bims-camemi 2025-10-26 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2025–10–26
34 papers selected by
Christian Frezza, Universität zu Köln

A lactate-acetate interaction between macrophages and cancer cells drives metastasis.
The mitochondrial disulphide relay substrate FAM136A safeguards IMS proteostasis and cellular fitness.
Mitochondrial one-carbon metabolism is required for TGF-β-induced glycine synthesis and fibrotic responses.
Mitochondrial and lysosomal signaling orchestrates heterogeneous metabolic states of regulatory T cells.
The protein phosphatase 6 subunit SAPS3 modulates lifespan by regulating metabolism.
Tumour-associated macrophages serve as an acetate reservoir to drive hepatocellular carcinoma metastasis.
Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia.
Round and round we go: phosphoenolpyruvate carboxykinase 1 (PCK1) in cataplerosis, mitochondrial, and kidney health.
Transgenerational adaptation to hypoxia.
Mitochondrial fatty acid oxidation is stimulated by red light irradiation.
Microbial metabolite indole-3-propionic acid drives mitochondrial respiration in CD4+ T cells to confer protection against intestinal inflammation.
Metabolic regulation of behavior by the intestinal enzyme FMO-2.
A constraint-based framework for exploring the impact of multireaction dependencies on metabolic functions.
Roles of lysosomal small-molecule transporters in metabolism and signaling.
Rewiring microbial metabolism through post-translational switches.
Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.
The Metabolic Transition Between Fasting and Feeding Alters Aging-Associated Metabolites, Lowers BCAAs, and Stimulates FGF21 Production in Humans.
CRATER tumor niches facilitate CD8+ T cell engagement and correspond with immunotherapy success.
TCA-cycle metabolites in the nucleus: drivers of chromatin and epigenetic control.
Unsaturated fat alters clock phosphorylation to align rhythms to the season in mice.
ZC3H4, a novel regulator of mitochondrial complex I, impacts prostate stromal cell senescence, attachment, adhesion and anoikis resistance.
TXNIP mediates LAT1/SLC7A5 endocytosis to limit amino acid uptake in cells entering quiescence.
PNPLA3-I148M genetic variant rewires lipid metabolism to drive programmed cell death in human hepatocytes.
FAP+ fibroblasts orchestrate tumor microenvironment remodeling in renal cell carcinoma with tumor thrombus.
p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program.
Intracellular pH regulates ubiquitin-mediated degradation of the MAP kinase ERK3.
Large transient assemblies of Apaf1 constitute the apoptosome in cells.
Dietary medium-chain triacylglycerols in metabolic regulation.
Multi-modal spatial characterization of tumor immune microenvironments identifies targetable inflammatory niches in diffuse large B cell lymphoma.
In situ characterization of mitochondrial Hsp60-Hsp10 chaperone complex under folding stress.
Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate pathway-dependent Rho/ROCK signaling.
Organellar pH as an emerging vulnerability to exploit in cancer.
The ancient dialogue between brain and body.
Label-free robotic mitochondrial biopsy.

Nat Metab. 2025 Oct 20.

A lactate-acetate interaction between macrophages and cancer cells drives metastasis.

DOI: https://doi.org/10.1038/s42255-025-01398-4
Redox Biol. 2025 Oct 08. pii: S2213-2317(25)00397-0. [Epub ahead of print]87 103884

The mitochondrial disulphide relay substrate FAM136A safeguards IMS proteostasis and cellular fitness.

Christine Zarges, Hanna Fieler, Robin Alexander Rothemann, Simon Poepsel, Lucas T Jae, Jan Riemer.

  The mitochondrial disulphide relay is the key machinery for import and oxidative protein folding in the mitochondrial intermembrane space. Among IMS proteins with unknown function, we identified FAM136A as a new substrate of the mitochondrial disulphide relay. We demonstrate a transient interaction between FAM136A and MIA40, and that MIA40 introduces four disulphide bonds in two twin-CX3C motifs of FAM136A. Consequently, IMS import of FAM136A requires these cysteines and its steady state levels in intact cells are strongly dependent on MIA40 and AIFM1 levels. Furthermore, we show that FAM136A forms non-covalent homodimers as a mature protein. Acute deletion of FAM136A curtails cellular proliferation capacity and elicits a robust induction of the integrated stress response, coincident with the aggregation and/or depletion of selected IMS proteins including HAX1 and CLPB. Together, this establishes FAM136A as a pivotal component of the IMS proteostasis network, with implications for overall cellular function and health.

Keywords:  FAM136A; Integrated stress response; MIA40; Oxidative protein folding

DOI:  https://doi.org/10.1016/j.redox.2025.103884
Nat Commun. 2025 Oct 20. 16(1): 9250

Mitochondrial one-carbon metabolism is required for TGF-β-induced glycine synthesis and fibrotic responses.

Angelo Y Meliton, Kun Woo D Shin, Rengül Cetin-Atalay, M Volkan Atalay, Yufeng Tian, Jennifer C Houpy Szafran, Takugo Cho, Kaitlyn A Sun, Parker S Woods, Obada R Shamaa, Bohao Chen, Nickolai O Dulin, Aliya N Husain, Alexander Muir, Hardik Shah, Gökhan M Mutlu, Robert B Hamanaka.

TGF-β-dependent activation of lung fibroblasts is a hallmark of Idiopathic Pulmonary Fibrosis (IPF) which results in excessive collagen deposition and progressive scarring. Collagen production by lung fibroblasts is supported by de novo synthesis of glycine, the most abundant amino acid in collagen protein. SHMT2 produces glycine by transferring a one-carbon (1 C) unit from serine to tetrahydrofolate (THF), producing 5,10-methylene-THF (meTHF). meTHF is then converted back to THF in the mitochondrial 1 C pathway. It is unknown how 1 C metabolism contributes to collagen protein production and fibrosis. Here, we demonstrate that TGF-β induces the expression of mitochondrial 1 C pathway enzymes, including MTHFD2, in human lung fibroblasts. MTHFD2 was required for TGF-β-induced cellular glycine accumulation and collagen protein production in lung fibroblasts. Pharmacologic inhibition of MTHFD2 ameliorated fibrotic responses after intratracheal bleomycin instillation in vivo. Our findings suggest that mitochondrial 1 C metabolism is a therapeutic target for IPF and other fibrotic diseases.

DOI: https://doi.org/10.1038/s41467-025-64320-2
Sci Immunol. 2025 Oct 24. 10(112): eads9456

Mitochondrial and lysosomal signaling orchestrates heterogeneous metabolic states of regulatory T cells.

Jordy Saravia, Nicole M Chapman, Yu Sun, Xiaoxi Meng, Isabel Risch, Wei Li, Cliff Guy, Hao Shi, Haoran Hu, Yogesh Dhungana, Jia Li, Zhiyuan You, Anil Kc, Seon Ah Lim, Jana L Raynor, Sharad Shrestha, Erienne G Norton, Sarah E La Grange, Camenzind G Robinson, Peter Vogel, Hongbo Chi.

