bims-mibica 2026-08-23 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–08–23
fifteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Functional partitioning of lipoic acid decouples cellular abundance from mitochondrial utilization.
Nonequilibrium temperature fluctuations as modulators of mitochondrial elastocapillary stability.
Nicotinamide nucleotide transhydrogenase directly couples redox homeostasis to proline biosynthesis in human glioma.
Dynamic S-acylation of IDH2 regulates mitochondrial redox homeostasis.
Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
Oncogenic DHX15 mutation enhances mitochondrial metabolism and sustains leukemia stemness.
Disease-mutations perturb proton transfer reactions in respiratory complex I.
Dual MYC and GSPT1 Protein Degrader for MYC-Driven Hematologic Malignancies.
Mitochondrial Oxygen Consumption Drives Lung Tumor Hypoxia and Resistance to Therapy via Copy Number Alteration in Mitochondrial Electron Transport Subunit NDUFB5.
Cross-species urinary metabolomics identifies 2-hydroxyisovalerate as a candidate biomarker for mtDNA-based disorders.
PKM2 modulation regulates leukemia cell survival.
NRAS knockdown reverses monocytic cell state and resensitizes resistant FLT3-AML cells to gilteritinib.
Excess intracellular lactate represses mRNA translation and tumor progression through lactate-tRNA charging.
Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism.
Succinate dehydrogenase germline mutation carriers: before tumours develop.

J Lipid Res. 2026 Aug 20. pii: S0022-2275(26)00156-2. [Epub ahead of print] 101126

Functional partitioning of lipoic acid decouples cellular abundance from mitochondrial utilization.

Pieter R Norden, Riley J Wedan, Abigail E Ellis, Madeleine L Hart, Megan R Gendjar, Morgan T Canfield, Ryan D Sheldon, Sara M Nowinski.

α-Lipoic acid (LA) is widely included in "mitochondrial cocktails" recommended to patients with primary mitochondrial disorders, yet its mechanism of action remains unclear. Here, we define the intracellular availability and functional utilization of LA in mammalian cells. We show that under typical culture conditions, free LA is near-completely absent in cells. Rather, any LA generated through mitochondrial fatty acid synthesis (mtFAS) remains in a protein-bound pool, as disruption of the mtFAS pathway does not alter free LA levels despite strong loss of protein lipoylation. Conversely, supplementation with exogenous LA markedly increases free intracellular LA in both control and mtFAS-deficient cells, but is incapable of restoring protein lipoylation, mitochondrial respiration, or cell proliferation in the absence of mtFAS. Instead, the cellular effects of LA supplementation resemble those of the antioxidant N-acetylcysteine. These findings clarify the mechanism of action of a widely used mitochondrial supplement and identify a fundamental disconnect between cellular LA abundance and mitochondrial utilization, challenging the rationale for using LA supplementation to restore mitochondrial function.

DOI: https://doi.org/10.1016/j.jlr.2026.101126
Phys Biol. 2026 Aug 17. 23(4):

Nonequilibrium temperature fluctuations as modulators of mitochondrial elastocapillary stability.

Peyman Fahimi.

  Recent studies have suggested that under high or near-maximal mitochondrial respiratory activity, ion-translocating proteins within the inner mitochondrial membrane may generate transient nonequilibrium temperature fluctuations in the adjacent mitochondrial matrix and intermembrane space. Such nonequilibrium temperature fluctuations may, in principle, influence mitochondrial mechanics and morphology. Building on elastocapillary models of mitochondrial dynamics, we investigate whether these nonequilibrium temperature fluctuations can modulate the stability of mitochondrial tubules through temperature-dependent changes in effective membrane tension and elasticity. Our numerical analysis predicts that this effect is strongly threshold-dependent: in deeply unstable states, thermal modulation remains insufficient to restore stability, whereas closer to the threshold, temperature-dependent reduction of effective membrane tension can overcome temperature-dependent elastic softening, thereby increasing the elastocapillary number, suppressing unstable modes, and shifting mitochondria toward mechanically more stable tubular states. In other words, when mitochondria begin shifting toward fission-promoting states, elevated respiratory activity, which increases the magnitude and cumulative temporal occupancy of transient thermal perturbations, tends to shift the system back toward mechanical stability. However, when mitochondria are already far within the mechanically unstable regime, transient thermal activity is no longer sufficient to restore stability. This stabilizing regime is qualitatively consistent with experimental observations linking elevated oxidative phosphorylation to mitochondrial elongation, fusion, or hyperfusion rather than fragmentation.

