bims-mibica 2026-05-03 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–05–03
nineteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

MTCH2 promotes BAX and BAK self-assembly and apoptotic pore growth.
SETD2 Deficiency Drives Mitochondrial DNA Leakage and Creates a Druggable Dependency on BCL-XL in Clear Cell Renal Cell Carcinoma.
Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.
The ATF4/PSAT1/JNK Signaling Axis Suppresses Ferroptosis to Drive Venetoclax Resistance in AML.
Functional assessment and quantitative kinetic analysis of BAX activation using large unilamellar vesicles.
Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.
Semi-automated, quantitative immunofluorescence analysis of single cell cytochrome c release during apoptotic cell death.
Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese.
DHODH inhibition suppresses cutaneous squamous cell carcinoma growth by the induction of differentiation through perturbation of the cellular redox balance.
Comprehensive genome sequencing associates elevated mitochondrial DNA and homoplasmy with early stage I of pancreatic cancer.
KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer.
SLIRP maintains energy metabolism homeostasis in colorectal cancer by stabilizing mitochondrial-encoded mRNAs.
Nuclear genetic modulation of tissue-specific mitochondrial RNA processing contributes to common disease risk.
Lactic acid promotes metastasis of papillary thyroid carcinoma by enhancing CPT1A lactylation.
Mitochondrial fusion heterogeneity drives bidirectional tumor phenotypic transition in combined hepatocellular-cholangiocarcinoma.
TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.
SIRT5 acts in the tumor microenvironment via endothelial cell metabolism to support breast cancer growth.
Mitochondrial double-stranded RNA fuels pancreatic cancer growth via RIG-I/TLR3 inflammation.
BCAT1-dependent HIF-1α stabilization is a targetable metabolic vulnerability in hepatocellular carcinoma.

Nat Struct Mol Biol. 2026 Apr 29.

MTCH2 promotes BAX and BAK self-assembly and apoptotic pore growth.

Hector Flores-Romero, Aida Pena-Blanco, Jonas Aufdermauer, Shashank Dadsena, Philip Neubert, Lisa Hohorst, Eileen Cors, Cristiana Zollo, Alvaro Larrañaga-SanMiguel, Jone Zaldunbide, Maria Nenchova, Yasmin Carvalho-Schaefer, Thomas Langer, Georg Häcker, Ana J Garcia-Saez.

During apoptosis, the BCL-2 family members BAX and BAK oligomerize and form a pore to mediate the decisive step of mitochondrial outer membrane permeabilization. However, the contribution of additional cellular components to apoptotic pore dynamics remains poorly understood. Here we map the protein environment of the apoptotic pore using in situ proximity labeling and identify the mitochondrial carrier homolog protein MTCH2 localizing nearby BAX and BAK assemblies specifically under apoptotic conditions. We show that cells lacking MTCH2 exhibit delayed BAX and BAK oligomerization at the single-particle level, which can be rescued by addition of lysophosphatidic acid. Accordingly, MTCH2 depletion decreases not only apoptosis sensitivity but also sublethal mitochondrial permeabilization during bacterial infection, mitochondrial DNA release into the cytosol and cGAS-STING activation under impaired caspases. Our findings uncover a key role of MTCH2 in promoting BAX and BAK high-order assembly with functional consequences for apoptotic pore growth and downstream responses.

DOI: https://doi.org/10.1038/s41594-026-01805-8
Cancer Res. 2026 Apr 30.

SETD2 Deficiency Drives Mitochondrial DNA Leakage and Creates a Druggable Dependency on BCL-XL in Clear Cell Renal Cell Carcinoma.

Anusha Uprety, Chandler Judd, Emily D Villella, Rebecca Keller, Ryan Wagner, Keith D Robertson, Jezabel Rodriguez-Blanco, Thibaut Barnoud, Frank M Mason, Thai H Ho, Aguirre A de Cubas.