Immunotherapies targeting regulatory T (Treg) cells often trigger inflammation and autoimmunity. How Treg cells undergo functional reprogramming to reestablish immune homeostasis under these conditions remains unclear. Here, we demonstrate that mitochondrial and lysosomal signaling orchestrates Treg cell metabolic and functional fitness. Treg cell-specific loss of the mitochondrial protein Opa1 led to disrupted immune homeostasis and pronounced inflammation, and reduced the generation of Treg cells with high mitochondrial metabolic and suppressive function. Opa1 deletion triggered mitochondrial bioenergetic stress, associated with increased adenosine monophosphate-activated protein kinase (AMPK) signaling and transcription factor EB (TFEB) activation. Further, Treg cell-specific deletion of the lysosomal signaling protein Flcn partially phenocopied Opa1 deficiency-associated inflammation and aberrant TFEB activation, and these effects were rectified by TFEB codeletion. Flcn-deficient Treg cells were enriched in a terminal "metabolic quiescence reset" state and failed to accumulate in nonlymphoid tissues and suppress antitumor immunity. Our study demonstrates that organelle-directed metabolic and signaling processes and mitochondria-lysosome interplay control Treg cell differentiation and function.

DOI: https://doi.org/10.1126/sciimmunol.ads9456
Sci Adv. 2025 Oct 24. 11(43): eadt3879

The protein phosphatase 6 subunit SAPS3 modulates lifespan by regulating metabolism.

Ying Yang, Da Eun Kang, Qi Fan, Eric A Hanse, Hosung Bae, Rocio A Barahona, Xiyu Shen, Bryan I Ruiz, Shelly H Lee, Katherine R Pasterczyk, Nainpriya Babbar, Katherine G Waldvogel, Roberto Tinoco, Kim N Green, Qin Yang, Cholsoon Jang, Mei Kong.

Aging is characterized by disruptions in metabolic homeostasis, yet the mechanisms that regulate these metabolic changes remain poorly understood. We show that the serine/threonine-protein phosphatase 6 (PP6) regulatory subunit 3, SAPS3, is a critical regulator of metabolism during aging. SAPS3 deletion significantly extends lifespan in mice and counteracts age-related impairments in metabolic health. SAPS3 deficiency improves the effects of aging on the affective behaviors, cognition, and motor functions in aged mice. We find that SAPS3 expression is increased during aging to inhibit adenosine monophosphate-activated kinase (AMPK) activity. Deletion of SAPS3 leads to AMPK activation and reverses cellular senescence and aging-induced metabolic alterations. Using in vivo U-13C6-D-glucose tracing and metabolomic analysis, we find that SAPS3 deficiency restores metabolic homeostasis with increased glycolysis, tricarboxylic acid (TCA) cycle, and decreased fatty acid synthesis in aged mice. These findings highlight a critical role of the SAPS3/PP6 phosphatase complex in aging and suggest that strategies targeting SAPS3 may promote longevity and healthy aging.

DOI: https://doi.org/10.1126/sciadv.adt3879
Nat Metab. 2025 Oct 20.

Tumour-associated macrophages serve as an acetate reservoir to drive hepatocellular carcinoma metastasis.

Li Shen, Shenghao Wang, Chao Gao, Qin Li, Shuya Feng, Weiyan Sun, Xu Liu, Yiyi Ba, Yihui Chu, Yu Zhou, Junjie Pan, Hao Xu, Xu Zhang, Wenwei Zhu, Lunxiu Qin, Ming Lu.

Increased acetyl-coenzyme A (acetyl-CoA) generation facilitates cancer metastasis and represents a critical metabolic characteristic of metastatic cancers. To maintain high acetyl-CoA levels, cancer cells often enhance the uptake of acetate for acetyl-CoA biosynthesis. However, the microenvironmental source of acetate remains largely unknown. Here we demonstrate that acetate is secreted by tumour-associated macrophages (TAMs) and taken up by hepatocellular carcinoma (HCC) cells to support acetate accumulation. Mechanistically, HCC cell-derived lactate activates the lipid peroxidation-aldehyde dehydrogenase 2 (ALDH2) pathway in TAMs, which promotes the TAMs' acetate production and secretion. Inhibition of ALDH2 or of lipid peroxidation in TAMs abrogates acetate-induced migration of HCC cells in vitro. In an orthotopic HCC model involving male mice, genetic ablation of ALDH2 in TAMs reduces HCC cell acetate levels and HCC lung metastases. Collectively, our findings reveal a metabolic interaction between HCC cells and TAMs-involving lactate, lipid peroxidation and acetate-and position TAMs as an acetate reservoir that drives HCC metastasis.

DOI: https://doi.org/10.1038/s42255-025-01393-9
Mol Metab. 2025 Oct 19. pii: S2212-8778(25)00182-6. [Epub ahead of print] 102275

Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia.

Fernando M Ponce-Garcia, Yasmin R Jenkins, Victoria D Assmann, Silpita Paul, Nitesh D Sharma, Catherine Moore, Eric H Ma, Paraskevi Diamanti, Marc Hennequart, Julianna Blagih, Le Le, Benjamin J Jenkins, Sophie Rouvray, James G Cronin, Russell G Jones, Marc Mansour, Allison Blair, Christina Halsey, Ksenia Matlawska-Wasowska, Daniel Herranz, Emma E Vincent, Nicholas Jones.

T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy commonly driven by NOTCH1 activating mutations. A concomitant feature associated with NOTCH1 mutations is heightened oxidative metabolism enabling the exponential proliferation of T-ALL blasts. As such, targeting mitochondrial metabolism in T-ALL is an attractive therapeutic avenue. Related to this, canagliflozin (cana), is an FDA-approved sodium glucose co-transporter 2 inhibitor with known off-target effects on complex I and glutamate dehydrogenase, but its potential anti-leukaemic effects remain unexplored. Here, we show that cana possesses potent anti-leukaemic effects underpinned by proliferative defects, cell cycle disruption and apoptosis. These anti-leukaemic effects driven by cana, are attributed to a perturbed tricarboxylic acid (TCA) cycle and mitochondrial metabolism, and elevated mitochondrial ROS. Proteomic analysis revealed that cana treatment resulted in a compensatory increase in the expression of ATF4 targets, including upregulation of serine biosynthesis pathway and one-carbon metabolism enzymes. As such, restriction of serine and glycine synergized with cana treatment, further enhancing its anti-leukaemic effects. Collectively, our study reveals a cana-driven metabolic vulnerability that can be further exploited via dietary manipulation to treat T-ALL.

DOI: https://doi.org/10.1016/j.molmet.2025.102275
Kidney Int. 2025 Nov;pii: S0085-2538(25)00663-5. [Epub ahead of print]108(5): 738-740

Round and round we go: phosphoenolpyruvate carboxykinase 1 (PCK1) in cataplerosis, mitochondrial, and kidney health.

Mitchell A Sullivan, Josephine M Forbes.

