bims-mibica 2026-05-31 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–05–31
28 papers selected by
Kelsey Fisher-Wellman, Wake Forest University

AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.
CPT1A drives cisplatin resistance via acetylation‑dependent activation of DRP1 and mitochondrial fission in small cell lung cancer.
Starving leukemia: nicotinamide phosphoribosyltransferase-dependent nicotinamide adenine dinucleotide salvage links metabolic vulnerability to therapeutic sensitivity in acute myeloid leukemia.
SIRT5-dependent desuccinylation licenses UBR5-mediated degradation of TAMM41 to regulate mitochondrial metabolism in lung adenocarcinoma.
A transport-independent role for SLC25A12 in mitochondrial stress signalling.
Mitochondrial NADH-redox inflexibility constrains genomic and epigenetic stability in pluripotent stem cells.
An MMP-independent fluorescent probe for simultaneously detecting viscosity and hydrogen peroxide in tumor tissues of cancer patients.
αKG-mediated carnitine synthesis drives DNA repair via histone acetylation.
Mechanism of age-related accumulation of mtDNA mutations in human blood.
Upregulation of TWNK promotes proliferation and invasion of liver cancer by enhancing mitochondrial respiration.
Detection of mitochondrial bioenergetics using a novel bimodal 3D microelectrode array (MEA)-based biosensor.
Transmembrane domain switching controls PINK1 import and fate in mitochondria.
MEN1/menin deficiency suppresses hepatocellular carcinogenesis via disrupting mitophagy-mediated mitochondrial homeostasis.
The iron-sulfur cluster assembly factor FDX2 is required for tumor initiation but not for growth of established tumors in transplantation models.
Mitochondria-Associated mRNAs Restore ATP During Oxidative Stress via Cytosolic Translation.
Kinase-independent signaling by PIM1 promotes drug resistance by increasing mitophagy and reducing oxidative stress.
Copper depletion boosts CNS leukemia therapy by inhibiting nucleotide synthesis through impairment of mitochondrial complex IV activity.
Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A phase 1 dose-escalation study of Navitoclax, Venetoclax, and Decitabine.
Hadhb Deficiency Inhibits Lung Tumorigenesis Via Activating ER Stress.
MiTo: tracing the phenotypic evolution of somatic cell lineages via mitochondrial single-cell multi-omics.
Tyrosine 48 Phosphorylation of Cytochrome c Alters Mitochondrial Respiration, ROS Production, and Apoptosis.
L-Carnitine Regulates Regeneration of Human Hematopoietic Stem and Progenitor Cells.
Mitochondrial Transfer-Driven Immune Evasion in the Tumor Microenvironment.
Mitochondrial genetic variation across tissues of the human body.
Unbiased CRISPR synthetic lethal screening for genetic vulnerabilities in a succinate dehydrogenase-loss model of paraganglioma.
Chaperone-mediated autophagy is a tumor-suppressive mechanism in hepatocellular carcinoma.
The SLC25A45-TML Axis as a Biological Foundation for a Multivariable Plasma Metabolite Signature for High-Precision Prostate Cancer Detection.
Spatially Resolved Metabolomic Profiling Reveals Progression-Associated Metabolic Reprogramming in Colorectal Liver Metastasis.

Mol Cancer. 2026 May 27.

AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.

Shakti P Pattanayak, Odai Darawshi, Omid Hajihassani, Jordan M Winter, Nicole Weiler, Melanie Ott, Florian Rothweiler, Jindrich Cinatl, Martin Michaelis, Daniel J Lindner, Thomas D Green, Polina Krassovskaia, Raphael T Aruleba, Kelsey H Fisher-Wellman, Jason A Mears, David Wald, Leif A Eriksson, Boaz Tirosh.

BACKGROUND: mTORC1 activity is oncogenic. However, in the presence of chemotherapy, suppression of mTORC1 is cytoprotective. mTOR suppression requires an intact tuberous sclerosis complex (TSC), composed of TSC1, TSC2 and TBC1D7. Small molecules that activate mTOR by blocking the TSC are lacking.
METHODS: We applied in silico docking and medicinal chemistry to generate AcTor, a potential first-of-its-kind TSC2 inhibitor. Because inhibition of TSC2 results in increased sensitivity to proteasome inhibitors, we combined AcTor and the proteasome inhibitor ixazomib (IXZ) in various cancer cell types.
RESULTS: Potentiation of cytotoxic activity of IXZ by AcTor was observed across multiple acute myeloid leukemia (AML) cell lines and primary patient samples. The combination triggered a collapse of mitochondrial respiratory capacity, loss of mitochondrial membrane potential, accumulation of ROS and apoptosis. These attributes increased in drug-resistant AML. Transcriptomic profiling revealed that AcTor alone induced anabolic and oxidative phosphorylation programs, whereas AcTor/IXZ redirected the signaling towards stress-associated and pro-apoptotic transcriptional states, including a p53 pathway signature. In vivo studies revealed reduction in AML burden, depletion of blasts and of leukemic stem cells, and retention of activity upon relapse. AcTor/IXZ was equally potent in a TP53-mutated patient-derived xenograft model, exceeding the efficacy of standard-of-care.
CONCLUSIONS: As a TSC2 inhibitor, AcTor should not be used alone in cancer. When combined with proteasome inhibitors, the pharmacodynamics of AcTor shifts towards the development of a mitochondrial catastrophe in AML, which is durable, broad range, agnostic to TP53 mutations and to the acquisition of resistance to common clinical anti-AML drugs.

DOI: https://doi.org/10.1186/s12943-026-02689-4
Cell Death Dis. 2026 May 28.

CPT1A drives cisplatin resistance via acetylation‑dependent activation of DRP1 and mitochondrial fission in small cell lung cancer.

Kuanbing Chen, Shi Zong, Kefeng Li, Li Yu.

Cisplatin resistance represents a major clinical challenge in small-cell lung cancer (SCLC), yet the underlying metabolic adaptations remain poorly understood. Here, we identify a novel regulatory axis centered on the fatty acid oxidation (FAO) enzyme carnitine palmitoyltransferase 1 A (CPT1A) that governs mitochondrial dynamics to drive chemoresistance. In cisplatin-resistant SCLC, CPT1A is markedly upregulated and undergoes functional acetylation. This modified CPT1A not only sustains cellular bioenergetics and redox balance through enhanced FAO but also directly recruits dynamin-related protein 1 (DRP1) to mitochondria. By facilitating DRP1-dependent mitochondrial fission, CPT1A orchestrates a metabolic adaptation that confers a survival advantage. Genetic or pharmacological inhibition of CPT1A reversed this phenotype, impairing mitochondrial fission, depleting energy stores, and resensitizing resistant cells to cisplatin. In vivo, targeting CPT1A markedly suppressed tumor growth and restored cisplatin sensitivity. Our results uncover an acetylated CPT1A-DRP1 axis as a critical metabolic vulnerability in cisplatin-resistant SCLC, providing a compelling therapeutic strategy to overcome treatment failure.