SETD2 is frequently mutated or deleted in clear cell renal cell carcinoma (ccRCC). Loss of SETD2 could create synthetic lethal dependencies that confer therapeutic vulnerabilities. Here, we demonstrated that SETD2 deficiency promotes cytoplasmic mitochondrial DNA (mtDNA) leakage, leading to basal activation of cGAS-STING inflammatory signaling and increased apoptotic priming. This inflammatory state upregulated the BH3-only protein NOXA, constrained MCL-1 function, and enforced a synthetic lethal dependency on the anti-apoptotic protein BCL-xL. Pharmacological inhibition of BCL-xL further amplified cGAS-STING signaling in SETD2-deficient cells through sublethal mitochondrial outer membrane permeabilization, resulting in increased mtDNA release and robust NOXA induction. Elevated NOXA neutralized the compensatory MCL-1-mediated survival signaling, triggering apoptosis. In contrast, SETD2 proficient ccRCC cells exhibited minimal cGAS-STING activation and failed to induce NOXA following BCL-xL inhibition, rendering them resistant. Genetic ablation of cGAS, STING, IRF3, or NOXA rescued sensitivity to BCL-xL inhibition, confirming that mtDNA-driven innate immune signaling is required for this dependency. In vivo, BCL-xL inhibition suppressed tumor growth and prolonged survival in SETD2-deficient xenograft models. Collectively, these findings establish a mechanistic link between SETD2 loss, mtDNA-driven innate immune activation, and enforced BCL-xL dependence in ccRCC, revealing a therapeutically targetable vulnerability in SETD2-deficient tumors.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-3195
Nat Metab. 2026 Apr 29.

Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.

Milan R Savani, Bingbing Li, Bailey C Smith, Wen Gu, Yi Xiao, Gerard Baquer, Tracey Shipman, Skyler S Oken, Namya Manoj, Lauren G Zacharias, Vinesh T Puliyappadamba, Sylwia A Stopka, Michael S Regan, Michael M Levitt, Charles K Edgar, William H Hicks, Soummitra Anand, Misty S Martin-Sandoval, Rainah Winston, João S Patrício, Xandria Johnson, Trevor S Tippetts, Diana D Shi, Andrew Lemoff, Timothy E Richardson, Pascal O Zinn, Ashley Solmonson, Thomas P Mathews, Nathalie Y R Agar, Ralph J DeBerardinis, Kalil G Abdullah, Samuel K McBrayer.

Stable isotope-tracing assays track few metabolites, yet cells use many nutrients to sustain nitrogen metabolism. Here we create a platform for tracing 30 nitrogen isotope-labelled metabolites in parallel to enable a system-level understanding of cellular nitrogen metabolism. This platform reveals that while primitive cells engage both de novo and salvage pyrimidine synthesis pathways, differentiated cells nearly exclusively salvage uridine. This link between cell state and pyrimidine synthesis pathway preference persists in murine and human tissues. Mechanistically, we find that S1900 phosphorylation of CAD, the first enzyme of the de novo pathway, is induced by uridine deprivation in differentiated cells and constitutively enriched in primitive cells. Mimicking CAD S1900 phosphorylation in differentiated cells constitutively activates de novo pyrimidine synthesis, while blocking this modification impairs the cellular response to uridine starvation. Collectively, we establish a method for nitrogen metabolism profiling and define a mechanism of cell state-specific pyrimidine synthesis pathway choice.

DOI: https://doi.org/10.1038/s42255-026-01520-0
Exp Cell Res. 2026 Apr 25. pii: S0014-4827(26)00162-X. [Epub ahead of print] 115045

The ATF4/PSAT1/JNK Signaling Axis Suppresses Ferroptosis to Drive Venetoclax Resistance in AML.

XunXun Zhu, WenHui Huang, MingYan Zhang, YanLing Tao, Hao Zhang.

  Metabolic reprogramming has emerged as a key driver of therapy resistance in acute myeloid leukemia (AML). Here, we identify phosphoserine aminotransferase 1 (PSAT1) as a critical metabolic determinant of venetoclax (VEN) resistance through the suppression of ferroptosis. PSAT1 was consistently upregulated in VEN-resistant cell lines and relapsed patient samples. Mechanistically, the transcription factor ATF4 directly bound the PSAT1 promoter, enhancing its expression and subsequently promoting glutathione synthesis, depleting the labile iron pool, and attenuating lipid peroxidation. Concurrently, PSAT1 functioned to restrain JNK/c-Jun signaling. Knockdown of PSAT1 restored VEN sensitivity by triggering ferroptosis and modulating the expression of BCL-2 and GPX4. Clinically, elevated PSAT1 expression predicted poor patient survival. Our findings unveil the ATF4/PSAT1/JNK axis as a master regulator of ferroptosis in AML, revealing a druggable pathway to overcome VEN resistance.

Keywords:  ATF4; Acute myeloid leukemia; JNK/c-Jun signaling; PSAT1; ferroptosis; venetoclax resistance

DOI:  https://doi.org/10.1016/j.yexcr.2026.115045
Methods Cell Biol. 2026 ;pii: S0091-679X(26)00085-3. [Epub ahead of print]206 55-80

Functional assessment and quantitative kinetic analysis of BAX activation using large unilamellar vesicles.

Jesse D Gelles, Thedoe Nyunt, Md Abdullah Al Noman, Jerry Edward Chipuk.