The kidneys require high levels of adenosine triphosphate production, rendering them particularly vulnerable to conditions that perturb mitochondrial function. A deficiency in phosphoenolpyruvate carboxykinase 1, a pivotal enzyme in central carbon metabolism, increases susceptibility to kidney injury, highlighting its importance in kidney health. Given phosphoenolpyruvate carboxykinase 1's central metabolic location in gluconeogenic and tricarboxylic acid cycle flux pathways, isolating the mechanism by which phosphoenolpyruvate carboxykinase 1 protection occurs remains complex. A recent study, however, claims that its role in cataplerosis may be the key.

DOI: https://doi.org/10.1016/j.kint.2025.08.006
Sci Adv. 2025 Oct 24. 11(43): eadv9451

Transgenerational adaptation to hypoxia.

Kathleen Kim, Ariel Telger, Gautam Sarkar, Sharan Surya, M Hafiz Rothi, Michael P Meers, Simon Yuan Wang, Eric Lieberman Greer.

Epigenetic inheritance alerts naïve descendants to prepare for stresses that could still be present, whereas distant descendants return to a basal state after several generations without stress. However, organisms are frequently exposed to stresses successively across generations. We found that parental hypoxia exposure increased P0 longevity, caused intergenerational lipid reduction, and elicited transgenerational fertility reduction that was dependent on generationally transmitted small RNAs. Here, we find that Caenorhabditis elegans adapt to repeated generational stresses. We show that, upon two repeated generational hypoxia exposures, the life-span extension is eliminated, and after four repeated generational hypoxia exposures, the reduced fertility is eliminated. Transgenerational adaptation also occurred in response to changes in glucose availability. Transgenerational hypoxia adaptation is dependent on the H3K27 trimethyltransferase PRC2 complex, and we identified transgenerationally adapted genes. Our findings reveal that transgenerational adaptation occurs and suggest that H3K27me3 is a critical modification for adapting to repeated generational stresses.

DOI: https://doi.org/10.1126/sciadv.adv9451
FEBS Lett. 2025 Oct 18.

Mitochondrial fatty acid oxidation is stimulated by red light irradiation.

Manuel Alejandro Herrera, Camille C Caldeira da Silva, Maiza Von Denz, Mauricio S Baptista, Alicia J Kowaltowski.

  Keratinocytes are the primary constituents of sunlight-exposed epidermis. In these cells, ultraviolet (UV) A light completely inhibited oxidative phosphorylation, while equivalent doses of blue and green light preserved metabolic fluxes but reduced viability. In contrast, red light enhanced proliferation and elevated basal and maximal oxygen consumption rates for 48 h without altering protein levels of the electron transport chain. Targeted flux analysis revealed that red light specifically activates AMP-activating protein kinase (AMPK)-dependent mitochondrial fatty acid oxidation. This was accompanied by reduced levels of free fatty acids and increased acetyl-CoA carboxylase phosphorylation. Together, our results characterize wavelength-selective regulation of keratinocyte metabolism: UV/visible wavelengths induce damage, while red light triggers AMPK-dependent fatty acid oxidation, providing a mechanistic explanation for photobiomodulation in epidermal cells. Impact statement Sunlight impacts skin cells in surprising ways. While UVA harms energy production and blue/green light reduces survival, red light boosts keratinocyte metabolism. We show that red light activates AMPK-dependent fatty acid oxidation, enhancing proliferation and energy use. These findings reveal how specific wavelengths can damage or stimulate skin cells.

Keywords:  AMPK; beta oxidation; light; metabolism; mitochondria; skin

DOI:  https://doi.org/10.1002/1873-3468.70195
Nat Metab. 2025 Oct 21.

Microbial metabolite indole-3-propionic acid drives mitochondrial respiration in CD4+ T cells to confer protection against intestinal inflammation.

Qing Li, Rodrigo de Oliveira Formiga, Virginie Puchois, Laura Creusot, Ahmad Haidar Ahmad, Salomé Amouyal, Márcio Augusto Campos-Ribeiro, Yining Zhao, Danielle M M Harris, Frederic Lasserre, Sandrine Ellero-Simatos, Hervé Guillou, Zhan Huang, Loic Brot, Yuhang Hu, Loic Chollet, Camille Danne, Cyril Scandola, Tatiana Ledent, Guillaume Chevreux, Rafael J Argüello, Marcelo De Carvalho Bittencourt, Jessica Bettinger, Maud D'Aveni-Piney, David Moulin, Stefan Schreiber, Konrad Aden, Nathalie Rolhion, Marie-Laure Michel, Timothy Wai, Harry Sokol.

The gut microbiota and its metabolites critically regulate immune cell phenotype, function and energy metabolism. We screened a collection of gut microbiota-related metabolites to identify modulators of mitochondrial metabolism in T cells. Here we show that indole-3-propionic acid (IPA) stimulates mitochondrial respiration of CD4+ T cells by increasing fatty acid oxidation (FAO) and amino acid oxidation (AAO), while inhibiting glycolytic capacity. IPA also impacts CD4+ T cell behaviour by inhibiting their differentiation to type 1 and type 17 helper T cell phenotypes. Mechanistically, the metabolic and immune effects of IPA are mediated by peroxisome proliferator-activated receptor-β/δ. The administration of IPA rescues mitochondria respiration in mice with gut bacteria depletion or colitis by enhancing FAO and AAO in colonic CD4+ T cells. Adoptive transfer experiments show that IPA acts on CD4+ T cells to exert its protective effect against inflammation. Collectively, our study reveals that the anti-inflammatory effects of IPA are mediated by metabolic reprogramming of CD4+ T cells toward the enhancement of mitochondrial respiration.

DOI: https://doi.org/10.1038/s42255-025-01396-6
Sci Adv. 2025 Oct 24. 11(43): eadx3018

Metabolic regulation of behavior by the intestinal enzyme FMO-2.

Elizabeth S Kitto, Safa Beydoun, Ella Henry, Megan L Schaller, Mira Bhandari, Sarah A Easow, Angela M Tuckowski, Marshall B Howington, Ajay Bhat, Aditya Sridhar, Eugene Chung, Charles R Evans, Scott F Leiser.

Many elements of an organism's behavior are intertwined with the organism's health. Over a long period of time, health status is also indicative of life span, with improved health correlating with a longer life. However, the relationship between longevity and behavior remains relatively unexplored. Here, we report that modification of a single longevity gene downstream of dietary restriction and hypoxia markedly alters behavior in Caenorhabditis elegans. We found that modified expression of flavin-containing monooxygenase (fmo-2) leads to altered sensory perception and decision-making in a variety of behavioral paradigms. This cell nonautonomous signaling pathway is linked to changes in tryptophan metabolism, where loss of fmo-2 requires the tryptophan metabolite serotonin and overexpressed fmo-2 requires the tryptophan metabolite quinolinic acid to change behavior. These results suggest a unique mechanism for gut metabolism to communicate positive satiety signals and negative depressive signals to the organism by modifying an essential amino acid. They also demonstrate the importance of examining pleiotropic effects in promising longevity interventions.

DOI: https://doi.org/10.1126/sciadv.adx3018
NPJ Syst Biol Appl. 2025 Oct 23. 11(1): 118

A constraint-based framework for exploring the impact of multireaction dependencies on metabolic functions.