DOI: https://doi.org/10.1038/s41419-026-08868-x
Transl Cancer Res. 2026 Apr 30. 15(4): 345

Starving leukemia: nicotinamide phosphoribosyltransferase-dependent nicotinamide adenine dinucleotide salvage links metabolic vulnerability to therapeutic sensitivity in acute myeloid leukemia.

Juan Luiz Coelho-Silva, Diego Antonio Pereira-Martins, João Agostinho Machado-Neto.



Keywords:  Acute myeloid leukemia (AML); B-cell lymphoma 2-mediated apoptosis (BCL2-mediated apoptosis); mitochondrial dysfunction; nicotinamide adenine dinucleotide metabolism (NAD+ metabolism); nicotinamide phosphoribosyltransferase inhibition (NAMPT inhibition)

DOI:  https://doi.org/10.21037/tcr-2026-1-0292
Biol Direct. 2026 May 25.

SIRT5-dependent desuccinylation licenses UBR5-mediated degradation of TAMM41 to regulate mitochondrial metabolism in lung adenocarcinoma.

Haoyang Yuan, Wenxuan Hu, Xin Lv, Yonghao Cao, Kang Hu, Yongsen Li, Zhike Chen, Jian Yang, Yin Wang, Jun Zhao, Chun Xu.

  Mitochondrial metabolic reprogramming is essential for lung adenocarcinoma (LUAD) progression, yet the regulatory mechanisms governing mitochondrial phospholipid synthesis remain poorly understood. TAMM41 is a mitochondrial inner-membrane enzyme required for cardiolipin biosynthesis, but its role in LUAD has not been defined. Here, we show that TAMM41 is significantly upregulated in LUAD tissues and cell lines, and its high expression correlates with poor patient prognosis. Functional studies demonstrate that TAMM41 promotes LUAD cell proliferation, migration, and invasion, whereas genetic ablation of TAMM41 suppresses malignant phenotypes. Mechanistically, TAMM41 maintains mitochondrial complex I activity, ATP production, and redox homeostasis, thereby limiting oxidative stress and apoptosis. We identify the E3 ubiquitin ligase UBR5 as a specific regulator of TAMM41 stability through ubiquitination at lysine 206. Moreover, the mitochondrial desuccinylase SIRT5 directly interacts with TAMM41 and removes succinylation at lysine 45, enhancing UBR5 binding and promoting TAMM41 degradation. In vivo, TAMM41 knockout markedly inhibits LUAD xenograft growth, accompanied by impaired mitochondrial respiration and increased apoptosis. Collectively, these findings identify TAMM41 as a mitochondrial oncogenic driver in LUAD and reveal a SIRT5-TAMM41-UBR5 axis that links lysine succinylation to mitochondrial metabolic control, highlighting TAMM41 as a potential therapeutic target.

Keywords:  Cardiolipin; LUAD; Mitochondria; NSCLC; TAMM41

DOI:  https://doi.org/10.1186/s13062-026-00832-1
Nat Cell Biol. 2026 May 27.

A transport-independent role for SLC25A12 in mitochondrial stress signalling.

Liu Jiang, Lan Li, Jialiang Guan, Ying Liu.

Mitochondria are central hubs for energy production and cellular adaptation to stress. When mitochondria are damaged, cells activate protective signalling pathways to restore homeostasis and ensure survival. One such pathway, known as the integrated stress response (ISR), reduces overall protein synthesis while enhancing the production of stress-responsive proteins. The mitochondrial carriers SLC25A12 and SLC25A13 transport similar metabolites but are expressed in different tissues and linked to distinct genetic diseases. Here we show that SLC25A12 plays a previously unrecognized role in stress signalling that is independent of its transport activity. SLC25A12 interacts with the mitochondrial protease OMA1, enabling activation of ISR during mitochondrial damage. This signalling function is disrupted by a disease-linked mutation but preserved in transport-deficient variants. Our findings reveal SLC25A12 as a dual-function mitochondrial protein, acting as both a metabolite transporter and a regulator of stress signalling, and suggest that defective ISR activation may contribute to certain SLC25A12-associated pathologies.

DOI: https://doi.org/10.1038/s41556-026-01973-1
EMBO J. 2026 May 27.

Mitochondrial NADH-redox inflexibility constrains genomic and epigenetic stability in pluripotent stem cells.

Tanveer Ahmed, Hui Zhang, Ghulam M Mushraf, Yongzhang Pan, Zeyu Zhang, Zhenzhu Sun, Mengran Yin, Xueting Xu, Xinyu Wu, Yin Gao, Yan Li, Peizhi Li, Liang Ding, Qiang Zhang, Runxia Lin, Khair Ullah, Yinghua Huang, Bushra Mirza, Yifeng Huang, Abdul Sammad, Xiangqian Kong, Dajiang Qin, Miguel A Esteban, Lulu Wang, Baoming Qin.

The electron transport chain (ETC) is essential for NAD+ regeneration and proliferation. While many cell types tolerate ETC inhibition when pyruvate or aspartate is supplied, pluripotent stem cells (PSCs) enter a reversible paused state even at abundant pyruvate levels. Here, we show that ETC inhibition triggers severe NADH reductive stress in mouse embryonic stem cells (mESCs), driven mainly by threonine dehydrogenase (TDH). TDH-derived NADH establishes a metabolic environment that disfavors cells with compromised mitochondrial function, maintains inhibition of pyruvate dehydrogenase (PDH), and is associated with increased genomic and epigenetic stability at the cellular population level. ETC inhibition similarly induces pausing in early mouse embryos and in human pluripotent stem cells (hPSCs). In hPSCs, combined inhibition of the one-carbon metabolism enzymes serine hydroxymethyltransferase (SHMT1/2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) effectively reduced reductive stress and rescued the paused phenotype. Together, these findings support a model in which limited mitochondrial redox adaptability represents a conserved metabolic feature of pluripotent stem cells and in which NADH reductive stress is associated with genomic and epigenetic stability.

DOI: https://doi.org/10.1038/s44318-026-00784-2
J Photochem Photobiol B. 2026 May 22. pii: S1011-1344(26)00125-9. [Epub ahead of print]280 113478

An MMP-independent fluorescent probe for simultaneously detecting viscosity and hydrogen peroxide in tumor tissues of cancer patients.

Jun-Yi He, Jie Niu, Peihang Jing, Yawen Li, Yanyan Ma, Zhenghua Lv.