  A myriad of diverse developmental and pro-death signals converge on the mitochondrial pathway of apoptosis, which is governed by the BCL‑2 family of proteins. Comprised of both pro- and anti-apoptotic family members, the BCL‑2 family functions to regulate mitochondrial outer membrane permeabilization (MOMP), often considered the "point of no return" in which a cell commits to an apoptotic outcome. Specifically, the effector BCL‑2 family proteins, BAX and BAK, are responsible for inducing MOMP and therefore investigations into their structural, cellular, and pharmacological regulation are critical to understanding the cellular commitment to apoptosis. A gold standard methodology for studying activation of BAX or BAK is the permeabilization of large unilamellar vesicles (LUVs), which are biochemically-defined model liposomes that mimic the major lipid composition of the outer mitochondrial membrane (OMM). Here, we provide a detailed protocol for generating LUVs containing a fluorescent dye/quencher pair to monitor real-time BAX activation and membrane permeabilization using a standard plate reader. Additionally, we detail example assay strategies to model interactions within the BCL‑2 family and provide a robust mathematical model for fitting and parameterizing kinetic LUV permeabilization data.

Keywords:  Apoptosis; BAX; BCL‑2 family; Large unilamellar vesicles; MOMP; Regulated dell death

DOI:  https://doi.org/10.1016/bs.mcb.2026.02.017
bioRxiv. 2026 Apr 17. pii: 2026.04.14.718012. [Epub ahead of print]

Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.

Kailash Venkatraman, Daniel Milshteyn, Carolina Sarto, Elida Kocharian, Cailyn M Sakurai, Aaron M Armando, Adrian M Wong, Edward A Dennis, Xi Fang, Christopher T Lee, Itay Budin.

Cardiolipin (CL) is a four-chained, mitochondrial-specific phospholipid crucial for maintenance of inner mitochondrial membrane (IMM) structure and function. In healthy tissues, CL acyl chains are highly unsaturated and maintained by a conserved remodeling pathway. However, dysregulation of CL acyl chain composition can arise from mutations in the CL transacylase, Tafazzin (TAZ), resulting in Barth syndrome (BTHS), where patients exhibit heightened mitochondrial dysfunction. Cells lacking TAZ accumulate three-chained monolysocardiolipin (MLCL) as well as CL species with saturated acyl chains (CLsat). While the presence of MLCL destabilizes electron transport chain (ETC) complexes and IMM-shaping proteins, the contributions of CLsat to mitochondrial dysfunction have not been elucidated. Here, we find that treatment of TAZ knockout cells with exogenous saturated fatty acids causes accumulation of CLsat and loss of mitochondrial inner membrane structure despite only minimal changes in MLCL composition. Imaging of cells with elevated CLsat showed reduced fluidity of the inner membrane. Biophysical measurements and molecular dynamics analyses showed that di-saturated (C16:0 18:1)2 CL species order and rigidify membranes, while also losing the intrinsic lipid curvature characteristic of tetra-unsaturated CL. These results implicate CLsat as a potential driver of mitochondrial dysfunction and an additional therapeutic target in mitigating BTHS pathology.

DOI: https://doi.org/10.64898/2026.04.14.718012
Methods Cell Biol. 2026 ;pii: S0091-679X(26)00095-6. [Epub ahead of print]206 23-42

Semi-automated, quantitative immunofluorescence analysis of single cell cytochrome c release during apoptotic cell death.

Fabian Klötzer, Daniela Stöhr, Markus Rehm.

  Apoptosis, a tightly regulated form of programmed cell death, eliminates damaged or malignant cells and is triggered by internal or external stress signals. A critical decision point is mitochondrial outer membrane permeabilization (MOMP), governed by BCL-2 family proteins. Pro-apoptotic members such as BAX and BAK form pores in the mitochondrial outer membrane, releasing intermembrane space proteins like cytochrome c into the cytoplasm. Once cytosolic, cytochrome c binds APAF-1 to form the apoptosome, which activates caspase-9 and subsequently caspase-3, driving apoptosis through cleavage of key cellular substrates. Cytochrome c release serves as a hallmark and point of no return in the apoptotic cascade. However, cytochrome c release can be variable, occurring at submaximal levels or from only a subset of mitochondria, which complicates detection in heterogeneous cell populations. To address this, we developed a semi-automated imaging-based method to quantify cytochrome c release at the single-cell level using immunofluorescence microscopy. Our approach uses CellProfiler, an open-source image analysis platform, to implement a pipeline that segments adherent cells into nuclear, mitochondrial, and cytoplasmic compartments based on compartment-specific reference stains. The pipeline quantifies cytochrome c distribution across these compartments, calculating the ratio of mitochondrially retained to cytoplasmic cytochrome c for each cell. Automation of segmentation and measurement ensures rapid, robust, and reproducible analysis, with only image acquisition and data interpretation performed manually. This method provides a quantitative readout of MOMP and can be readily adapted to any immunofluorescence-detectable protein given an appropriate compartmental marker, expanding its utility for broader cellular studies.