Anika Küken, Damoun Langary, Angela Angeleska, Zoran Nikoloski.

Metabolism operates under physico-chemical constraints that result in multireaction dependencies. Understanding how multireaction dependencies affect metabolic phenotypes remains challenging, hindering their biotechnological applications. Here, we propose the concept of a forcedly balanced complex that allows to efficiently determine the effects of specific multireaction dependencies on metabolic network functions in constrained-based models. Using this concept, we found that the fraction of multireaction dependencies induced by forcedly balanced complexes in genome-scale metabolic networks followed power law with exponential cut-off. We identified forcedly balanced complexes that are lethal in cancer but have little effect on growth in healthy tissue models. In addition, these forcedly balanced complexes are largely specific to models of particular cancer types. Therefore, multireaction dependencies resulting from forced balancing of complexes represent an innovative means to control cancers that, we argue, can be implemented via transporter engineering. The presented constraint-based approaches pave the way for using multireaction dependencies in metabolic engineering for diverse biotechnological applications.

DOI: https://doi.org/10.1038/s41540-025-00608-9
Trends Cell Biol. 2025 Oct 17. pii: S0962-8924(25)00222-3. [Epub ahead of print]

Roles of lysosomal small-molecule transporters in metabolism and signaling.

Markus Damme, Océane Guelle, Christian Löw, Bruno Gasnier.

  Lysosomes degrade damaged or unwanted cell/tissue components and recycle their building blocks through small-molecule transporters of the lysosomal membrane. They also act as signaling hubs that sense and signal internal cues, such as amino acids, to coordinate cell responses. Recently, the activity of several lysosomal metabolite transporters has been elucidated, bringing new insights into lysosomal functions. Cell biological and structural studies of lysosomal transporters have also highlighted their roles in recruiting signaling complexes to lysosomes and delineated how their substrates gate such hybrid transporter/receptor, or 'transceptor', function. In this review, we summarize recent progress in our understanding of lysosomal transporters, with a focus on the export of lysosomal degradation intermediates, the existence of lysosomal amino acid shuttles that regulate the redox state and pH of the lysosomal lumen, and the role of lysosomal transceptors in nutrient and immune signaling.

Keywords:  lysosomes; metabolism; signaling; transceptor; transporter

DOI:  https://doi.org/10.1016/j.tcb.2025.09.004
Trends Biotechnol. 2025 Oct 23. pii: S0167-7799(25)00409-3. [Epub ahead of print]

Rewiring microbial metabolism through post-translational switches.

Xianhao Xu, Yang Li, Jiaheng Liu, Xueqin Lv, Long Liu.

  Recent advances in post-translational regulatory tools have enabled precise and rapid control of metabolic flux in microbial cell factories. In this review, we systematically summarize current post-translational regulatory tools for modulating the abundance, localization, and activity of key metabolic enzymes. We first discuss protein degradation tags for tunable control of enzyme levels. Then, we discuss spatial regulation through natural and synthetic subcellular compartments. We also highlight emerging approaches for engineering allosteric switches, including computational and de novo design methods. Finally, we outline future directions toward orthogonal, efficient, and cross-species compatible systems. This review provides conceptual and technical insights to guide the development of next-generation post-translational regulatory tools for dynamic metabolic control in microbial cell factories.

Keywords:  allosteric regulation; metabolic flux control; post-translational regulation; protein degradation tags; subcellular compartmentalization

DOI:  https://doi.org/10.1016/j.tibtech.2025.10.002
Mol Cell. 2025 Oct 20. pii: S1097-2765(25)00815-9. [Epub ahead of print]

Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.

Nils Bertram, Toshiaki Izawa, Felix Thoma, Serena Schwenkert, Stéphane Duvezin-Caubet, Sae-Hun Park, Nikola Wagener, Anne Devin, Christof Osman, Walter Neupert, Dejana Mokranjac.

  Ribosome-associated protein quality control (RQC) protects cells against the toxic effects of faulty polypeptides produced by stalled ribosomes. However, mitochondria are vulnerable to C-terminal alanyl and threonyl (CAT)-tailed proteins that are generated in this process, and faulty nuclear-encoded mitochondrial proteins are handled by the recently discovered mitoRQC. Here, we performed a genome-wide screen in yeast to identify additional proteins involved in mitoRQC. We found that peptidyl-tRNA hydrolase 2 (Pth2), present in the mitochondrial outer membrane, influences aggregation of CAT-tailed proteins without majorly affecting the CAT-tailing process itself. Peptidyl-tRNA hydrolase activity is essential during this process, yet the activity of Pth2 can be substituted by another peptidyl-tRNA hydrolase upon proper localization. Our data suggest that Pth2 acts by modulating protein translocation and that the mitochondrial proteostasis network is relieved through increased access of CAT-tailed proteins to cytosolic chaperones. Other hits obtained in the screen show that, in general, delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.

Keywords:  RQC; TOM complex; cellular homeostasis; mitoRQC; mitochondria; peptidyl-RNA hydrolase; protein translocation

DOI:  https://doi.org/10.1016/j.molcel.2025.09.030
Aging Cell. 2025 Oct 21. e70270

The Metabolic Transition Between Fasting and Feeding Alters Aging-Associated Metabolites, Lowers BCAAs, and Stimulates FGF21 Production in Humans.

Maria Lastra Cagigas, Nancy T Santiappillai, Serena Commissati, Giovanni Fiorito, Andrius Masedunskas, Gayathiri Rajakumar, Isabella de Ciutiis, Alan Goldhamer, Brian K Kennedy, Andrew J Hoy, Luigi Fontana.

  Fasting-based interventions are gaining momentum as strategies to modulate longevity. Conversely, the same metabolic adaptations that once ensured survival during starvation now contribute to the global obesity epidemic. While previous studies have characterized metabolic changes during fasting, few have examined the refeeding phase, and most lack an integrated analysis of key hormonal and metabolic regulators, including insulin, leptin, adiponectin, free T3, FGF21, and the plasma metabolome. To address this gap, we profiled 134 plasma metabolites using mass spectrometry, covering pathways involved in lipid, amino acid, and ketone metabolism, in a cohort of 20 adults (mean age 52.2 ± 11.8 years, 55% women, BMI 28.8 ± 6.4 kg/m2) undergoing medically supervised prolonged fasting (mean duration 9.8 ± 3.1 days), followed by plant-based refeeding (5.3 ± 2.4 days). Fasting reduced metabolic rate, reflected by lower free T3 levels (p < 0.0001), and markedly reprogrammed the plasma metabolome, including shifts in seven aging-associated metabolites (glucose, 3-hydroxybutyric acid, glycine, glutamine, alanine, phenylalanine, and tyrosine). Notably, plasma branched-chain amino acid (BCAA) levels remained stable during fasting, suggesting active tissue release to support energy homeostasis alongside ketogenesis. Upon refeeding, 81% of metabolite levels normalized, yet BCAAs declined sharply (valine -45%, leucine -52%, isoleucine -48%; all p < 0.001), consistent with insulin-stimulated tissue uptake. Changes in BCAAs were inversely associated with a fivefold increase in FGF21 levels (243.2-1176 pg/mL, p = 0.0007), which occurred exclusively during refeeding, unlike in rodent models where FGF21 levels rise during fasting. Together, our findings identify refeeding as a critical window for modulating aging-related metabolites and highlight the importance of post-fast refeeding dynamics.