  Elucidating the fundamental interrelation between hydrogen peroxide (H2O2)/viscosity and mitochondria related diseases still is a major issue due to the lack of an excellent tool for long-term tracking of mitochondrial viscosity and hydrogen peroxide. Herein, we devised an MMP-independent probe, BKI, which could simultaneously detect fluctuations of viscosity and H2O2. BKI shows a good response to H2O2 with a low detection limit of 34 nM, mediated by the specific reaction between H2O2 and the borate ester moiety. Moreover, BKI can also monitor the viscosity fluctuations with green emission at 475 nm due to the rotation of its vinyl double bond. Notably, BKI not only localizes in mitochondria accurately but also firmly immobilizes in mitochondrial inner membrane through hydrophobic interactions between its long alkyl chains and lipids on the mitochondrial membrane, enabling long-term monitoring mitochondrial viscosity and H2O2. Using BKI, the viscosity changes induced by monensin or nystatin, as well as exogenous and endogenous H2O2 in living cell were successfully visualized. In particular, the unique probe can distinguish between normal tissues and tumor tissues of cancer patients by detecting viscosity and H2O2. These results imply that BKI can be served as a powerful tool for long-term visualizing mitochondrial viscosity and H2O2 in vitro and in vivo.

Keywords:  Cancer tissue; Hydrogen peroxide; Mitochondria; Mitochondrial membrane potential-independent; Viscosity

DOI:  https://doi.org/10.1016/j.jphotobiol.2026.113478
Nature. 2026 May 27.

αKG-mediated carnitine synthesis drives DNA repair via histone acetylation.

Apoorva Uboveja, Baixue Yang, Raquel Buj, Amandine Amalric, Hui Wang, Naveen Kumar Tangudu, Aidan R Cole, Julie A Disharoon, Richard S Fang, Evan Levasseur, Miho Naruse, Zhentai Huang, Emily Megill, Daniel S Kantner, Adam Chatoff, Hafsah Ahmad, Mariola M Marcinkiewicz, Sarah Graff, Ellen De Pieri, Andrea Andress Huacachino, Frank P Vendetti, Jeff Danielson, Erika S Dahl, Jennifer L Pennise, Esther Elishaev, Alison Jaccard, Lauren Borho, Miriam D Post, Kristine Cooper, Francesmary Modugno, Nadine Hempel, Wayne Stallaert, Christopher J Bakkenist, Simone Sidoli, Kathryn E Wellen, Benjamin G Bitler, David T Long, Nathaniel W Snyder, Katherine M Aird.

Homologous recombination (HR) deficiency increases sensitivity to DNA-damaging agents that are commonly used to treat cancer1. In HR-proficient cancers, the metabolic mechanisms that drive response or resistance to DNA-damaging agents remain unclear. Here we have identified that depletion of α-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA-damaging agents by metabolic regulation of histone acetylation. αKG is required for the activity of αKG-dependent dioxygenases2 (αKGDDs), and previous work has focused almost exclusively on the demethylase functions of αKGDD. Using a targeted CRISPR knockout library consisting of 64 αKGDDs, we discovered that trimethyllysine hydroxylase epsilon (TMLHE), the first and rate-limiting enzyme in de novo carnitine synthesis, is necessary for the survival of HR-proficient cells in the presence of DNA-damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation and was non-redundant with other nucleo-cytosolic acetyl-CoA-generating pathways. The increase in histone acetylation by means of the αKG-carnitine axis promoted HR-mediated DNA repair through site-specific histone acetylation. Finally, we observed a positive correlation between TMLHE and histone acetylation in patient samples and found that high TMLHE or acetylcarnitine correlates with worse progression-free survival in patients treated with DNA-damaging agents. This study demonstrates for the first time, to our knowledge, that αKG affects site-specific histone acetylation and provides a mechanism of HR proficiency through carnitine synthesis. Moreover, these data provide a metabolic avenue for inducing HR deficiency and promoting sensitivity to DNA-damaging agents.

DOI: https://doi.org/10.1038/s41586-026-10584-7
Nature. 2026 May 27.

Mechanism of age-related accumulation of mtDNA mutations in human blood.

Rahul Gupta, Timothy J Durham, Grant Chau, Masahiro Kanai, Md Mesbah Uddin, Wenhan Lu, M Austin Argentieri, Konrad J Karczewski, Daniel Howrigan, Pradeep Natarajan, Wei Zhou, Benjamin M Neale, Vamsi K Mootha.

Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing1. Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT, TCL1A and SMC4, all of which have been linked to clonal haematopoiesis (CH)2. Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which 'cryptic' mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT, CH and observed accrual of mtDNA mutations.

DOI: https://doi.org/10.1038/s41586-026-10569-6
Pathol Res Pract. 2026 May 24. pii: S0344-0338(26)00214-1. [Epub ahead of print]285 156561

Upregulation of TWNK promotes proliferation and invasion of liver cancer by enhancing mitochondrial respiration.

Xiaojun Xu, Jing Zhang, Jianhua Yuan, Bing Wu, Zhe Jing, Jie He, Hantao Mu, Hulin Chang, Peng Yuan, Xiaohong Zhang.

  TWNK, a mitochondrial hexameric DNA helicase, is crucial for the replication of mtDNA. Nonetheless, its biological functions in human cancers still largely unexplored. In this study, we reveal that TWNK expression is significantly elevated in hepatocellular carcinoma (HCC) tissues, and its elevation associates with poor patient prognosis. We further demonstrate that TWNK knockdown suppresses HCC proliferation and metastasis by inducing G1-to-S cell cycle arrest and inhibiting epithelial-to-mesenchymal transition (EMT). Conversely, forced TWNK expression enhances HCC cell proliferation and motility. Mechanistically, TWNK promotes HCC cell proliferation and invasion through augmenting mitochondrial DNA (mtDNA) content, which in turn boosts mitochondrial respiration and energy production through upregulation of mtDNA-encoded electron transport chain (ETC) genes. Additionally, we found that DNA hypomethylation and decreased miR-766-3p expression contribute, at least in part, to the upregulation of TWNK in HCC cells. Together, our results elucidate a novel oncogenic role for TWNK in HCC and highlight its potential as a target for therapeutic intervention.

Keywords:  HCC; Mitochondrial respiration; MtDNA content; TWNK

DOI:  https://doi.org/10.1016/j.prp.2026.156561
Microsyst Nanoeng. 2026 May 28. pii: 208. [Epub ahead of print]12(1):

Detection of mitochondrial bioenergetics using a novel bimodal 3D microelectrode array (MEA)-based biosensor.

Randall K James, Tatiana C Hostios, Ji Chang, Aakash Patel, Faisal Bin Kashem, Isaac Johnson, Jorge Manrique Castro, James Hickman, Swaminathan Rajaraman.