Keywords:  Apoptosis; Cell segmentation; CellProfiler; Cytochrome c release; Immunofluorescene staining; MOMP; Semi-automated quantification

DOI:  https://doi.org/10.1016/bs.mcb.2026.03.002
Nucleic Acids Res. 2026 Apr 23. pii: gkag233. [Epub ahead of print]54(8):

Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese.

Amaia Lopez de Arbina, Angelica Zamudio-Ochoa, Mikel Muñoz-Oreja, Diego Perez-Rodriguez, Laura Mosqueira-Martín, Rebecca Lasalandra, Marina Villar-Fernandez, Uxoa Fernandez-Pelayo, Laura Rodriguez-Gomez, Seungtae Lee, Francisco Gil-Bea, Nerea Osinalde, Ainara Vallejo-Illaramendi, Dmitry Temiakov, Antonella Spinazzola, Ian J Holt.

Mitochondrial DNA replication occurs at contact sites between the endoplasmic reticulum (ER) and mitochondria (ERMCS). Beyond the known role of the tubular ER protein RTN4, the factors regulating this process are poorly defined. Here, we show that repressing the ER protein ERLIN2 in human fibroblasts depletes ER-mitochondrial contact sites and inhibits mitochondrial DNA replication, as does silencing RTN4 or the ER-mitochondrial tether GRP75. GRP75 or RTN4 scarcity also decreases the level of the mitochondrial calcium uniporter (MCU), whose inhibition blocks mitochondrial DNA synthesis. Because ERMCS depletion did not diminish mitochondrial calcium, and MCU complex can transport manganese, we tested whether manganese could bypass these defects. Manganese supplementation restored mitochondrial DNA replication in cells lacking ERMCS or with inhibited MCU, identifying manganese as a critical mediator. We then considered mitochondrial transcription as a potential manganese target, since it provides both transcripts for gene expression and primers for DNA replication. In vitro, manganese inhibits transcription re-start and stimulates RNA synthesis at the light-strand origin of replication. These findings support a model in which ER-mitochondrial contact sites, in conjunction with MCU, deliver manganese from the ER to mitochondria to promote DNA replication, potentially by modulating mitochondrial RNA polymerase activity.

DOI: https://doi.org/10.1093/nar/gkag233
Cell Death Dis. 2026 Apr 28.

DHODH inhibition suppresses cutaneous squamous cell carcinoma growth by the induction of differentiation through perturbation of the cellular redox balance.

Ferial Khalife, Elodie Muzotte, Fatima Naji, Walid Mahfouf, Julien Izotte, Benoît Pinson, Stéphane Claverol, Nivea Amoedo, Hussein Fayyad-Kazan, Lea Dousset, Rodrigue Rossignol, Hamid-Reza Rezvani.

Dihydroorotate dehydrogenase (DHODH), a key enzyme in de novo pyrimidine biosynthesis, has recently emerged as a therapeutic target in various cancers. We have previously identified a pivotal role of DHODH in the initiation of cutaneous squamous cell carcinoma (cSCC), the second most common type of non-melanoma skin cancer. We also showed that pharmacological inhibition of this enzyme suppresses ultraviolet (UV)-induced tumor formation. However, the key mechanisms driving the anticancer activity of DHODH inhibition remain unexplored in cSCC. We investigated the biological consequences of pharmacological and genetic DHODH inhibition in cSCC using xenograft models derived from two human cell lines, A431 and SCC13, implanted in immunodeficient NSG mice. DHODH activity was suppressed pharmacologically with leflunomide (LFN) and the potent DHODH inhibitor PTC299, or genetically via lentiviral shRNA-mediated DHODH silencing (shDHODH). Proteomic and metabolomic analyses were integrated with histopathological, immunohistochemical, and immunoblotting evaluations to delineate the downstream effects of DHODH blockade. Comprehensive proteomic and metabolomic profiling revealed that DHODH inhibition induces a coordinated adaptive program involving keratinization, differentiation, redox homeostasis, and metabolic stress responses. Histological and immunostaining analyses demonstrated marked reductions in Ki67-positive proliferating cells and a corresponding increase in pan-cytokeratin (PanCK) and keratin 10 (Krt10) expression, indicative of enhanced epithelial differentiation. These changes were most pronounced in PTC299-treated and shDHODH xenografts, whereas LFN displayed minimal or no efficacy in SCC13 tumors. DHODH inhibition drives tumor differentiation and suppresses proliferation in cSCC, highlighting metabolic dependency as a potential therapeutic vulnerability. PTC299 exhibited superior antitumor activity and differentiation-inducing capacity compared with LFN. These findings position DHODH as a promising target for bioenergetic vulnerability-based cancer therapy in advanced or treatment-resistant cSCC.