Keywords:  BCAA; FGF21; fasting; ketogenesis; refeeding

DOI:  https://doi.org/10.1111/acel.70270
Cell. 2025 Oct 17. pii: S0092-8674(25)01089-X. [Epub ahead of print]

CRATER tumor niches facilitate CD8+ T cell engagement and correspond with immunotherapy success.

Aya Ludin, Georgia L Stirtz, Asaf Tal, Ajit J Nirmal, Kathleen L Pfaff, Michael Manos, Naomi Besson, Nebiyat Eskndir, Billie Porter, Stephanie M Jones, Hannah M Faulkner, Qiyu Gong, Sophia Liu, Irving Barrera, Lijian Wu, Cecilia Pessoa Rodrigues, Aditi Sahu, Elizabeth Jerison, Joao V Alessi, Biagio Ricciuti, Douglas S Richardson, Jodi D Weiss, Hadley M Moreau, Meredith E Stanhope, Alexander B Afeyan, James Sefton, Wyatt D McCall, Emily Formato, Song Yang, Yi Zhou, David P Hoytema van Konijnenburg, Hannah L Cole, Miguel Cordova, Liang Deng, Milind Rajadhyaksha, Stephen R Quake, Mark M Awad, Fei Chen, Kai W Wucherpfennig, Peter K Sorger, F Stephen Hodi, Scott J Rodig, George F Murphy, Leonard I Zon.

  T cell-mediated tumor killing underlies immunotherapy success. Here, we used long-term in vivo imaging and high-resolution spatial transcriptomics of zebrafish endogenous melanoma, as well as multiplex imaging of human melanoma, to identify domains facilitating the immune response during immunotherapy. We identified cancer regions of antigen presentation and T cell engagement and retention (CRATERs) as pockets at the stroma-melanocyte boundaries of zebrafish and human melanoma. CRATERs are rich in antigen-recognition molecules, harboring the highest density of CD8+ T cells in tumors. In zebrafish, CD8+ T cells formed prolonged interactions with melanoma cells within CRATERs, characteristic of antigen recognition. Following immunostimulatory treatment, CRATERs expanded, becoming the major sites of activated CD8+ T cell accumulation and tumor killing. In humans, elevation in CRATER density in biopsies following immune checkpoint blockade (ICB) therapy correlated with a clinical response to therapy. CRATERs are structures that show active tumor killing and may be useful as a diagnostic indicator for immunotherapy success.

Keywords:  CD8+ T cells; cancer; immune response; immunotherapy; melanoma; zebrafish

DOI:  https://doi.org/10.1016/j.cell.2025.09.021
BMC Biol. 2025 Oct 21. 23(1): 316

TCA-cycle metabolites in the nucleus: drivers of chromatin and epigenetic control.

Serena Ghisletti, Marta Russo.

  Mitochondrial enzymes are increasingly recognized for their ability to translocate to the nucleus, where they generate metabolites essential for epigenetic regulation and gene expression. Yet, whether this phenomenon broadly involves metabolic enzymes or is restricted to specific subunits remains unclear. In this review, we assess current evidence, highlight knowledge gaps, and suggest future directions on the nuclear localization and functions of metabolic enzymes, with a focus on acyl-CoA producers. Emerging studies reveal multiple mechanisms guiding these enzymes to chromatin for localized metabolite synthesis. Key questions concern nuclear import machinery, chromatin interactions, and the regulatory impact of their activity.

Keywords:  Histone modifications; Metabolism; Mitochondrial enzymes; Transcriptional regulation

DOI:  https://doi.org/10.1186/s12915-025-02423-4
Science. 2025 Oct 23. 390(6771): eadp3065

Unsaturated fat alters clock phosphorylation to align rhythms to the season in mice.

Daniel C Levine, Rasmus H Reeh, Thomas McMahon, Thomas Mandrup-Poulsen, Ying-Hui Fu, Louis J Ptáček.

The circadian clock maintains synchrony between biological processes and light/dark cycles by integrating environmental cues. How the clock adapts to seasonal variations in the environment is incompletely understood. We found that a high-fat diet increased phosphorylation of the clock protein PERIOD2 (PER2) on serine 662 (S662), which was necessary and sufficient for regulating phase shifting of daily locomotor activity to entrain to seasonal light cycles. PER2-S662 phosphorylation correlated with genome-wide expression pathways that regulate polyunsaturated fatty acid (PUFA) conversion into oxylipins in the hypothalamus. Partial hydrogenation of dietary PUFAs increased hypothalamic PER2-S662 phosphorylation and entrainment to a summer photoperiod in control mice, but not in mice for which PER2-S662 could not be phosphorylated. PER2-S662 phosphorylation is influenced by, and alters the regulation of, unsaturated fat to control circadian phase shifting across the seasons.

DOI: https://doi.org/10.1126/science.adp3065
Cell Death Dis. 2025 Oct 21. 16(1): 741

ZC3H4, a novel regulator of mitochondrial complex I, impacts prostate stromal cell senescence, attachment, adhesion and anoikis resistance.

Teresa T Liu, Mia J Carrarini, Livianna K Myklebust, Kegan O Skalitzky, Nathalie El-Khoury, Ian J Sipula, Alexander Chang, Vishal Soman, Ailing Liu, Nnamdi Ihejirika, Uma R Chandran, Michael J Jurczak, William A Ricke, Donald B DeFranco, Laura E Pascal.

Declining mitochondrial function is an established feature of aging and contributes to most aging-related diseases through its impact on various pathologies such as chronic inflammation, fibrosis and cellular senescence. Our recent work suggests that benign prostatic hyperplasia, which is an aging-related disease frequently associated with inflammation, fibrosis and senescence, is characterized by a decline in mitochondrial function. Here, we utilize glycolytic restriction and pharmacologic inhibition of the mitochondrial electron transfer chain complex I to promote mitochondrial dysfunction and identify the cellular processes impacted by declining mitochondrial function in benign prostate stromal cells. Using this model, we show that mitochondrial dysfunction induced alterations in cell-cell and cell-matrix adhesion, elevated fibronectin expression, resistance to anoikis and stress-induced premature senescence (SIPS). We also showed that ablation of ZC3H4, a transcription termination factor implicated in anoikis-resistance and reduced in BPH relative to normal prostates, phenocopied various phenotypes in the human BHPrS1 prostate stromal cell line that resulted from inhibition of complex I. Furthermore, ZC3H4 ablation resulted in the elevation of mitochondrial superoxide (mtROS) and mitochondrial membrane potential, altered mitochondrial morphology and NAD+/NADH ratio, and reduced CI function in BHPrS1 cells. Thus, ZC3H4 loss promotes mitochondrial dysfunction to drive pathophysiologic changes in the stromal compartment that are features of the aging prostate.