Developing new label-free paradigms for functional assays in biomedical research has the potential to catalyze efforts in drug discovery and improve the understanding of complex disorders. Mitochondria are an essential organelle in nearly every eukaryotic organism that perform vital functions such as adenosine triphosphate (ATP) production, redox signaling, reactive oxygen species (ROS) homeostasis and regulation of programmed cell death. These activities are regulated by electrophysiological processes that occur in the inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM) in response to metabolic demands, making them an important physiological marker for bioenergetic studies. Mitochondria dysfunction is an early pathological biomarker of complex diseases, such as diabetes, neurodegeneration, myopathy, cancer, and cardiovascular disease. Built atop a novel microfabrication strategy for 3D Microelectrode Arrays (MEAs), we demonstrate a 3D mitochondria biosensor capable of bimodal sensing of mitochondrial electrophysiology from the OMM and IMM using electrochemical impedance spectroscopy (EIS) and electrophysiology recordings. Data obtained using EIS displays impedance magnitude and phase characterization of mitochondria isolated from NIH3T3 and induced pluripotent stem cells (iPSC) models, these measurements represent the major functional outputs of cellular respiration and electron transport chain (ETC) activity through the detection of conductive and capacitive properties of the IMM. Additionally, time-resolved electrophysiological recordings from an NIH3T3 derived mitochondrial pellet captured sub-millisecond voltage transients, establishing a complementary real-time electrophysiological profile of mitochondrial membrane activity that can be attributed voltage dependent anion channel (VDAC) gating or IMM potential dynamics.

DOI: https://doi.org/10.1038/s41378-026-01275-4
EMBO J. 2026 May 26.

Transmembrane domain switching controls PINK1 import and fate in mitochondria.

James S Lorriman, Rhiannon J Hughes, Adam G Grieve, Robin A Corey, Ian Collinson.

Mitochondrial targeting of the PINK1 kinase results, under normal conditions, in membrane-potential-driven inner membrane penetration and cleavage by the resident protease PARL before retro-translocation and proteasomal degradation. In compromised mitochondria, with reduced membrane potential, inner membrane incorporation is not achieved, which leads to surface activation of the full-length protein, Parkin recruitment and mitophagy. Here, we identify a third pathway in which PINK1 is imported into the mitochondrial matrix. Structural modelling predicts that PINK1's transmembrane domain (TMD) is conformationally plastic, forming either an α-helix or α/β-hybrid at the interface between Tim17 of the TIM23-complex for engagement of either ROMO1 or PARL. These mutually exclusive assemblies define distinct protein-import channels with differing biological roles. PINK1's α-helical TMD adopts a pose suggestive of translocation through the ROMO1/Tim17-channel, while the α/β-hybrid engages PARL and is cleaved. We propose that TMD structural plasticity determines whether PINK1 is imported into the matrix or cleaved and retro-translocated. The results expand the role of PINK1 beyond that of a damage sensor and imply a role in healthy mitochondrial function with potential relevance to Parkinson's disease.

DOI: https://doi.org/10.1038/s44318-026-00789-x
Autophagy. 2026 May 28.

MEN1/menin deficiency suppresses hepatocellular carcinogenesis via disrupting mitophagy-mediated mitochondrial homeostasis.

Chaochun Chen, Dafang Yu, Dekun Tang, Mengyuan Liu, Jiamei Zhu, Xuyan Wang, Guixue Dan, Lan Chen, Shumei Tang, Qianting Tian, Houmei Wang, Fuxue Meng, Tuo Zhang, Bing Guo, Tengxiang Chen, Haiyang Li, Bangming Jin.

  Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with complex pathogenesis intertwined with metabolic and mitochondrial dysfunction. MEN1/menin is a protein with context-dependent functions in liver diseases. While MEN1 has been linked to HCC progression and mitochondrial homeostasis, its precise regulatory mechanism in these processes remains incompletely understood. Here, we report that MEN1 localizes to the outer mitochondrial membrane (OMM) in HCC cells, which is mediated by its N-terminal mitochondrial targeting sequence and the TOMM20 translocase complex. In a genetically engineered DEN- and CCl4-induced HCC mouse model, hepatocyte-specific men1 deficiency significantly suppressed tumorigenesis, a phenotype associated with impaired mitochondrial homeostasis. Mechanistically, MEN1 deficiency disrupted mitochondrial function by manifesting as promoted mitochondrial fission, impaired oxidative phosphorylation, reduced ATP levels, and elevated reactive oxygen species during energy stress. Critically, MEN1 loss inhibited mitophagy via downregulating the PINK1-PRKN/Parkin pathway, which impaired clearance of dysfunctional mitochondria and promotes their cytotoxic accumulation. Moreover, MEN1 expression was upregulated in human HCC tissues, correlated with poor clinical outcomes and was positively associated with autophagy signatures. Notably, pharmacological activation of mitophagy reversed the tumor-suppressive effects of MEN1 deficiency in vitro and in vivo. These findings identified a noncanonical role of mitochondrial MEN1 in driving HCC progression via regulating mitophagy homeostasis, and highlight the MEN1-mitophagy axis as a potential therapeutic target for HCC. Abbreviations: Alb-Cre: albumin promoter-driven recombinase Cre; Baf A1: bafilomycin A1; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; CCl4: carbon tetrachloride; Co-IP: co-immunoprecipitation; CQ: chloroquine; DEN: diethylnitrosamine; DNM1L: dynamin 1 like; DQ-BSA: self-quenched BODIPY-conjugated bovine serum albumin; Gal: galactose; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic - pyruvic transaminase; HCC: hepatocellular carcinoma; WT: wild type; HMKO: hepatocyte-specific men1 knockout; IF: immunofluorescence; IHC: immunohistochemistry; IMM: inner mitochondrial membrane; KEGG: Kyoto Encyclopedia of Genes and Genomes; MEFs: mouse embryonic fibroblasts; MEN1-FL: full-length MEN1; MFF: mitochondrial fission factor; MFN1: mitofusin 1; MTS: mitochondrial targeting sequence; OCR: oxygen consumption rate; OMM: outer mitochondrial membrane; OXPHOS: oxidative phosphorylation; PINK1: PTEN induced kinase1; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; PRKN: parkin RBR E3 ubiquitin protein ligase; qPCR: RNA extraction and quantitative polymerase chain reaction; RNA-seq: RNA-sequencing; ROS: reactive oxygen species; shMEN1: small hairpin RNA-mediated MEN1 knockdown; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TOMM20: translocase of outer mitochondrial membrane 20.

Keywords:  Energy metabolism; MEN1; mitochondrial MEN1; mitochondrial fission; mitophagy

DOI:  https://doi.org/10.1080/15548627.2026.2677182
J Biol Chem. 2026 May 27. pii: S0021-9258(26)02072-7. [Epub ahead of print] 113200

The iron-sulfur cluster assembly factor FDX2 is required for tumor initiation but not for growth of established tumors in transplantation models.

Eifumi Hashimoto, Mai Ohuchi, Miyuki Nomura, Shuko Miyahara, Kayoko Hayashi, Masatoshi Saito, Yoji Yamashita, Muneaki Shimada, Hidekazu Yamada, Nobuhiro Tanuma.