DOI: https://doi.org/10.1038/s41419-026-08815-w
iScience. 2026 May 15. 29(5): 115453

Comprehensive genome sequencing associates elevated mitochondrial DNA and homoplasmy with early stage I of pancreatic cancer.

Appolinaire A Olou, Wesley Tom, M Rohan Fernando.

  Mitochondrial genome (mtDNA) presents higher fold mutation rates in cancers, creating heteroplasmy. While mtDNA mutations are drivers of cancers, heteroplasmic mutations appear theoretically unlikely drivers. However, whether high homoplasmy can characterize the early stage of cancers, along with high mtDNA genome coverage, has not yet been explored. Here, we directly profile stage I treatment naive pancreatic cancer patients' cfDNA using high throughput genome sequencing technology. Our analysis uncovered an elevated mitochondrial, not nuclear, genome coverage, correlating with high homoplasmy and rates of single-nucleotide variants. Heteroplasmy is the most expected and common biologically relevant mitochondrial genomic state in cells, but it can disrupt cellular phenotype and fitness. Conversely, homoplasmy is uncommon but can be selected for in certain cellular contexts. The high mtDNA coverage, along with a high mutation load at stage I of this cancer, concomitantly with a high homoplasmy, argues that mtDNA homoplasmy and its associated mutations accumulated non-passively.

Keywords:  biological sciences; omics

DOI:  https://doi.org/10.1016/j.isci.2026.115453
Cancer Res. 2026 Apr 29.

KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer.

Ravi Thakur, Dezhen Wang, Tuo Hu, Chunbo He, Junzhang Zhao, Voddu Suresh, Girish H Rajacharya, Anjan K Pradhan, Vira Chumak, Carlos A Valenzuela, Asha D Kushwaha, Drew A Labreck, Tae Gyu Oh, Kar-Ming Fung, Daniel Zhao, Naoko Takebe, Susanna V Ulahannan, Surendra K Shukla, Kirsten L Bryant, Channing J Der, Kamiya Mehla, Pankaj K Singh.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent KRAS mutations, which activate the MAPK pathway to promote PDAC progression. Here, we explored metabolic vulnerabilities of PDAC by assessing initial metabolic reprogramming upon ERK inhibition using metabolomics, lipidomics, and isotope-tracing experiments. ERK inhibition enhanced lipid turnover and fatty acid oxidation while inhibiting glycolysis, glucose oxidation, and glutamine metabolism in PDAC cells. Moreover, lipophagy, but not cytosolic lipolysis, was responsible for the increased lipid turnover and fatty acid oxidation upon ERK inhibition. Lipophagy and lipophagy-fueled fatty acid oxidation were induced by increased nuclear translocation and activity of the transcription factor TFEB. Pharmacological inhibition of fatty acid oxidation in combination with KRASG12D/MEK/ERK inhibitors synergistically decreased the growth of PDAC cell lines and organoids. The combination decreased tumor burden and improved survival in orthotopic cell line and patient-derived xenograft PDAC models. Overall, this study provides mechanistic insights into the development of metabolic resistance to KRAS signaling inhibition and demonstrates that fatty acid oxidation is a metabolic vulnerability following KRAS signaling inhibition that can be utilized as an effective therapeutic target to treat PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1984
Br J Cancer. 2026 Apr 28.

SLIRP maintains energy metabolism homeostasis in colorectal cancer by stabilizing mitochondrial-encoded mRNAs.

Chenyu Yang, Yue Ming, Qingbin Wu, Zixia Ye, Yingying Duan, Hulin Ma, Xiaomin Xu, Rong Wei, Xingyang Qiu, Huaping Yang, Yang Yang, Jiawei Guo, Yong Peng.