DOI: https://doi.org/10.1038/s41419-025-08027-8
EMBO J. 2025 Oct 20.

TXNIP mediates LAT1/SLC7A5 endocytosis to limit amino acid uptake in cells entering quiescence.

Jennifer Kahlhofer, Nikolas Marchet, Kristian Zubak, Brigitta Seifert, Madlen Hotze, Anna-Sophia Egger-Hörschinger, Lucija Kucej, Claudia Manzl, Yannick Weyer, Sabine Weys, Martin Offterdinger, Sebastian Herzog, Veronika Reiterer, Chiara Volani, Marcel Kwiatkowski, Saskia B Wortmann, Siamak Nemati, Johannes A Mayr, Johannes Zschocke, Bernhard Radlinger, Kathrin Thedieck, Leopold Kremser, Bettina Sarg, Lukas A Huber, Hesso Farhan, Mariana E G de Araujo, Susanne Kaser, Sabine Scholl-Bürgi, Daniela Karall, David Teis.

  Entry into and exit from cellular quiescence require dynamic adjustments in nutrient acquisition, yet the mechanisms by which quiescent cells downregulate amino acid (AA) transport remain poorly understood. Here we show that cells entering quiescence selectively target plasma membrane-resident amino acid transporters for endocytosis and lysosomal degradation. This process matches amino acid uptake with reduced translational demand and promotes survival during extended periods of quiescence. Mechanistically, we identify the α-arrestin TXNIP as a key regulator of this metabolic adaptation, since it mediates the endocytosis of the SLC7A5-SLC3A2 (LAT1-4F2hc) AA transporter complex in response to reduced AKT signaling. To promote transporter ubiquitination, TXNIP interacts with NEDD4L and other HECT-type ubiquitin ligases. Loss of TXNIP disrupts this regulation, resulting in dysregulated amino acid uptake, sustained mTORC1 signaling, and ultimately cell death under prolonged quiescence. The characterization of a novel TXNIP loss-of-function variant in a patient with a severe metabolic disease further supports its role in nutrient homeostasis and human health. Together, these findings highlight TXNIP's central role in controlling nutrient acquisition and metabolic plasticity with implications for quiescence biology and diseases.

Keywords:  Amino Acids Uptake; Endocytosis; Quiescence; SLC7A5/LAT1; TXNIP

DOI:  https://doi.org/10.1038/s44318-025-00608-9
JCI Insight. 2025 Oct 21. pii: e193805. [Epub ahead of print]

PNPLA3-I148M genetic variant rewires lipid metabolism to drive programmed cell death in human hepatocytes.

Rodrigo M Florentino, Olamide Animasahun, Nils Haep, Minal Nenwani, Kehinde Omoloja, Leyla Nurcihan Altay, Abhinav Achreja, Kazutoyo Morita, Takashi Motomura, Ricardo Diaz-Aragon, Lanuza Ap Faccioli, Yiyue Sun, Zhenghao Liu, Zhiping Hu, Bo Yang, Fulei Wuchu, Ajay Shankaran, Miya Paserba, Annalisa M Baratta, Shohrat Arazov, Zehra N Kocas-Kilicarslan, Noah Meurs, Jaideep Behari, Edgar N Tafaleng, Jonathan Franks, Alina Ostrowska, Takahiro Tomiyama, Kyohei Yugawa, Akinari Morinaga, Zi Wang, Kazuki Takeishi, Dillon C Gavlock, Mark Miedel, D Lansing Taylor, Ira J Fox, Tomoharu Yoshizumi, Deepak Nagrath, Alejandro Soto-Gutierrez.

  Genetic variants in lipid metabolism influence the risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD), cirrhosis, and end-stage liver disease (ESLD). The mechanisms by which these variants drive disease are poorly understood. Because of the PNPLA3-I148M variant's strong correlation with all stages of the MASLD spectrum and the lack of tractable therapeutic targets, we sought to understand its impact on cellular function and liver metabolism. Primary human hepatocytes (HAH) and iPSC-derived hepatocytes (iHeps) from healthy individuals possessing the PNPLA3-I148M mutation were characterized for changes in lipid metabolism, cellular stress, and survival. Using lipidomics, metabolomics, stable isotope tracing, and flux propensity analysis, we created a comprehensive metabolic profile of the changes associated with the PNPLA3-I148M variant. Functional analysis showed that the presence of the PNPLA3-I148M variant increased endoplasmic reticulum stress, mitochondrial dysfunction, and peroxisomal β-oxidation, ultimately leading to cell death via ferroptosis. Nutritional interventions, ferroptosis-specific inhibitors, and genetic approaches modulating GPX4 activity in PNPLA3-I148M HAH and iHeps decreased programmed cell death. Our findings indicate that therapies targeting ferroptosis in patients carrying the PNPLA3-I148M variant could affect the development of MASLD and ESLD and highlight the utility of iPSC-based models for the study of genetic contributions to hepatic disorders.

Keywords:  Cell stress; Fatty acid oxidation; Gastroenterology; Hepatology; Lipidomics

DOI:  https://doi.org/10.1172/jci.insight.193805
Nat Commun. 2025 Oct 23. 16(1): 9387

FAP+ fibroblasts orchestrate tumor microenvironment remodeling in renal cell carcinoma with tumor thrombus.

Jiacheng Ma, Yan Huang, Jie Chen, Yang Li, Rongyan Yao, Xiubin Li, Qiyang Liang, Xinran Chen, Cheng Peng, Kan Liu, Yuanjun Zhai, Xu Zhang, Xin Ma, Xiaowen Wang, Qingbo Huang, Fuchu He.

Tumor thrombus (TT) worsens prognosis and complicates surgery in renal cell carcinoma (RCC), yet its formation mechanisms remain unclear. Here, we perform integrative single-cell and spatial transcriptomic analyses on 71 tissues and 48 sections from RCC patients with or without TT. The cellular and spatial atlas reveals distinct TT-associated tumor microenvironment remodeling characterized by the enrichment of FAP+ fibroblasts. These FAP+ fibroblasts are spatially contiguous to aggressive cancer cells and promote their malignant phenotypes in vitro. Their abundance inversely correlates with functional NK cells, suggesting roles in tumor invasion and immune evasion. Furthermore, single-cell multiomics analysis identifies tumor pericytes as a source of FAP+ fibroblasts and delineates transcription factor dynamics underlying pericyte-fibroblast transition. Finally, high levels of FAP+ fibroblasts are associated with poor prognosis and predict a weaker response to anti-VEGF-based therapy. In conclusion, our study highlights FAP+ fibroblasts as drivers of aggressive RCC with TT, suggesting potential therapeutic targets.

DOI: https://doi.org/10.1038/s41467-025-64447-2
Cancer Discov. 2025 Oct 21.

p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program.