Keywords:  elastocapillary stability; membrane tension and elasticity; nonequilibrium thermodynamics; temperature fluctuations

DOI:  https://doi.org/10.1088/1478-3975/ae934f
Mol Cell. 2026 Aug 21. pii: S1097-2765(26)00517-4. [Epub ahead of print]

Nicotinamide nucleotide transhydrogenase directly couples redox homeostasis to proline biosynthesis in human glioma.

Lisa A Vettore, Adam Boufersaoui, Yingying Lyu, Anaïs Oudin, Keene L Abbott, Sonu Subudhi, Yetiş Gültekin, Katherine L Eales, Ishana Rajgopal, Cristina Escribano-Gonzalez, Rahatil A Chowdhury, Himani Rana, Victoria Wykes, Rakesh K Jain, Anna Golebiewska, Matthew G Vander Heiden, Daniel A Tennant.

  Cancer cell proliferation requires a precise balance between biomass production and nutrient catabolism. The pyridine nucleotide cofactors nicotinamide adenine dinucleotide NAD(H) and NAD phosphate NADP(H) are central to this process, but their compartment-specific regulation is incompletely understood. Using in vivo isotope-labeled metabolite tracing in an orthotopic xenograft model, we find that human gliomas extensively synthesize proline, an amino acid previously associated with hypoxia tolerance. In glioma cells, we identify a hypoxia-enhanced proliferative sensitivity to environmental proline dependent on NADH to NADPH transhydrogenation from a spatially compartmentalized mitochondrial pool by the enzyme nicotinamide nucleotide transhydrogenase (NNT). We demonstrate NNT-dependent generation of mitochondrial NADPH is important for proline accumulation, maintenance of antioxidant systems, and reductive metabolism in hypoxic glioma cells in vitro and tumor progression in vivo. Collectively, these results highlight proline accumulation as a marker of mitochondrial NAD(P)(H) homeostasis and NNT as a specific metabolic dependency in human glioma.

Keywords:  NNT; glioma; hypoxia; proline; redox

DOI:  https://doi.org/10.1016/j.molcel.2026.07.031
Cell Rep. 2026 Aug 18. pii: S2211-1247(26)00954-X. [Epub ahead of print]45(9): 117876

Dynamic S-acylation of IDH2 regulates mitochondrial redox homeostasis.

Chen Miao, Zhen Wang, Jian Lin, Ziye Zhu, Jinan Wang, Baoen Chen.

  Mitochondrial redox homeostasis is fundamental for cellular function, and its dysregulation is associated with various diseases, including cancer. Isocitrate dehydrogenase 2 (IDH2) is a key enzyme that maintains this balance by generating NADPH. However, the mechanisms controlling IDH2 subcellular localization remain incompletely understood. Here, we identify reversible S-acylation as a critical regulator of IDH2 localization. Using chemical reporters, we demonstrate that IDH2 is S-acylated at a conserved cysteine residue, mediated by ZDHHC3 and APT1. Loss of IDH2 S-acylation disrupts its mitochondrial localization by reducing its interaction with the mitochondrial import receptor TOMM20, leading to NADPH deficiency, redox imbalance, and impaired oxidative phosphorylation. Consistently, ZDHHC3 knockout phenocopies IDH2 S-acylation deficiency, impairing its mitochondrial localization and function. Genetic ablation of IDH2 S-acylation suppresses tumor growth in vitro and in vivo. Our work establishes dynamic S-acylation of IDH2 as an essential regulator of mitochondrial redox homeostasis, thereby revealing a potential metabolic vulnerability in cancer.

Keywords:  APT1; CP: molecular biology; IDH2; S-acylation; ZDHHC3; breast cancer; metabolic reprogramming; mitochondrial localization; palmitoylation; protein lipidation; redox homeostasis

DOI:  https://doi.org/10.1016/j.celrep.2026.117876
Sci Adv. 2026 Aug 21. 12(34): eaed6318

Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.