BACKGROUND: Colorectal cancer (CRC) is a highly vascularised tumour often characterised by elevated oxidative phosphorylation (OXPHOS) activity, positioning OXPHOS as a potential metabolic vulnerability for targeted therapy. SLIRP is an RNA-binding protein involved in the post-transcriptional regulation of mitochondrial gene expression. However, its specific function and underlying mechanism in CRC remain poorly understood.
METHODS: Clinical specimens and public databases were utilised to analyse both the subcellular localisation and expression of SLIRP in CRC. The functional role of SLIRP in CRC progression was assessed through cell growth, apoptosis, and metabolic analyses. Post-transcriptional regulation of mitochondrial-encoded mRNAs by SLIRP was investigated using RNA immunoprecipitation and mRNA stability assays.
RESULTS: SLIRP expression was significantly elevated in CRC tissues compared to adjacent normal tissues, and high SLIRP expression correlated with poor patient survival. SLIRP knockdown induced an ATP crisis, leading to suppressed tumour growth and increased apoptosis in CRC cells. Mechanistically, SLIRP globally binds to mitochondrial-encoded mRNAs and maintains their stability, functioning as a key post-transcriptional regulator of mitochondrial gene expression.
CONCLUSIONS: These findings uncover a critical role for SLIRP in maintaining OXPHOS activity in CRC and highlight its potential as both a prognostic biomarker and a therapeutic metabolic target.

DOI: https://doi.org/10.1038/s41416-026-03453-7
Nat Commun. 2026 Apr 30.

Nuclear genetic modulation of tissue-specific mitochondrial RNA processing contributes to common disease risk.

Eleonora Centanini, Oliver Pain, Patrick F Chinnery, Alan Hodgkinson.

Mitochondrial dysfunction is widely implicated in human disease, yet whether it plays a causal role and why effects are tissue-specific remain unclear. Here, we analyse over 15,000 RNA-sequencing datasets from 49 tissue types integrated with germline genetic data to investigate the impact of mitochondrial DNA (mtDNA) transcription on disease risk. We identify 25 nuclear genetic variants associated with mtDNA transcript abundance, revealing gene- and tissue-specific regulatory architectures. We then develop tissue-specific genetic scores to predict mtDNA transcript levels and validate them in independent datasets. Applying these scores to 377,439 UK Biobank participants reveals significant associations between predicted mtDNA transcript abundance and multiple common diseases and quantitative traits, many showing marked tissue specificity, including associations with hypertension and Parkinson's disease in biologically relevant tissues. These findings provide genetic evidence that variation in mtDNA transcriptional processes contributes to complex disease biology and highlight mitochondrial RNA processing as a compelling therapeutic target.

DOI: https://doi.org/10.1038/s41467-026-72649-5
Cell Death Dis. 2026 Apr 27.

Lactic acid promotes metastasis of papillary thyroid carcinoma by enhancing CPT1A lactylation.

Mingjian Zhao, Haifeng Han, Min Sun, Ruowen Li, Huimin Chen, Fangyu Liu, Chengxu Miao, Yongkang Wu, Xiaojia Shi, Mengting Wu, Gabriele Materazzi, Paolo Miccoli, Jinghui Lu, Xuetian Yue.

Papillary thyroid carcinoma (PTC), the most prevalent thyroid malignancy, exhibits aggressive behavior in subsets with metastasis. Despite advances in risk stratification, biomarkers predicting metastatic potential remain limited. Here, we identify lactate as a critical driver of PTC metastasis through lactylation of carnitine palmitoyltransferase 1 A (CPT1A), the rate-limiting enzyme in fatty acid β-oxidation (FAO). Multi-omics profiling of 27 paired PTC tissues revealed elevated lactate levels and FAO activation, corroborated by TCGA data. Functional assays demonstrated that exogenous lactate enhances PTC cell migration via CPT1A-dependent FAO. Mechanistically, lactate upregulated CPT1A transcription by promoting histone H3K18 lactylation (H3K18la), simultaneously stabilized CPT1A protein via lactylation of CPT1A at K180/K285 to suppress its ubiquitin-proteasomal degradation. Genetic or pharmacological inhibition of CPT1A abolished lactate-driven migration and FAO activity. In vivo, lactylation-deficient CPT1A mutants (K180R/K285R) attenuated lung metastasis and subcutaneous tumor growth in nude mice. This study reveals that lactate-CPT1A axis synergistically amplifies FAO to fuel PTC progression, suggesting CPT1A lactylation as a therapeutic vulnerability for metabolic intervention.

DOI: https://doi.org/10.1038/s41419-026-08790-2
Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2521310123

Mitochondrial fusion heterogeneity drives bidirectional tumor phenotypic transition in combined hepatocellular-cholangiocarcinoma.

Lin Chen, Dalin Wang, Weidong Qin, Gang Wang, Dan Wu, Jiaying Li, Xingchen Wang, Yinping Wang, Xiacheng Sun, Jing Zhao, Shanshan Guo, Lele Ji, Jiming Tian, Rui Ding, Yongzhan Nie, Jinliang Xing, Qichao Huang.