Mengxiong Wang, Kathryn T Bieging-Rolett, Alyssa M Kaiser, Colleen A Brady, John H Lockhart, Sofia Ferreira, Kha T Nguyen, Arati Rajeevan, Simone A Evans, Tianyu Zhao, Nitin Raj, Arielle Elkrief, Sam E Tischfield, Marc Ladanyi, Michael G Ozawa, Nam Q Bui, Christopher T Chen, Elsa R Flores, Laura D Attardi.

Pharmacological restoration of p53 tumor suppressor function is a conceptually appealing therapeutic strategy for the many deadly cancers with compromised p53 activity, including lung adenocarcinoma (LUAD). However, the p53 pathway has remained undruggable, partly because of insufficient understanding of how to drive effective therapeutic responses without toxicity. Here, we use mouse and human models to deconstruct the transcriptional programs and sequelae underlying robust therapeutic responses in LUAD. We show that p53 drives potent tumor regression by direct Tsc2 transactivation, leading to mTORC1 inhibition and TFEB nuclear accumulation, which in turn triggers lysosomal gene expression programs, autophagy, and cellular senescence. Senescent LUAD cells secrete factors to recruit macrophages, precipitating cancer cell phagocytosis and tumor regression. Collectively, our analyses reveal a surprisingly complex cascade of events underlying a p53 therapeutic response in LUAD and illuminate targetable nodes for p53 combination therapies, thus establishing a critical framework for optimizing p53-based therapeutics.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0525
Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2501825122

Intracellular pH regulates ubiquitin-mediated degradation of the MAP kinase ERK3.

Chloé Tesnière, Fadia Boudghene-Stambouli, Marc Severin, Mallorie Poët, Laure Voisin, Muthulakshmi Ponniah, Mirela Pascariu, Eric Bonneil, Jean-François Trempe, Pierre Thibault, Laurent Counillon, Stine Falsig Pedersen, Sylvain Meloche.

  Intracellular pH (pHi) influences diverse cellular processes, including cell proliferation, metabolism, and migration, and is linked to metabolic diseases and cancer. Protonation alters protein charge and conformation, modulating different aspects of protein function. How pHi fluctuations are sensed by signaling proteins and translated into cellular responses remains incompletely understood. Here, we reveal that pHi plays a key role in regulating the stability of the mitogen-activated protein kinase Extracellular signal-regulated kinase 3 (ERK3). Intracellular acidification markedly increases the half-life of ERK3, whereas alkalinization accelerates its degradation. The pH-dependent regulation of ERK3 is rapid, reversible, and consistent across cell types. Mechanistically, we identified a region in the C-terminus of ERK3 that contains pH-sensing motifs. We further show by quantitative proteomics that short-term acidification or alkalinization globally affects the cellular proteome. Our findings underscore the critical role of pHi in ERK3 turnover and suggest a broader role for pH in regulating protein stability and cell signaling.

Keywords:  ERK3; MAP kinases; intracellular pH; proteomics

DOI:  https://doi.org/10.1073/pnas.2501825122
Nat Commun. 2025 Oct 24. 16(1): 9429

Large transient assemblies of Apaf1 constitute the apoptosome in cells.

Alicia C Borgeaud, Iva Ganeva, Calvin Klein, Amandine Stooss, Daniela Ross-Kaschitza, Liyang Wu, Joel S Riley, Stephen W G Tait, Thomas Lemmin, Thomas Kaufmann, Wanda Kukulski.

Upon cell death signals, the apoptotic protease-activating factor Apaf1 and cytochrome c interact to form the apoptosome complex. The apoptosome is crucial for mitochondrial apoptosis, as it activates caspases that dismantle the cell. However, the in vivo assembly mechanism and appearance of the apoptosome remain unclear. We show that upon onset of apoptosis, Apaf1 molecules accumulate into multiple foci per cell. Disassembly of the foci correlates with cell survival. Structurally, Apaf1 foci resemble organelle-sized, cloud-like assemblies. They form through specific interactions with cytochrome c, contain caspase-9, and depend on procaspase-9 expression for their formation. We propose that Apaf1 foci correspond to the apoptosome in cells. Transientness and ultrastructure of Apaf1 foci suggest that the dynamic spatiotemporal organisation of apoptosome components regulates progression of apoptosis.

DOI: https://doi.org/10.1038/s41467-025-64478-9
Trends Endocrinol Metab. 2025 Oct 19. pii: S1043-2760(25)00216-4. [Epub ahead of print]

Dietary medium-chain triacylglycerols in metabolic regulation.

Ye Cao, Josephine M Kanta, Christopher A Bishop, Bente Kiens, Andreas M Fritzen, Maximilian Kleinert.

  Dietary medium-chain triacylglycerols (MCTs; C8:0-C12:0) are absorbed and utilized differently compared with long-chain fats. They directly enter the portal vein as free medium-chain fatty acids, most of which are converted to ketone bodies in the liver, with a significant proportion entering the circulation. Accumulating evidence links MCT intake to improved glucose homeostasis; increased energy expenditure and satiety with concomitant modest weight loss; and chain length-dependent modulation of circulating lipoprotein profiles and liver metabolism. Emerging data also suggest direct benefits for cardiac contractility, hinting at a broader cardiometabolic advantage. Here, we synthesize the current evidence, outlining how MCTs influence cardiometabolic health. We further discuss mechanistic insights, from cellular substrate partitioning and mitochondrial dynamics to gut-liver signaling to propose mechanisms of MCT action.

Keywords:  energy balance, cardiometabolic health, ketone bodies; glucose homeostasis; medium-chain fatty acids; medium-chain triacylglycerols

DOI:  https://doi.org/10.1016/j.tem.2025.09.010
Nat Genet. 2025 Oct 21.

Multi-modal spatial characterization of tumor immune microenvironments identifies targetable inflammatory niches in diffuse large B cell lymphoma.

Yibo Dai, Atish Kizhakeyil, Dai Chihara, Xubin Li, Yunhe Liu, Tania Patricia Sainz Zuniga, Ashley Wilson, Jared Henderson, Daniil Vibe, Arman Petrosyants, Connor Jacobson, Alexander Sarachakov, Krystle Nomie, Kirill Kryukov, Aleksander Bagaev, Ayushi Chauhan, Jason R Westin, Christopher R Flowers, Francisco Vega, Linghua Wang, Michael R Green.

Diffuse large B cell lymphomas (DLBCLs) are a heterogeneous group of malignancies that can arise in lymph nodes or extranodal locations, including immune-privileged sites. Here, we applied highly multiplexed spatial transcriptomics and proteomics together with genomic profiling to characterize the immune microenvironment architecture of 78 DLBCL tumors. We define seven distinct cellular niches, each characterized by unique cellular compositions, spatial organizations and patterns of intercellular communication associated with niche-specific phenotypes of both T cells and tumor B cells. Among these, DLBCLs from immune-privileged sites showed abundant T cell infiltration into diffuse niches, where immune cells were intermixed with tumor B cells and bore transcriptional hallmarks of activation and effector function, suggesting that they may be primed for anti-tumor immunity. Spatial characterization of the DLBCL immune microenvironment, therefore, reveals cellular niches that foster divergent patterns of cell-cell interactions contributing to the phenotypic heterogeneity of both niche-resident tumor and immune cells.