  Iron-sulfur (Fe-S) clusters bind to Fe-S proteins and are required for their function and/or structural stability. Recent work reveals an essential role for Fe-S cluster biosynthesis in cancer cell proliferation in vitro, but how Fe-S cluster metabolism contributes to tumor activity in vivo is unclear. Here we report analysis suggesting a stage-specific requirement for FDX2, a critical component of the Fe-S cluster assembly complex, in cancer progression. Using inducible loss-of-function transplant models of a human ovarian cancer line, we show that FDX2 is required for tumor initiation and metastasis but not for growth of established tumors in mice. We report global upregulation of Fe-S proteins under low oxygen conditions and concomitant attenuation of FDX2 loss-mediated disruption of many Fe-S proteins, enabling FDX2-independent proliferation. Our findings highlight a differential requirement of Fe-S cluster biosynthesis for tumor metastasis versus growth and low oxygen-mediated mitigation of Fe-S protein loss promoted by FDX2 deficiency.

Keywords:  cancer biology; cancer metastasis; cellular senescence; gene knockout; hypoxia; iron-sulfur cluster; iron-sulfur protein; ovarian cancer; oxygen

DOI:  https://doi.org/10.1016/j.jbc.2026.113200
Antioxidants (Basel). 2026 May 03. pii: 580. [Epub ahead of print]15(5):

Mitochondria-Associated mRNAs Restore ATP During Oxidative Stress via Cytosolic Translation.

Dong-Bin Back, Gen Hamanaka, Ji-Hyun Park, Shin Ishikane, Masayoshi Tanaka, Takafumi Nakano, Yoshihiko Nakamura, Kazuhide Hayakawa.

  Mitochondrial transplantation has been proposed as a strategy to restore cellular bioenergetics after oxidative injury, but the mechanisms governing ATP recovery remain unclear. Using placental mitochondria, we examined ATP restoration following H2O2-induced oxidative stress. Unmodified mitochondria modestly increased ATP under baseline conditions but failed to restore ATP after injury. In contrast, lipid-coated mitochondria (MitoCoat) and lipid-encapsulated mitochondria-associated mRNAs (MitoCoat-mRNA) significantly increased ATP levels in injured cells. Transcriptomic analyses revealed that ATP recovery occurred without the normalization of canonical glycolytic or oxidative phosphorylation (OXPHOS) gene programs. Instead, unmodified mitochondria induced broad transcriptional responses associated with immune activation and cellular stress, whereas MitoCoat elicited a more restricted transcriptional profile. Notably, mitochondria-associated mRNAs alone restored ATP without detectable changes in host transcriptional programs. The removal of mitochondrial surface-associated ribosomes or the inhibition of cytosolic but not mitochondrial translation attenuated ATP recovery. The restoration of key metabolic enzymes through cytosolic translation, including PFKP, pyruvate dehydrogenase, and ATP synthase subunit ATP5A suggests that mitochondria-associated mRNAs promote recovery by re-establishing coupling between glycolysis and mitochondrial OXPHOS. Together, these findings identify encapsulated mitochondria-associated mRNAs as a potential strategy to restore cellular bioenergetics under oxidative stress.

Keywords:  MitoCoat; lipid modification; mRNA; mitochondria

DOI:  https://doi.org/10.3390/antiox15050580
Cancer Lett. 2026 May 22. pii: S0304-3835(26)00374-5. [Epub ahead of print]654 218611

Kinase-independent signaling by PIM1 promotes drug resistance by increasing mitophagy and reducing oxidative stress.

Hope Liou, Shailender S Chauhan, Caitlyn E Flores, Rose Kinkade, Madeline R Ressel, Anne E Cress, Paul R Langlais, Yogesh B Sutar, Abhijit A Date, Noel A Warfel.

  PIM kinases are overexpressed in castration resistant prostate cancer (CRPC) and many small molecule PIM kinase inhibitors (smPIM inhibitors) have been designed to block the catalytic activity of PIM. However, smPIM inhibitors have shown limited efficacy in solid tumors. Notably, all these inhibitors share the common property that they increase total PIM protein levels, which limits their efficacy because PIM1 has kinase-independent pro-survival effects. Here, we identify high mobility box group 1 (HMGB1) as a novel PIM1 binding partner. Stabilization of PIM1 by smPIM inhibitors increases the cytosolic accumulation of HMGB1, which leads to activation of mitophagy and suppresses oxidative-stress induced cell death. Knockdown of PIM1/2/3 and/or HMGB1 sensitizes cancer cells to smPIM inhibitors. In contrast, treatment with a PIM PROTAC (PIMTAC) that we developed overcomes the kinase-independent pro-survival effects of PIM1 and is more effective than smPIM inhibitors in vitro and in vivo. These results uncover a mechanism of resistance that has limited the success of smPIM inhibitors and provides compelling evidence that targeted degradation of PIM is needed to realize its potential as an anti-cancer target.

Keywords:  HMGB1; Mitophagy; PIM inhibitor; PIM1; PROTAC; Resistance

DOI:  https://doi.org/10.1016/j.canlet.2026.218611
Nat Cancer. 2026 May 25.

Copper depletion boosts CNS leukemia therapy by inhibiting nucleotide synthesis through impairment of mitochondrial complex IV activity.

Alan Y L Wong, Jacob W Myers, Gyan Prakash, Alice Ma, Jeannette R Brook, Boryana Petrova, Baran Bulut, Ralph White, Catherine Merz, Maeve de Souza, Adam G Maynard, Peng Wang, Amy Yu, Nancy K Pohl, Michal Weitman, Lewis B Silverman, Kimberly Stegmaier, L Stirling Churchman, Peter D Cole, Donita C Brady, Naama Kanarek.

The nutrient-sparse cerebrospinal fluid (CSF) poses a major challenge to spreading cancer cells. Despite this challenge, leukemia cells spread to the CSF, requiring aggressive central nervous system (CNS)-directed treatment that can lead to neurotoxicity. Here we used a targeted in vivo CRISPR screen to identify nutritional dependencies of systemic and CNS acute lymphoblastic leukemia (ALL). We show that copper depletion, either by genetic deletion of the transporter SLC31A1 or by dietary intervention, slows the growth of both systemic and CNS leukemia in a xenograft model. Mechanistically, copper depletion inhibits complex IV and nucleotide synthesis to slow the growth of leukemia cells. Furthermore, dietary depletion of copper combined with the standard-of-care therapy methotrexate inhibits leukemia progression in cell-line-derived and patient-derived xenograft models. Our findings identify copper as an actionable micronutrient to disrupt nucleotide synthesis in ALL and proposes copper depletion as a way to boost leukemia therapy in the hard-to-treat CNS.

DOI: https://doi.org/10.1038/s43018-026-01177-4
Clin Cancer Res. 2026 May 26.

Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A phase 1 dose-escalation study of Navitoclax, Venetoclax, and Decitabine.