Joan Blanco-Fernandez, Miriam Lisci, Mads M Foged, Chloé Chapuis, Tim Pflästerer, Tatjana Kleele, Alexis A Jourdain.

Mitochondria drive cellular reprogramming by integrating metabolism and signaling. In macrophages, mitochondria are central to immunometabolic responses to external cues, but the extent to which they are remodeled and participate in macrophage reprogramming remains unclear. Here, we integrate transcriptomics with whole-cell and purified mitochondrial proteomics to profile lipopolysaccharide (LPS)/interferon-γ (IFN-γ)- and interleukin-4 (IL-4)/IL-13-stimulated macrophages. We reveal a notable disconnect between mitochondrial transcript and protein levels following either stimulus and a signal transducer and activator of transcription 6 (STAT6)-dependent increase in mitochondrial DNA (mtDNA) expression and intramitochondrial translation in IL-4/IL-13 macrophages. We demonstrate that pharmacological inhibition of mitochondrial translation or individual respiratory chain complexes variably impairs reprogramming, whereas ATP synthase inhibition uniquely triggers a heme-regulated inhibitor (HRI)-dependent integrated stress response (ISR) through mitochondrial hyperpolarization, thereby preventing IL-4/IL-13 reprogramming. Mechanistically, we show that restoring mitochondrial membrane potential or inhibiting the ISR rescues IL-4/IL-13-mediated reprogramming. Together, we identify mtDNA expression, intramitochondrial translation, and mitochondrial membrane potential as critical, drug-sensitive determinants of the IL-4/IL-13 response.

DOI: https://doi.org/10.1126/sciadv.aed6318
Leukemia. 2026 Aug 21.

Oncogenic DHX15 mutation enhances mitochondrial metabolism and sustains leukemia stemness.

Qilong Li, Peiqi Xing, Jin Xu, Jifei Li, Liangjie Chen, Xinlu Li, Yinpeng Bai, Gang Li, Ting Xie, Luzhen Wang, Yuan Wang, Guoliang Qing, Huafeng Wang, Liang Shao, Wei Wu, Zhaoqi Liu, Hudan Liu.

The RUNX1::RUNX1T1 translocation, also termed AML1-ETO, is one of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML) and is associated with variable clinical outcomes. The R222G hotspot mutation, located in the RNA helicase gene DHX15, is enriched and predominantly found in AML with this translocation, but its diagnostic significance and underlying mechanism remain largely unclear. In this study, we show that pediatric AML patients carrying DHX15 mutations exhibit an inferior prognosis. Functional analysis demonstrates that DHX15R222G cooperates with AML1-ETO fusion protein to enhance AML leukemia stem cell (LSC) activity and promote resistance to standard chemotherapy. Mechanistically, AML1-ETO transcriptionally upregulates mitochondrial transcription factor A (TFAM), while DHX15R222G promotes TFAM protein stabilization and nuclear translocation, resulting in robust activation of oxidative phosphorylation (OXPHOS) gene expression and mitochondrial respiration. Inhibition of oxidative phosphorylation by the Complex V inhibitor S-Gboxin exerts strong anti-leukemic effects and efficiently circumvents chemotherapy resistance in AML1-ETO+ DHX15R222G leukemia. These findings underscore the pivotal role of oncogenic DHX15 mutations in regulating AML LSC activity and identify DHX15R222G as a potential genetic biomarker for AML risk stratification. Moreover, this mutation may predict therapeutic vulnerability to OXPHOS inhibition.

DOI: https://doi.org/10.1038/s41375-026-03102-1
Biochim Biophys Acta Bioenerg. 2026 Aug 17. pii: S0005-2728(26)00022-8. [Epub ahead of print] 149602

Disease-mutations perturb proton transfer reactions in respiratory complex I.

Patricia Saura, Sofia Badolato, Andrea Gangdal, Adel Beghiah, Ville R I Kaila.