  Dysregulation of mitochondrial dynamics modulates malignant cell fate; however, the substantial heterogeneity in mitochondrial dynamics among tumor cells within individual tumor nodules and the resultant functional consequences remain inadequately characterized. In this study, we induced mosaic impairment of mitochondrial fusion in mouse liver under tumorigenic conditions and unexpectedly identified the formation of combined hepatocellular-cholangiocarcinoma (cHC), a monoclonal tumor displaying features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Restoration of the mitochondrial fusion protein MFN1 effectively suppressed cHC development. Analysis of human cHC samples revealed that ICC-like cells exhibit more pronounced mitochondrial fusion impairment compared to HCC-like cells. Mechanistically, increasing impairment of mitochondrial fusion resulted in a dose-dependent elevation of reactive oxygen species (ROS). Low levels of ROS upregulated HNF4α, promoting HCC-like differentiation, whereas high ROS levels activated HES1, facilitating ICC-like differentiation. Collectively, these results demonstrate that heterogeneity in mitochondrial dynamics is a critical determinant of cHC path-ogenesis.

Keywords:  HES1; HNF4α; ROS; combined hepatocellular-cholangiocarcinoma; mitochondrial fusion impairment

DOI:  https://doi.org/10.1073/pnas.2521310123
Cell Stem Cell. 2026 Apr 24. pii: S1934-5909(26)00144-X. [Epub ahead of print]

TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.

Eleni Kafkia, David Pladevall-Morera, Lidia Argemi-Muntadas, Gangqi Wang, Roberta Noberini, Arnau Casòliba-Melich, Sandra Bagés-Arnal, Matthias Anagho-Mattanovich, Rita Silvério-Alves, Johanna Gassler, Tiziana Bonaldi, Ton J Rabelink, Thomas Moritz, Jan Jakub Żylicz.

  Metabolism shapes stem cell differentiation and epigenome regulation, especially during the exit from naive pluripotency in vitro. Yet how metabolic networks reorganize at implantation remains unclear. Here, we map metabolite routing in pre- and post-implantation mouse embryos and across dynamic pluripotency transitions in stem cells, revealing that the tricarboxylic acid (TCA) cycle undergoes spatio-temporal rewiring rather than a simple shutdown. Pyruvate emerges as a central metabolic nexus, where pyruvate carboxylase and malic enzyme activities create a cyclical carbon flow essential for balanced metabolic and transcriptional states, timely exit from naive pluripotency, and differentiation. As cells leave naive pluripotency, glutamine increasingly fuels the TCA cycle; unexpectedly, it is also the dominant carbon source for histone acetylation. The necessary acetyl-CoA is generated via IDH1-mediated reductive glutamine carboxylation and is coupled to pyruvate cycling, sustaining histone acetylation. These findings uncover a metabolically rewired, route-specific nutrient utilization program that links metabolism to epigenomic regulation and pluripotency transitions at implantation.

Keywords:  13C isotope tracing; development; differentiation; embryo; epigenetics; histone acetylation; metabolism; pluripotency; spatial metabolomics; stem cells

DOI:  https://doi.org/10.1016/j.stem.2026.04.004
bioRxiv. 2026 Apr 13. pii: 2026.04.09.717584. [Epub ahead of print]

SIRT5 acts in the tumor microenvironment via endothelial cell metabolism to support breast cancer growth.

Anthony M Chen, Issahy Cano, Qian Zhao, Pei-Yin Tsai, Elijah A Bacchus, Sadhan Jana, Irma R Fernandez, Zeribe C Nwosu, Andrew Miller, Joeva Barrow, Hening Lin, Esak Lee, Robert S Weiss.

Triple-negative breast cancer (TNBC) is characterized by aggressive progression and poor prognosis, partly due to abnormal angiogenesis. While the metabolic reprogramming of tumor cells is well characterized, the metabolic regulation of tumor-associated endothelial cells (ECs) remains unclear. Here, we identified the mitochondrial deacylase SIRT5, which has established tumor-promoting roles in TNBC cells, as a key regulator of endothelial metabolic homeostasis and tumor angiogenesis. SIRT5-deficient host mice showed significant defects in supporting the growth of orthotopic SIRT5-proficient mammary tumor transplants, and the resulting neoplasms showed defects in tumor vascularization. In a 3D microfluidic vessel-on-chip model, SIRT5 loss compromised vascular barrier integrity and EC sprouting. Mechanistically, SIRT5 -deficient ECs exhibited diminished mitochondrial respiratory capacity but apparently normal glycolysis. SIRT5 loss also caused increased mitochondrial reactive oxygen species levels, and a mitochondrial antioxidant rescued the endothelial cell defects following SIRT5 loss, indicating that SIRT5-mediated mitochondrial redox homeostasis in the tumor microenvironment is necessary to maintain vascular function. Orthotopic co-transplantation of TNBC and EC cells with or without SIRT5 knockdown demonstrated that endothelial SIRT5 promotes increased tumor growth in vivo . These results suggest that targeting SIRT5 offers a potential therapeutic strategy to disrupt tumor angiogenesis and suppress TNBC progression by targeting the metabolic vulnerabilities of the tumor endothelium.