Evan C Chen, Yiwen Liu, Hayden L Bell, Jeremy Ryan, Jason Wu, Emma-Jayne Minihane, Marlise R Luskin, Eric S Winer, Rahul Vedula, Virginia Volpe, Maximillian Stahl, Daniel Roberts, Ilene Galinsky, Mary Gerard, Matthew Hersch, Jessica Lee, Donna Neuberg, Richard M Stone, Daniel J DeAngelo, Anthony Letai, Andrew A Lane, Jacqueline S Garcia.

BACKGROUND: The BCL-2 inhibitor venetoclax in combination with a hypomethylating agent is effective treatment for most subtypes of acute myeloid leukemia (AML), but it is less effective for other high-risk myeloid neoplasms. One resistance mechanism to BCL-2 inhibition is increased dependence on alternate anti-apoptotic proteins, such as BCL-xL. Navitoclax is a BCL-2/BCL-xL inhibitor that has been previously studied in hematologic malignancies.
PATIENTS AND METHODS: We conducted a Phase 1 study (NCT05455294) of dose-escalated navitoclax added to venetoclax and decitabine for subjects with 1) secondary (s-AML) or therapy-related AML, 2) accelerated- or blast-phase myelofibrosis (AP/BP-MF), 3) myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes with excess blasts, or 4) relapsed/refractory (R/R) MDS with excess blasts.
RESULTS: Sixteen subjects were enrolled. Most common grade ≥3 treatment-emergent adverse events included neutropenia (69%), thrombocytopenia (69%), and febrile neutropenia (44%). No clinically significant bleeding was observed. One dose-limiting toxicity of delayed neutrophil recovery occurred. Among 15 evaluable subjects, the overall objective response rate was 60% (9/15). The recommended phase 2 dose was decitabine 20mg/m2 days 1-5, venetoclax 400mg/day days 1-14, and navitoclax 50mg/day days 1-14 for AP-MF, MDS/MPN, and R/R MDS. Correlative studies indicate preserved immature platelet fractions despite on-target reduction of mature platelets, a reduction in disease-associated monocytes in subjects with monocytic disease, and higher myeloblast dependence on BCL-2 and BCL-xL in responding subjects.
CONCLUSION: Navitoclax added to venetoclax/decitabine is safe and tolerable with preliminary activity in patients with high-risk myeloid malignancies.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-4905
J Cancer. 2026 ;17(5): 990-1001

Hadhb Deficiency Inhibits Lung Tumorigenesis Via Activating ER Stress.

Wuhou Dai, Dong Xu, Yubin Lei, Shujing Zhang, Tonglu Yu, Wufan Tao, Xiaofeng Chen, Xingrong Du.

  Lung cancer remains the leading cause of cancer-related mortality worldwide, yet its molecular pathogenesis is not fully understood. Here, we identify HADHB, encoding a mitochondrial β-ketothiolase as a novel oncogene in lung cancer. Using a HadhbPB/PB mouse model, we demonstrate that Hadhb deficiency in mice significantly suppresses K-Ras G12D-driven lung tumor progression by impairing cancer cell proliferation and enhancing apoptosis. Mechanistically, Hadhb loss induces proteotoxic endoplasmic reticulum (ER) stress, as evidenced by increased ATF6(N) and phosphorylation of eIF2α and subsequent upregulation of the pro-apoptotic factor CHOP. Crucially, knockdown of Chop partially restores oncogenic potential in HadhbPB/PB mice and rescues the growth defect of HADHB-depleted cells, establishing CHOP as a key downstream mediator. Consistent with its oncogenic role, HADHB protein is upregulated in 52% (19/36) of human lung tumors compared to adjacent normal tissues, and low HADHB mRNA levels are correlated with good prognosis in lung cancer patients. Our findings unveil a previously unrecognized HADHB-CHOP regulatory axis in lung cancer progression and provide preclinical rationale for targeting mitochondrial metabolism in combination with ER stress modulators as a therapeutic strategy.

Keywords:  Chop; ER stress; Hadhb; lung cancer

DOI:  https://doi.org/10.7150/jca.130384
Nat Commun. 2026 May 25.

MiTo: tracing the phenotypic evolution of somatic cell lineages via mitochondrial single-cell multi-omics.

Andrea Cossa, Alberto Dalmasso, Guido Campani, Elisa Bugani, Chiara Caprioli, Noemi Bulla, Andrea Tirelli, Yinxiu Zhan, Pier Giuseppe Pelicci.

Mitochondrial single-cell lineage tracing has recently emerged as a scalable and non-invasive tool to trace somatic cell lineages. However, the reliability and resolution of this technology remains highly debated. Here, we present MiTo, a novel end-to-end framework for robust mitochondrial single-cell lineage tracing data analysis. Benchmarked against real-world datasets, MiTo outperforms state-of-the-art methods and baselines in data pre-processing and clonal inference. Applied to a time-resolved dataset of breast cancer evolution (>2,500 cells), MiTo accurately infers ground-truth cell lineages (ARI = 0.94) and cell state transitions, detects clonal fitness markers, and quantifies heritability of gene regulatory networks. Comparing alternative lineage markers, MiTo quantifies the resolution limit of existing mitochondrial single-cell lineage tracing systems, which currently enable reliable inference of coarse-grained cellular ancestries, but not high-resolution phylogenetic inference. In conclusion, this work provides robust tools and practical guidelines to dissect somatic evolution with single-cell multi-omics.

DOI: https://doi.org/10.1038/s41467-026-71607-5
Biomolecules. 2026 Apr 24. pii: 632. [Epub ahead of print]16(5):

Tyrosine 48 Phosphorylation of Cytochrome c Alters Mitochondrial Respiration, ROS Production, and Apoptosis.

Paul T Morse, Susanna Vuljaj, Nabil Yazdi, Matthew P Zurek, Junmei Wan, Icksoo Lee, Asmita Vaishnav, Brian F P Edwards, Tasnim Arroum, Maik Hüttemann.

  Cytochrome c (Cytc) tyrosine 48 (Y48) has been previously shown to be phosphorylated in bovine liver, and phosphomimetic substitution (Y48E) inhibits key functions of Cytc in vitro, including respiration and apoptosis. In this study, we investigated the effect of Y48 modification in a double-knockout cell culture model that stably expressed either unphosphorylated wild-type (WT) Cytc, control Y48F Cytc, or phosphomimetic Y48E Cytc. Our findings revealed that Y48E Cytc caused partial inhibition of mitochondrial respiration in intact cells, which corresponded with lower mitochondrial membrane potentials (ΔΨm) and reduced reactive oxygen species (ROS) production. When subjected to an oxygen-glucose deprivation/reoxygenation (OGD/R) model, which simulates ischemia/reperfusion injury, the Y48E phosphomimetic cell line showed lower ROS production compared to the unphosphorylated WT and Y48F Cytc cell lines, the latter of which generated higher levels of ROS upon reoxygenation. As a result, the Y48E Cytc cell line had significantly lower cell death rates when exposed to OGD/R, confirming the cytoprotective role of Y48 phosphorylation of Cytc. In summary, our research indicates that the loss of Y48 phosphorylation in Cytc during ischemia leads to reperfusion injury by driving maximum electron transport chain flow, hyperpolarization of ΔΨm, bursts of ROS, and death of cells through apoptosis.