  Respiratory Complex I powers oxidative phosphorylation by a long-range proton-coupled electron transfer (PCET) reaction, with mutations linked to more than half of all human mitochondrial disorders. Yet, the molecular principles underlying the functional impairment remain difficult to test, as most mutations impede both the proton pumping and oxidoreductase activities due to the tightly coupled PCET process. Here, we probe how key disease mutations in the terminal ND5 subunit (NuoL/Nqo12), linked to the development of Leigh's syndrome (LS) and LHON/MELAS (F124L, M252T, D393N), affect the proton transport activity within the dissected antiporter module Nqo12. All constructs result in fully folded antiporter modules, with the introduced substitutions showing enhanced proton conduction rates across the proteoliposome membranes relative to the wild type module. Our molecular dynamics simulations reveal that the mutations perturb the internal water network and ion-pair dynamics that are central for the long-range PCET activity in Complex I. Taken together, we suggest that the mitochondrial disease mutations alter the redox-driven proton pumping activity of Complex I by perturbing the function of local proton gates, and result in an uncontrolled proton translocation across the antiporter module. The molecular consequences of disease mutations are discussed in the context of the proposed pumping mechanism.

Keywords:  Cellular respiration; LHON, MELAS; Leigh syndrome; Mitochondrial disease; Molecular mechanism

DOI:  https://doi.org/10.1016/j.bbabio.2026.149602
Blood. 2026 Aug 17. pii: blood.2025030170. [Epub ahead of print]

Dual MYC and GSPT1 Protein Degrader for MYC-Driven Hematologic Malignancies.

Yuki Nishida, Valeria Impedovo, Edward Ayoub, Natalia Baran, Darah A Scruggs, Hideaki Mizuno, Shayaun Khazaei, Lauren B Ostermann, Kazuharu Kamachi, Liang Zhang, Jo Ishizawa, Sandeep Singh, Andrea D Bedoy, Po Yee Mak, Bing Z Carter, Eiji Sugihara, Tetsuya Takimoto, Youzhi Tong, Honghua Yan, Dong Chen, Ji Huang, Hsu-Feng Chu, Liang Tong, Zamal Ahmed, Sarita Namjoshi, John Tainer, Mihai Gagea, Thomas Huynh, Abhishek Maiti, Koji Sasaki, Branko Cuglievan, Steffen Boettcher, Torsten Haferlach, Stefano Tiziani, Liandong Ma, Michael Andreeff.

Direct targeting of the oncoprotein MYC has not yet been successful. We here report a novel dual protein degrader, GT19630, which binds directly to MYC and G1 to S phase transition protein 1 (GSPT1). GT19630 disrupts a novel feedforward loop of MYC and GSPT1, where MYC promotes transcription of GSPT1, and GSPT1 senses the stop codon of MYC to properly terminate its translation. The agent induces integrated stress response and abrogates oxidative phosphorylation through inhibition of the TCA cycle, resulting in apoptosis. GT19630 has superior activity compared to GSPT1- targeting molecular glues. GT19630 induces profound anti-proliferative effects and apoptosis at low nanomolar concentrations in a multitude of leukemia and lymphoma cell lines and primary samples, including those with TP53 mutations. GT19630 is highly active in vivo in models of therapy-resistant hematologic malignancies, including Burkitt's lymphoma, acute myeloid leukemia (AML) and multiple myeloma. CD34+ AML blasts overexpress MYC protein compared to normal hematopoietic stem/progenitor cells (HSPCs) and GT19630 induces greater cytotoxicity in AML cells compared to normal HSPCs. Further, GT19630 restores sensitivity to venetoclax and profoundly prolongs survival in vivo in venetoclax-resistant AML. GT19630 was well tolerated in humanized Crbn mice. In conclusion, our data support the development of the MYC/GSPT1 degrader GT19630 as a therapeutic strategy of MYC-driven hematologic malignancies.

DOI: https://doi.org/10.1182/blood.2025030170
bioRxiv. 2026 Jul 28. pii: 2026.07.27.741033. [Epub ahead of print]

Mitochondrial Oxygen Consumption Drives Lung Tumor Hypoxia and Resistance to Therapy via Copy Number Alteration in Mitochondrial Electron Transport Subunit NDUFB5.

Martin Benej, Katarina Benejova, Adel Fergatova, Rebecca Lisi, Kristina Travis, McKenzie Kreamer, Amy Webb, Caroline Dravillas, Rebecca Hoyd, Esin Bayrali- Ulker, Aashrith Sai Thoutham, Daniel Spakowicz, Nicholas C Denko.