DOI: https://doi.org/10.64898/2026.04.09.717584
Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2528281123

Mitochondrial double-stranded RNA fuels pancreatic cancer growth via RIG-I/TLR3 inflammation.

Andrew T Milcarek, Minjeong Yeon, Camilla Esposito, Prerna Kulkarni, Andrew V Kossenkov, Jozef Madzo, Anneliese M Faustino, Hsin-Yao Tang, Alessandra M Storaci, Alessandro Palleschi, Marco Locatelli, Valentina Vaira, Mary V Iacocca, Andrea Ward, Arvind Sabesan, Nicholas J Petrelli, Michela Perego, Dario C Altieri.

  Mitochondria activate inflammation and innate immunity to protect against infections, but the role in cancer is unknown. Here, we report that patients with pancreatic ductal adenocarcinoma (PDAC) with reduced levels of the mitochondrial scaffold, Mic60, or inner mitochondrial membrane protein, exhibit increased inflammation, high NFκB activity and production of TNFα. This is mediated by double-stranded RNA (dsRNA) released from structurally defective, Mic60-low mitochondria, which engages TLR3/RIG-I sensing, activates NFκB gene expression and reprograms transcriptional and signaling networks to promote PDAC proliferation. Preclinical targeting of mitochondrial dsRNA signaling triggers rapid cell death and inhibition of tumor growth, selectively in Mic60-knockdown PDAC, without overt toxicity, in vivo. Therefore, dsRNA released from defective mitochondria generates protumorigenic inflammation and provides an actionable therapeutic target in selected PDAC patients.

Keywords:  TLR3; dsRNA; inflammation; pancreatic cancer; viral mimicry

DOI:  https://doi.org/10.1073/pnas.2528281123
Cell Rep Med. 2026 Apr 29. pii: S2666-3791(26)00201-6. [Epub ahead of print] 102784

BCAT1-dependent HIF-1α stabilization is a targetable metabolic vulnerability in hepatocellular carcinoma.

Misty Shuo Zhang, Kenneth Kin-Leung Kwan, Aki Pui-Wah Tse, Gengchao Wang, Larry Lai Wei, Kejie Sun, Noreen Nog-Qin Chui, Derek Lee, Macus Hao-Ran Bao, Xiaoxuan Pang, Zhenqi Wu, Yanyan Chen, Yangyang Wang, Zifan Yang, Xue Jiang, Qidong Li, Yan Zhang, Yajie Zhong, Jacinth Wing-Sum Cheu, Yiling Chen, Weixing Li, Chun-Ming Wong, Jianing Wang, Zongwei Cai, Qi Zhang, Tingbo Liang, Irene Oi-Lin Ng, Adonia E Papathanassiu, Carmen Chak-Lui Wong.

  Hypoxia is a common characteristic of solid tumors, especially in hepatocellular carcinoma (HCC). Hypoxia-inducible factors (HIFs), particularly HIF-1α, mediate metabolic adaptation, which is crucial for survival of hypoxic cells. Branched-chain amino transferase 1 (BCAT1) catalyzes the reversible transamination reaction between branched-chain amino acids (BCAAs) and branched-chain keto acids (BCKAs), involving the inter-conversion of α-ketoglutarate (α-KG) and glutamate. We investigate and delineate the mechanisms by which BCAT1 consumes α-KG and stabilizes HIF-1α, suppressing α-KG-dependent oxygen dehydrogenase, prolyl hydroxylase-domain protein (PHD), inducing HIF-1α-mediated metabolic reprogramming and promoting hypoxic survival of HCC. We evaluate the potency of a BCAT1 inhibitor, ERG245, as a single or combination treatment with tyrosine kinase inhibitor (TKI) in vivo. We further validate the over-expression and correlation of BCAT1 and HIF-1α downstream metabolic genes in HCC clinical samples. Our results indicate that BCAT1 benefits HCC growth through HIF-1α-induced metabolic reprogramming. Targeting BCAT1 will provide an effective therapeutic strategy for HCC patients.

Keywords:  EGR245; branched-chain amino transferase 1; hepatocellular carcinoma; hypoxia; hypoxia-inducible factor; metabolic reprogramming; prolyl hydroxylase-domain protein; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.xcrm.2026.102784