bims-mibica 2026-04-05 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–04–05
fourteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Inhibition of mitochondrial RNA polymerase sensitizes cancer cells to radiation by inhibiting mitochondrial respiration.
Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.
Mitochondrial protein translation is a heightened dependence and therapeutic vulnerability of chemo-refractory triple negative breast cancer.
Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.
MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.
Pharmacological blockade of rho kinase enhances venetoclax responses in translational models of acute myeloid leukemia.
Specialized high-capacity mitochondria fuel cell invasion.
Targeting systemic and tumor metabolic balances with ketogenic diets enhance efficacy of therapy in FLT3-ITD acute myeloid leukemia.
Suppression of de novo lipogenesis and dietary PUFA supplementation inhibit prostate cancer progression.
Protein lactylation: a metabolic signal driving cancer therapy resistance.
Bcl-xL blockade targets neutrophils and synergizes with chemotherapy in lung squamous cell carcinoma.
Mitochondrial ATP production promotes T cell differentiation and function by regulating chromatin accessibility.
Melanoma cells release dysfunctional mitochondria to the tumor microenvironment and circulation in association with tumor progression.
Acid Ceramidase Inhibition Disrupts Ceramide Homeostasis and Induces Mitochondrial Apoptosis in IDH1-Mutant Oligodendroglioma.

J Radiat Res. 2026 Apr 01. pii: rrag021. [Epub ahead of print]

Inhibition of mitochondrial RNA polymerase sensitizes cancer cells to radiation by inhibiting mitochondrial respiration.

Sachiko Tsunoda, Yukina Osawa, Noriko Hosoya.

  Radiotherapy is a cornerstone of cancer treatment, but its efficacy is limited by tumor radioresistance and toxicity to normal cells. Thus, radiosensitizing agents that selectively target cancer-specific pathways are needed. Mitochondria contain their own deoxyribonucleic acid (DNA) that encodes proteins essential for oxidative phosphorylation (OXPHOS), the primary energy source for cell growth and survival. Recently, IMT1, a specific inhibitor of mitochondrial transcription targeting mitochondrial RNA polymerase (POLRMT), was developed and shown to suppress tumor growth in several cancers overexpressing POLRMT. However, the effect of combining IMT1 with radiation remains uncharacterized. Here, we show that IMT1 enhances radiosensitivity in cancer cells by inhibiting mitochondrial respiration. We inhibited POLRMT by administrating sublethal dose of IMT1 in OXPHOS-dependent cancer cell lines HeLa, A549, MDA-MB-468, HCT116, A431 and AN3CA, and observed increased radiosensitivity. While radiation alone upregulated mitochondrial respiration, IMT1 abolished this capacity when combined with radiation, showing very low oxygen consumption rates in all respiratory states. IMT1 enhanced radiation-induced apoptosis, but did not affect DNA damage repair and cell cycle regulation. Supplementation with galactose rescued hyper-radiosensitivity induced by IMT1. These findings support the mechanistic link between impaired mitochondrial respiration and radiosensitization induced by POLRMT inhibition. The radiosensitizing effect of IMT1 was not observed in normal cell lines RPE1 and HME1 and the glycolysis-dominant cancer cell line HT1080, suggesting that OXPHOS-dominant cancers would profit most from POLRMT inhibition. Thus, this study presents a novel therapeutic strategy that may improve the efficacy of radiotherapy in OXPHOS-dependent cancer cells while minimizing damage to normal cells.

Keywords:  IMT1; mitochondrial RNA polymerase; mitochondrial respiration; mitochondrial transcription; radiosensitization

DOI:  https://doi.org/10.1093/jrr/rrag021
iScience. 2026 Apr 17. 29(4): 115184

Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.

Edziu Franczak, McLane M Montgomery, Zoe S Terwilliger, Raphael T Aruleba, Polina Krassovskaia, Ilya N Boykov, James T Hagen, Emely A Pacheco, Brett R Chrest, Tonya N Zeczycki, Kayla J Vandiver, P Darrell Neufer, Joseph M McClung, Kelsey H Fisher-Wellman.