Decades of research have shown that tumor hypoxia is associated with resistance to anti-cancer treatments. Analysis of TCGA gene expression profiles indicates that NSCLC is among the most hypoxic of cancers despite the high levels of oxygen in the surrounding lung tissue. Several groups have shown that extrinsic factors such as poorly formed tumor vascular contributes to tumor hypoxia. Here, we have investigated the possibility that genetic abnormalities within the tumor also contribute to the development of hypoxia. Our analysis of NSCLC patient datasets in the Cancer Genome Atlas (TCGA) PanCancer and ORIEN datasets revealed a strong correlation between tumor hypoxia and amplification of chromosome 3q which is found in up to 40% of NSCLC. Several oncogenic driver genes have been identified in 3q, and we identified a passenger gene encoding mitochondrial complex I subunit NDUFB5 at 3q26.33. To provide experimental evidence that NDUFB5 amplification can drive tumor hypoxia, we have used CRISPR activation technology to generate murine cells overexpressing the endogenous NDUFB5 gene. We found that cells overexpressing NDUFB5 have elevated rates of oxygen consumption, and tumors grown from these cells have increased amounts of hypoxia with associated treatment resistance. Here, we investigate the impact of manipulating NDUFB5 gene expression on mitochondrial complex I activity and experimentally validate the clinical observations that NDUFB5 overexpression leads to increased levels of intratumoral hypoxia and increased resistance to radiation therapy and immunotherapy.

DOI: https://doi.org/10.64898/2026.07.27.741033
Metabolomics. 2026 Aug 20. pii: 140. [Epub ahead of print]22(5):

Cross-species urinary metabolomics identifies 2-hydroxyisovalerate as a candidate biomarker for mtDNA-based disorders.

Marianne Venter, Karin Terburgh, Jeremie Z Lindeque, Emi Ogasawara, Mirian C H Janssen, Jan A M Smeitink, Kazuto Nakada, Roan Louw.

  Pathogenic mitochondrial DNA (mtDNA) mutations contribute to a broad spectrum of both common and rare metabolic diseases. However, clinical presentation is highly variable and only partially explained by the proportion of mutant mtDNA or heteroplasmy. With the relationship between mutation burden and clinical manifestation poorly defined, controlled models are required to uncover underlying mechanisms. Here, we explore the metabolic consequences of increasing heteroplasmy in a well-characterised mouse model harbouring a pathogenic mtDNA deletion. Untargeted urinary metabolomics reveals distinct mutation load-dependent metabolic shifts with some metabolites declining early on, while others exhibit threshold-like increases beyond ~ 60% mutation load - the level at which lactic acidemia and OXPHOS defects become apparent in this model. To assess translational relevance, we examined these heteroplasmy-associated metabolites in urine from patients carrying the most common mtDNA mutation, m.3243 A > G. Several of these metabolites were differentially expressed in patients relative to controls, with conserved directionality across species. Among these, 2-hydroxyisovalerate (2-HIVA), which was most strongly affected in the mouse model, also emerged as the top discriminator in patients. Receiver operating characteristic analysis indicated that urinary 2-HIVA has strong discriminatory power, supporting its potential utility as a biomarker for mtDNA-based disorders. These findings enhance our understanding of mtDNA-related disease pathophysiology and establish a foundation for further validation studies.

Keywords:  2-Hydroxyisovalerate; Heteroplasmy; M.3243A > G; Metabolomics; Mito-mice; Mitochondrial disease; MtDNA

DOI:  https://doi.org/10.1007/s11306-026-02518-1
Cancer Metab. 2026 Jul 24. pii: 26. [Epub ahead of print]14(1):

PKM2 modulation regulates leukemia cell survival.

Nikolina Vrdoljak, Ekaterina N Parfenova, Alessia Roma, Drake A Mosca, Mark D Minden, Paul A Spagnuolo.

