associated virus serotype 9 (AAV9). Mitochondrial oxidative stress, Ca2+ distribution, and the expression of MCU, SIRT3, GSK3β, and β-catenin, along with GSK3β activity, SIRT3 ubiquitination, and GSK3β acetylation, were evaluated. The expression of MCU and SIRT3 in rat cerebral arteries was downregulated following HU and Ang II administration, which resulted in an increase in cytoplasmic Ca2+, a decrease in mitochondrial Ca2+, and a shift toward a synthetic phenotype in VSMCs. In vitro, Ang II treatment of VSMCs led to reduced expression of MCU, SIRT3, and GSK3β, and increased nuclear translocation of β-catenin. Knockdown of MCU caused an increase in cytoplasmic Ca2+ and a reduction in mitochondrial Ca2+, while MCU overexpression had the opposite effect, decreasing cytoplasmic Ca2+ and increasing mitochondrial Ca2+. Additionally, MCU overexpression decreased SIRT3 ubiquitination, mitochondrial oxidative stress, GSK3β acetylation, nuclear translocation of β-catenin, and VSMC phenotypic switching-these effects were blocked by SIRT3 knockdown. Moreover, MCU overexpression partially mitigated vascular remodeling in HU and hypertensive rats by inhibiting the GSK3β/β-catenin pathway and preserving SIRT3. Ang II regulates MCU protein expression, which is reduced in the HU and Ang II-induced hypertensive rat cerebral arteries. This reduction impairs cellular Ca2+ buffering and promotes mitochondrial oxidative stress. The stress response triggers the downstream degradation of SIRT3, which subsequently inhibits the activity of GSK3β via acetylation and promotes the nuclear translocation of β-catenin, thereby facilitating phenotypic switching and vascular remodeling.

Keywords:  GSK3β/β‐catenin; SIRT3; angiotensin II; calcium; hindlimb unloading; microgravity; mitochondrial calcium uniporter; vascular remodeling

DOI:  https://doi.org/10.1096/fj.202500369RR
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2504080122

HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise.

Amy M Ehrlich, Kirstin A MacGregor, Stephen P Ashcroft, Lewin Small, Ali Altıntaş, Alexander V Chibalin, Matthias Anagho-Mattanovich, Ben Stocks, Thomas Moritz, Jonas T Treebak, Juleen R Zierath.

  The regulation of metabolism in peripheral tissues is intricately linked to circadian rhythms, with hypoxia-inducible factor-1α (HIF1α) implicated in modulating time-of-day-specific exercise responses. To investigate this relationship, we generated a skeletal muscle-specific HIF1α knockout (KO) mouse model and performed extensive metabolic phenotyping and transcriptomic profiling under both basal conditions and following acute exercise during early rest (ZT3) and active (ZT15) phases. Our findings reveal that HIF1α drives a more robust transcriptional and glycolytic response to exercise at ZT3, promoting glucose oxidation and mannose-6-phosphate production while potentially sparing fatty acid oxidation. In the absence of HIF1α, skeletal muscle metabolism shifts toward oxidative pathways at ZT3, with notable alterations in glucose fate. These results establish HIF1α as an important regulator of time-of-day-specific metabolic adaptations, integrating circadian and energetic signals to optimize substrate utilization. This work highlights the broader significance of HIF1α in coordinating circadian influences on metabolic health and exercise performance.

Keywords:  circadian; energy metabolism; exercise; metabolism; transcription factor

DOI:  https://doi.org/10.1073/pnas.2504080122
bioRxiv. 2025 Jul 02. pii: 2025.06.30.662349. [Epub ahead of print]

Polyamines buffer labile iron to suppress ferroptosis.

Pushkal Sharma, Heather R Keys, Sebastian Müller, Ivan S Pires, Ryan Mansell, Shinya Imada, Tenzin Kunchok, Millenia Waite, Christalyn Ausler, Bingbing Yuan, Amy Deik, Paula T Hammond, Raphaël Rodriguez, Whitney Henry, Ankur Jain.

Polyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells. Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines function as endogenous buffers of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis. Using genome-wide CRISPR screens, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, GPX4. Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin. To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron. Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution. These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance.

DOI: https://doi.org/10.1101/2025.06.30.662349