Keywords:  ROS; Y48; apopotosis; cytochrome c; electron transport chain; hepatic; liver; mitochondria; phosphorylation; reactive oxygen species

DOI:  https://doi.org/10.3390/biom16050632
Blood. 2026 May 26. pii: blood.2025032136. [Epub ahead of print]

L-Carnitine Regulates Regeneration of Human Hematopoietic Stem and Progenitor Cells.

Honglin Duan, Bohong Wang, Yawei Zheng, Yanling Lv, Ting Lu, Haoyuan Li, Pujiao Li, Ruonan Li, Xiaowei Xie, Zining Yang, Guohuan Sun, Xiangnan Zhao, Meng Yang, Yicheng He, Chang Xu, Shuangshuang Pu, Linmin Zhang, Jun Shi, ErLie Jiang, Tao Cheng, Zeping Hu, Hui Cheng.

Understanding how metabolism governs human hematopoietic stem cells (HSCs) function is essential for advancing regenerative therapies, yet direct metabolic profiling of human HSCs has been limited by their extreme scarcity and the technical limitations of conventional methods. Here, we apply a low-input mass spectrometry-based metabolomics platform, optimized for rare cell populations, to generate metabolic profiles of 13 immunophenotypically defined hematopoietic cell types from adult human bone marrow. Using as few as ~10,000 cells per sample, we detect over 80 metabolites and uncover both conserved metabolic programs in primitive hematopoietic stem and progenitor cells (HSPCs) and lineage-specific metabolic specializations. Notably, we identify L-carnitine-driven fatty acid oxidation (FAO) as a key metabolic feature supporting HSPC function. Mechanistically, L-carnitine activates the PPARA-TFEB signalling axis, promoting mitochondrial metabolism and autophagy to preserve regenerative capacity. Functional assays in primary CD34+ HSPCs derived from healthy donors or patients with aplastic anemia confirm that L-carnitine supplementation improves stem cell function ex vivo and in vivo. Together, this work provides a foundation for human hematopoietic metabolism and reveals a targetable metabolic circuit governing HSPC regenerative fitness with therapeutic potential for improving stem cell-based interventions.

DOI: https://doi.org/10.1182/blood.2025032136
Int Immunol. 2026 May 29. pii: dxag027. [Epub ahead of print]

Mitochondrial Transfer-Driven Immune Evasion in the Tumor Microenvironment.

Li Zhu, Yosuke Togashi.

  The tumor microenvironment (TME) is a complex landscape where metabolic interactions significantly dictate antitumor immunity. Immune evasion in cancer is typically discussed in terms of inhibitory receptors and ligands, suppressive cytokines, defective antigen presentation, and metabolic competition. However, recent evidence reveals that intercellular mitochondrial transfer adds a new mechanism of immune evasion in the TME. The mitochondrial fitness of T cells is central to sustained effector function, memory formation, and responsiveness to immune checkpoint blockade. Tumor cells can act as pathogenic mitochondrial donors, transferring functional or dysfunctional mitochondria to neighboring T cells via tunneling nanotubes and extracellular vesicles. This process involves a mitophagy imbalance that leads to the homoplasmic replacement of endogenous mitochondria, thereby driving T-cell senescence, impairing memory formation and long-term antitumor function, and ultimately weakening cancer immunosurveillance. Overall, mitochondrial transfer should be considered a new part of the tumor immune evasion framework. It also provides new therapeutic opportunities for improving cancer immunotherapy.

Keywords:  Mitochondrial transfer; T-cell exhaustion; immune checkpoint blockade; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1093/intimm/dxag027
Nucleic Acids Res. 2026 May 20. pii: gkag513. [Epub ahead of print]54(10):

Mitochondrial genetic variation across tissues of the human body.

Nathaniel Fisher, Liying Xue, Karan K Smith, Brian Tao, Jason A Cunha, Scott Ladenheim, Jesse D Moreira-Bouchard, Zachary J Milstone, Anna Zhebrun, Xiaoling Zhang, Gyungah R Jun, Thor D Stein, Ting Fang Alvin Ang, Lindsay A Farrer, Melissa G Farb, Robert F Padera, Emelia J Benjamin, Daniel Levy, Deepa M Gopal, R Stefan Isaac, Marc E Lenburg, Seung Hoan Choi, Jessica L Fetterman.

Each mitochondrion contains 2-10 copies of the mitochondrial genome. Multiple mitochondria in a cell allow for mitochondrial genomes carrying different variants to co-exist within a cell or tissue, termed heteroplasmy. The extent to which mitochondrial genetic variation differs across tissues of the human body and the origins of heteroplasmic variants is largely unknown. Using next-generation sequencing of 47 paired tissues from 947 donors in the Genotype-Tissue Expression dataset, we found that 39% of unique mitochondrial DNA variants identified were present in one tissue (tissue-specific) and 7% of unique variants were found in several but not all tissues of a donor. Tissue-specific variants were more likely to be transversions, nonsynonymous, deleterious, and present at lower variant allele fractions compared to variants shared across all tissues within a donor. Tissues primarily composed of proliferative cell types had the most tissue-specific variants, while highly energetic tissues had the least. The number of tissue-specific variants was associated with donor age for the tissues with the most tissue-specific variants. We determined that most of the heteroplasmic variants likely arise de novo after tissue differentiation. Our study suggests that mitochondrial DNA variants arise throughout an individual's lifetime in a tissue-dependent manner, which may have disease implications.

DOI: https://doi.org/10.1093/nar/gkag513
iScience. 2026 Jun 19. 29(6): 115885

Unbiased CRISPR synthetic lethal screening for genetic vulnerabilities in a succinate dehydrogenase-loss model of paraganglioma.

Fatimah J Al Khazal, Michael J Emch, Cristina Correia, Judith Favier, John R Hawse, L James Maher.

  Succinate dehydrogenase (SDH)-deficient paraganglioma and pheochromocytoma (PPGL) are rare neuroendocrine neoplasms for which no effective targeted therapies currently exist. To uncover potential therapeutic targets, we performed an unbiased CRISPR-Cas9 genetic screen in immortalized mouse chromaffin cells (imCCs) with and without Sdhb loss. Our screen identified genes that differentially affect cell proliferation in Sdhb-deficient versus normal imCCs. Subunits of the transcriptional mediator complex emerged as potential tumor suppressors, as their loss selectively promoted growth of Sdhb-deficient cells. The neddylation pathway, required for ubiquitin-mediated selective protein degradation, plays a critical role in Sdhb-deficient imCC growth and survival: loss of the neddylation regulator Ube2m led to increased proliferation, while loss of Ube2f suppressed growth of Sdhb-deficient imCCs. Neddylation inhibitors MLN4924 (Pevonedistat) and HA-9104 reduced UBE2F activity and selectively inhibited growth of Sdhb-deficient imCCs. This unexpected result highlights the neddylation pathway as a promising druggable vulnerability to be studied in SDH-deficient PPGL.