Acute myeloid leukemia (AML) cells exhibit aberrant metabolism defined by a shift away from oxidative phosphorylation and towards anaerobic glycolysis, favouring cell growth. Glycolytic enzymes are altered for this change to occur, including pyruvate kinase (PK), where the tetrameric and high activity M1 isoform (PKM1) is replaced with the predominantly dimeric and low activity M2 isoform (PKM2). Dimeric PKM2 produces less pyruvate and acts as a protein kinase in the nucleus, demonstrating divergent roles in both cell metabolism and as a transcriptional co-activator. In this study, the role of PKM2 in AML was defined, as PKM2 levels were elevated but PK enzymatic activity was reduced in AML cells compared to normal hematopoietic cells. Genetic and pharmacological studies show that decreasing and increasing PKM2 activity resulted in anti-AML effects both in vitro and in vivo. Indeed, these models show that inhibition and activation of PKM2 disrupt the native oligomeric state of the protein, resulting in reduced nuclear PKM2 accumulation and c-Myc expression, ultimately leading to cell death. Together, these results highlight the importance of PKM2 in AML, uncover the mechanisms by which both inhibition and activation cause AML cell death, and identify a novel modulator of PKM2 activity.

DOI: https://doi.org/10.1186/s40170-026-00440-7
Blood. 2026 Aug 11. pii: blood.2026033305. [Epub ahead of print]

NRAS knockdown reverses monocytic cell state and resensitizes resistant FLT3-AML cells to gilteritinib.

Sunil K Joshi, Hadi Maazi, Janét Pittsenbarger, Belinda B Garana, Andy Kaempf, Ariane Huang, Marina A Gritsenko, Chelsea Hutchinson-Bunch, Karl K Weitz, Rosalie K Chu, Sara J C Gosline, Paul D Piehowski, Ann-Kathrin Eisfeld, Martin P Carroll, Alexander E Perl, Karin D Rodland, Bill H Chang, Alexey S Revenko, Jeffrey W Tyner, Brian J Druker, Elie Traer.

While the FLT3 inhibitor gilteritinib is initially effective in patients with FLT3-mutated acute myeloid leukemia (AML), patients invariably relapse within months of treatment. Gilteritinib resistance is commonly driven by the emergence of NRAS mutations and a shift towards a more monocytic cell state. We hypothesized that directly targeting and depleting NRAS protein would reverse these adaptive differentiation changes and restore therapeutic sensitivity. To test this, we utilized a mutation-agnostic antisense oligonucleotide (ASO) to selectively knock down NRAS expression across gilteritinib-resistant AML cell lines, in vivo cell-line-derived xenografts, and primary patient samples. NRAS ASO successfully resensitized gilteritinib resistant cells with multiple distinct NRAS mutations, displaying superior efficacy compared to downstream MEK inhibition. This therapeutic efficacy was independent of NRAS mutant variant allele frequency, suggesting that wild-type NRAS may also contribute to resistance. Comprehensive multi-omic profiling (transcriptomics, proteomics, phosphoproteomics) revealed that NRAS knockdown consistently reversed monocytic phenotype, shifting cells back toward a more primitive cell state. Monocytic differentiation and NRAS mutations are established drivers of resistance to diverse targeted regimens in AML, including FLT3, IDH, and BCL2 inhibitors, so we also tested venetoclax resistant primary cells with NRAS mutations. Resistant cells were resensitized to venetoclax after NRAS knockdown, suggesting that NRAS knockdown may be more broadly applicable in overcoming monocytic cell state and drug resistance in AML.

DOI: https://doi.org/10.1182/blood.2026033305
Mol Cell. 2026 Aug 17. pii: S1097-2765(26)00512-5. [Epub ahead of print]

Excess intracellular lactate represses mRNA translation and tumor progression through lactate-tRNA charging.

Xinyu Wang, Chi Lin, Yixin Zhang, Huan Wang, Biru Shi, Zhiwen Bu, Pengtao Xu, Huimin Zheng, Yanhong Wang, Xiaojing Lan, Qi Hu, Min Huang, Ying Wang, Huiru Tang, Yichen Xu.

  Tumor cells rely on sustained protein synthesis despite fluctuating metabolic stress. To examine how metabolic state directly influences translational output, we investigated lactate utilization. Intracellular accumulation of lactate, a central glycolytic product, acutely represses mRNA translation. Mechanistically, alanyl-tRNA synthetase 1 (AARS1) charges tRNAs with lactate instead of amino acids. Unlike the rapid and selective transfer of alanine to cognate tRNAAla, slower lactyl transfer permits lactate modification of non-cognate tRNAs, broadly compromising elongation fidelity. Functionally, this direct metabolic control over a fundamental process of the central dogma reshapes the translatome, operating as an intrinsic metabolic brake that aligns biosynthetic capacity with energy state. Notably, aggressive tumors elevate lactate transporters, limiting intracellular lactate accumulation and evading translational repression. Pharmacological blockade of monocarboxylate transporters restores intracellular lactate accumulation, re-establishes translational repression, and impairs tumor progression in mice. These findings uncover a metabolite-tRNA charging event directly rewiring translational output and reveal a metabolic vulnerability with therapeutic potential.