DOI: https://doi.org/10.1038/s41588-025-02353-5
Sci Adv. 2025 Oct 24. 11(43): eadw6064

In situ characterization of mitochondrial Hsp60-Hsp10 chaperone complex under folding stress.

Mingyu Jung, Minjung Kim, Su Jin Ham, Jongkyeong Chung, Soung-Hun Roh.

Mitochondrial proteostasis is critical for maintaining mitochondrial function, and its disruption induces mitochondrial unfolded protein response, which up-regulates chaperones to alleviate protein-folding stress. However, how these chaperones mitigate protein-folding stress remains unclear. Here, using correlated cryo-electron tomography, we show that folding stress triggers marked mitochondrial morphological changes, including the accumulation of amorphous protein aggregates and increased abundance and spatial clustering of the mitochondrial heat shock protein 60-heat shock protein 10 (mtHsp60-Hsp10) complex. Subtomogram analysis revealed the in situ architecture and conformational heterogeneity of mtHsp60-Hsp10 under stress, which retains its canonical double-ring structure while adopting distinct football, half-football, and bullet-like states. Notably, the mtHsp60-Hsp10 complex encapsulates unstructured substrates through conserved hydrophobic interactions. We further demonstrate that knockdown of the mtHsp60-Hsp10 complex exacerbates folding stress, as evidenced by elevated cellular stress responses and activation of mitophagy. Our study defines the in situ structural properties of the mtHsp60-Hsp10 complex and provides mechanistic insight into how it safeguards mitochondrial proteostasis under folding stress.

DOI: https://doi.org/10.1126/sciadv.adw6064
Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2424904122

Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate pathway-dependent Rho/ROCK signaling.

Asja Guzman, Tatsuya Kawase, Alexander J Devanny, Gizem Efe, Raúl Navaridas, Karen Yu, Kausik Regunath, Iris G Mercer, Rachel C Avard, Rafaela Muniz de Queiroz, Anil K Rustgi, Laura J Kaufman, Carol Prives.

  Certain TP53 mutations can confer neomorphic gain of function (GOF) activities to the p53 protein that affect cancer progression. Yet the concept of mutant p53 GOF has been challenged. Here, using various strategies to alter the status of mutant versions of p53 in different cell lines, we demonstrate that mutant p53 stimulates cancer cell invasion in three-dimensional environments. Mechanistically, mutant p53 enhances RhoA/ROCK-dependent cell contractility and cell-mediated extracellular matrix (ECM) reorganization via increasing mevalonate pathway-dependent RhoA localization to the membrane. In line with this, RhoA-dependent proinvasive activity is also mediated by IDI-1, a mevalonate pathway product. Further, the invasion-enhancing effect of mutant p53 is dictated by the biomechanical properties of the surrounding ECM, thereby adding a cell-independent layer of regulation to mutant p53 GOF activity that is mediated by dynamic reciprocal cell-ECM interactions. Together our findings link mutant p53 metabolic GOF activity with a context-dependent invasive cellular phenotype.

Keywords:  IDI-1; Rho/ROCK signaling; invasion; mevalonate pathway; mutant p53

DOI:  https://doi.org/10.1073/pnas.2424904122
Trends Cancer. 2025 Oct 23. pii: S2405-8033(25)00234-1. [Epub ahead of print]

Organellar pH as an emerging vulnerability to exploit in cancer.

Cheska Marie Galapate, Cosimo Commisso.

  Cancer cells undergo metabolic reprogramming to sustain their energy demands, and favor glycolysis despite the presence of functional mitochondria. This metabolic shift leads to the rapid production of lactate and protons. If not managed, this accumulation of acidic byproducts would lower the intracellular pH (pHi). To counteract this, cancer cells employ diverse mechanisms to extrude excess protons through membrane transporters, and also sequester them within acidic organelles. Consequently, an alkaline pHi provides cancer cells with a survival advantage by promoting their proliferation, migration, and resistance to cell death. Given the role of organellar acidification in sustaining this altered pH balance, targeting this process represents a potential therapeutic vulnerability in cancer. We explore the mechanisms by which cancer cells maintain pH homeostasis, with a particular focus on organellar pH and its impact on tumor progression. In addition, we assess inhibitors of the key transporters involved in organellar acidification and discuss their therapeutic potential in cancer.

Keywords:  cancer metabolism; organelle acidification; pH homeostasis

DOI:  https://doi.org/10.1016/j.trecan.2025.09.006
Curr Biol. 2025 Oct 20. pii: S0960-9822(25)01169-8. [Epub ahead of print]35(20): R963-R967

The ancient dialogue between brain and body.

Nilay Yapici.

The brain rarely works alone to control our behavior or physiology. From the rhythm of our heartbeat to the flutter of 'butterflies' in our stomach, it is in constant dialogue with our body. This connection affects how we feel, influences what we pay attention to in our environment and ultimately affects the choices we make. Over the past several decades, research in model organisms has uncovered brain-body circuits that detect and interpret interoceptive (internal) and exteroceptive (external) signals. These studies have revealed how nervous systems integrate sensory inputs with essential homeostatic processes, such as hunger, thirst, reproduction and immune responses1,2,3,4,5,6,7. We now know that our brain continuously monitors the physiological and metabolic state of our body through both direct neural pathways and indirect neuroendocrine routes. In turn, the body influences our cognitive and metabolic states through a dynamic interplay of hormonal, neural and metabolic signals. This bidirectional communication between the brain and body regulates our sensory perception, modulates our motivation and cognition, and ultimately guides our behavior (Figure 1).

DOI: https://doi.org/10.1016/j.cub.2025.08.069
Sci Adv. 2025 Oct 24. 11(43): eadx4289

Label-free robotic mitochondrial biopsy.

Yanmei Ma, Weikang Hu, Muyang Ruan, Feixiang Bao, Xingguo Liu, Dong Sun, Hongri Gu, Chengzhi Hu.

Robotic micromanipulation has advanced cellular probing, yet achieving precise, minimally invasive intracellular operations without fluorescent labeling remains challenging. Fluorescent techniques often cause photodamage and cytotoxicity and interfere with downstream analyses. Here, we introduce an automated, multifunctional nanoprobing platform capable of label-free extraction of mitochondria from living cells with high spatiotemporal resolution. The nanoprobe integrates two individually addressable nanoelectrodes that perform electrochemical detection of reactive oxygen and nitrogen species, produced by mitochondrial metabolism, followed by dielectrophoretic trapping, manipulation, and extraction of mitochondria. We successfully demonstrated the extraction of mitochondria from living cells, which is validated through fluorescence labeling before and after extraction. Subsequent quantitative polymerase chain reaction further confirmed that the extracted sample contained mitochondria. The fusion of the transplanted mitochondria within the recipient cell's mitochondrial network confirms their activity. This automated, label-free, in situ organelle extraction micromanipulation system offers a powerful tool for understanding disease mechanisms linked to dysfunctional organelles and enables single-cell surgeries for organelle transplantation.

DOI: https://doi.org/10.1126/sciadv.adx4289