Keywords:  Cancer; Genomics

DOI:  https://doi.org/10.1016/j.isci.2026.115885
Cell Rep. 2026 May 28. pii: S2211-1247(26)00468-7. [Epub ahead of print]45(6): 117390

Chaperone-mediated autophagy is a tumor-suppressive mechanism in hepatocellular carcinoma.

Khushbu Patel, Begoña Zapateria, Alexander J Ledet, Saba S Hazaveh, Floralba Gjergjova, Antonio Diaz, Simone Sidoli, Amaia Lujambio, Ana María Cuervo, Fernando Macian, Esperanza Arias.

  Chaperone-mediated autophagy (CMA) is a selective lysosomal pathway essential for proteostasis and stress adaptation that declines with aging and metabolic disease, conditions closely linked to hepatocellular carcinoma (HCC). Using genetically engineered mouse models with systemic, hepatocyte-specific, or T cell-specific deletion of the CMA regulator LAMP2A in an MYC-driven, TP53-deficient HCC context, we demonstrate that CMA exerts cell-type-dependent tumor-suppressive functions. Hepatocyte-intrinsic CMA loss promotes early malignant transformation, whereas T cell-specific CMA deficiency impairs early immune-mediated tumor control but is also required to sustain tumor growth. Proteomic profiling identifies the cohesin complex component STAG2 as a putative CMA substrate that accumulates in CMA-dysregulated hepatocytes, a finding validated in human HCC tissues, shown to drive cell cycle dysregulation and proliferation, contributing to hepatocarcinogenesis. These results establish CMA as a dual hepatocyte- and immune-dependent mechanism that suppresses liver tumorigenesis and positions STAG2 as a CMA-controlled node with therapeutic relevance in HCC.

Keywords:  CP: cancer; CP: immunology; cancer; cell-type specificity; liver disease; lysosomal degradation; malignant transformation; proteostasis; stromal antigen 2; tumor suppression

DOI:  https://doi.org/10.1016/j.celrep.2026.117390
Cancers (Basel). 2026 May 12. pii: 1571. [Epub ahead of print]18(10):

The SLC25A45-TML Axis as a Biological Foundation for a Multivariable Plasma Metabolite Signature for High-Precision Prostate Cancer Detection.

Liang Zhao, Raghothama Chaerkady, Naseruddin Höti, Eric Zhao, Anirudh Kashyap, Morgan Fair, Qing Wang, Xiaonan Kang.

   BACKGROUND: Prostate cancer remains a significant global health burden, yet current diagnostic reliance on PSA screening is heavily hampered by limited specificity and high rates of overdiagnosis.
METHODS: To address this clinical bottleneck, we utilized a highly sensitive Complete360®-MyMeta targeted-metabolomics platform to perform high-resolution profiling of 43 metabolites across the carnitine, polyamine, and methylation networks in plasma from a discovery cohort of all-stage (I-IV) PCa patients and healthy controls.
RESULTS: Our analysis identified 28 significantly altered metabolites (p < 0.05), revealing profound systemic metabolic reprogramming characterized by the depletion of circulating TML and putrescine, alongside the elevation of L-acetylcarnitine and sarcosine. These systemic shifts are consistent with a localized tumoral "metabolic sink", wherein upregulated mitochondrial TML import via the SLC25A45 transporter actively fuels fatty acid oxidation, while parallel androgen signaling drives massive polyamine synthesis. Translating these mechanistic insights into a clinical tool, we developed a multivariable diagnostic signature utilizing mathematically stable bipartite metabolic ratios. An optimized, cross-validated model combining L-acetylcarnitine/TML and sarcosine/putrescine effectively mitigated physiological noise to achieve robust diagnostic separation, yielding an area under the curve (AUC) of 0.99.
CONCLUSIONS: Ultimately, this study provides a discovery-phase proof-of-concept for the SLC25A45-TML axis as a mechanistically grounded, stage-independent liquid biopsy, offering a rational, non-invasive framework to significantly improve PCa detection.

Keywords:  SLC25A45-TML axis; bipartite metabolic ratios; fatty acid oxidation; metabolomics; polyamine metabolism; prostate cancer diagnosis

DOI:  https://doi.org/10.3390/cancers18101571
Metabolites. 2026 Apr 24. pii: 293. [Epub ahead of print]16(5):

Spatially Resolved Metabolomic Profiling Reveals Progression-Associated Metabolic Reprogramming in Colorectal Liver Metastasis.

Ying Zhu, Yixuan Cai, Qianyu Wang, Hanchuan Guo, Qianqian Xie, Yingshi Xiang, Songlin Yu, Bin Wu, Ling Qiu.

  Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with colorectal liver metastasis (CRLM) being the major determinant of poor prognosis. Tumor metabolic reprogramming and spatial heterogeneity complicate biomarker discovery and clinical management. This study aimed to characterize the spatial metabolomic landscape of CRC and identify progression-associated metabolic alterations and potential metabolic signatures for liver metastasis. Methods: A total of 23 tissue samples were collected from patients with CRC, with and without liver metastasis. Air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) was used to map the spatial metabolite distributions. Region-of-interest analysis guided by histopathology enabled comparative metabolomic profiling across different tissue types. Multivariate statistical analysis, pathway enrichment, and receiver operating characteristic (ROC) curve analyses were performed to identify key metabolic alterations and evaluate potential biomarker performance. Results: Distinct spatial metabolomic profiles were observed across normal mucosa, primary tumors, liver metastases, and normal liver tissues. In primary colorectal tumors, amino acid, purine, and choline metabolism were significantly upregulated, whereas liver metastases were characterized by elevated levels of triglycerides, diglycerides, cholesteryl esters, and acylcarnitines, indicating enhanced lipid synthesis, incomplete fatty acid oxidation, and/or mitochondrial dysfunction. Progression-associated analyses across tissue types revealed consistently increasing trends in glycerides and acylcarnitines, along with heterogeneous alterations in amino acids and phospholipids. Furthermore, 122 differential metabolites were identified between metastatic and non-metastatic CRC, and a four-lipid panel demonstrated strong discriminatory performance. Conclusions: This study provides a spatially resolved characterization of metabolic reprogramming during CRC progression and liver metastasis, highlighting lipid and amino acid metabolism as key features and revealing the metabolic signatures of CRLM.

Keywords:  colorectal cancer; liver metastasis; mass spectrometry imaging; metabolic landscape; spatially resolved metabolomics

DOI:  https://doi.org/10.3390/metabo16050293