Keywords:  cancer; lactate; lactyl-tRNA; metabolism-translation coupling; tRNA charging; translation control

DOI:  https://doi.org/10.1016/j.molcel.2026.07.026
Nat Metab. 2026 Aug;8(8): 1772-1790

Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism.

Zhongchi Li, Shuchen Liu, Wenbing Jin, Leyi Xiao, Olivia Kester, Nayah Bullen, Xuanrong Chen, Un In Chan, Jude Owiredu, Zhucui Li, Rabia Khan, Jennifer Endress, Moniquetta Shafer, Vivien Low, Nikolaos Koundouros, Sungyun Cho, Christopher Barbieri, Chun-Jun Guo, John Blenis.

Enhanced cholesterol synthesis and lipid droplet accumulation are hallmarks of aggressive prostate cancer, yet how tumour cells sense metabolic inputs to dynamically regulate cholesterol homeostasis remains poorly defined. Here we uncover a metabolic signalling mechanism in which prostate cancer cells remodel propionyl-CoA metabolism to support stress adaptation during disease progression. We show that the catabolism of branched-chain amino acid, specifically isoleucine and valine, is the primary source of intracellular propionyl-CoA in prostate cancer cells. Beyond its metabolic role, propionyl-CoA functions as a signalling molecule that stabilizes nuclear sterol regulatory element-binding protein 2 (SREBP2) through site-specific lysine propionylation, thereby enhancing its transcriptional activity. This activation promotes cholesterol biosynthesis, fuels de novo androgen production, and sustains androgen receptor signalling under metabolic and therapeutic stress, including androgen deprivation. Together, our findings establish propionyl-CoA as a key metabolic signal linking amino acid catabolism to cholesterol-driven oncogenic programmes and highlight targeting isoleucine and valine metabolism as a potential strategy to disrupt lipid reprogramming in prostate cancer.

DOI: https://doi.org/10.1038/s42255-026-01583-z
Endocr Relat Cancer. 2026 Aug 21. pii: ERC-26-0282. [Epub ahead of print]

Succinate dehydrogenase germline mutation carriers: before tumours develop.

Eugenie S Lim, Jean-Pierre Bayley, Anne-Paule Gimenez-Roqueplo, Roderick J Clifton-Bligh, Susan Richter.

  Succinate dehydrogenase (SDH) is an enzyme complex that plays a major role in cellular metabolism, as it sits at the interface between carbon metabolism in the Krebs cycle and oxidative phosphorylation for energy production. The precursor and product of the enzymatic reaction, succinate and fumarate, respectively, are regulators of various cellular and biological processes such as epigenetic status, hypoxia responses and angiogenesis, metabolic reprogramming, tumorigenesis, and immune responses. Succinate is considered an oncometabolite, and SDHx genes are tumour suppressor genes. Carriers of germline pathogenic variants (PV) in one of the SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2) carry a life-long risk of developing tumours, predominantly paragangliomas and phaeochromocytomas (PPGL). Research has focused mainly on the disease state in which, in accordance with the Knudson two-hit model, the second allele is inactivated in tumour cells; the biological consequences of which are massive intracellular accumulation of succinate and/or reactive oxygen species (ROS), which in turns leads to tumourigenesis. Little is known about the haplo-insufficient state, in which the wild-type SDHx copy at least partially sustains SDH function and keeps intracellular succinate and ROS levels in ranges that are, if not normal, then at least non-tumourigenic. This review will consolidate the literature regarding genotype differences between SDHx PV carriers, the phenotype of non-tumoral cells in healthy individuals, and the role of environmental factors in influencing tumour development, potentially via tipping succinate (or ROS) levels above a tumourigenic threshold.

Keywords:  endogenous; exogenous; genotype-phenotype; haploinsufficiency; tumour predisposition

DOI:  https://doi.org/10.1530/ERC-26-0282