  Oxidative phosphorylation (OxPhos) relies on coordinated synthesis of nuclear- and mitochondrial-encoded protein subunits comprising mitochondrial respiratory complexes. Despite a causal link between accumulated mtDNA mutations and age-related diseases, the impact of mtDNA mutation burden on cellular bioenergetics across major organ systems remains only partially resolved. Herein, we leveraged a comprehensive mitochondrial phenotyping platform to assess the phenotypic consequences of heightened mtDNA mutation burden across 8 murine tissues using the polymerase γ (PolG) mutator mouse, incapable of mtDNA proofreading. Despite reductions in OxPhos protein expression, maximal mitochondrial respiratory capacity remained largely intact in PolG Mut mice. Further analysis revealed partial functional deficits in NADH-linked respiration exhibited in brown adipose, colon, kidney, lung, and bone marrow-derived mononuclear cells. In contrast, respiration routed from CII-CIII-CIV was largely preserved across all tissues. Together, these findings suggest that NADH oxidation at respiratory complex I (CI) is the primary functional consequence of heightened mtDNA mutational load.

Keywords:  Biochemistry; Genomics; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2026.115184
bioRxiv. 2026 Mar 26. pii: 2026.03.23.712647. [Epub ahead of print]

Mitochondrial protein translation is a heightened dependence and therapeutic vulnerability of chemo-refractory triple negative breast cancer.

Mariah J Berner, Steven W Wall, Mokryun L Baek, Audra Lane, Allison S Greer, Karen Wang, Lacey E Dobrolecki, Ivy Strope, Qian Zhu, Bing Zhang, Jonathan T Lei, Michael T Lewis, Gloria V Echeverria.

Triple negative breast cancer (TNBC) patients harboring residual cancer burden following completion of conventional neoadjuvant chemo-immunotherapy regimens have poor relapse-free and overall survival rates despite recent advances in immunotherapies and antibody drug conjugates. We and others have demonstrated the requirement of mitochondrial function for survival of chemo-refractory TNBC, as well as its pervasive association with chemoresistance in human and patient-derived xenograft (PDX) cohorts. We sought to gain new mechanistic insights into the mitochondrial vulnerability of TNBC. Analyses of human and PDX mass spectrometry proteomics datasets revealed that mitochondrial protein translation-related signatures were among the top significantly associated with chemoresistance. Those signatures encompassed many core mitoribosome components as well as the mitoribosome accessory protein, Oxidase (Cytochrome C) Assembly 1-Like (OXA1L), which was consistently enriched in chemoresistant versus chemosensitive TNBCs across datasets. OXA1L, while not yet characterized in cancer, has been reported to be crucial for the termination of translation of the 13 mtDNA-encoded electron transport chain (ETC) proteins and for the insertion of those proteins, as well as nDNA-encoded ETC proteins, into the inner mitochondrial membrane. Together, those functions are crucial for the proper formation and function of the ETC. Therefore, we hypothesized that mitochondrial translation supported by OXA1L supports mitochondrial dependence and chemoresistance in TNBC. Knockdown (KD) of OXA1L in human TNBC cells reduced ETC protein levels, mitochondrial 'respirasome' supercomplex levels, ATP production, and oxidative phosphorylation (oxphos). Of note, OXA1L was required for the characteristic oxphos elevation induced by carboplatin (CRB), and KD significantly enhanced CRB sensitivity. To explore the translational potential of targeting the mitoribosome in TNBC, we leveraged the bacterial ancestry of mitochondria to repurpose the FDA-approved antibiotic tigecycline (TIG) as a chemo-sensitizing drug based on its mitoribosome inhibitory function. Direct measurement of mitochondrial nascent peptide levels revealed that, while CRB elevated mitochondrial translation, TIG potently diminished mitochondrial translation as monotherapy and when combined with CRB or docetaxel (DTX). Further, TIG abolished CRB-induced oxphos, decreased oxphos in combination with DTX, and significantly improved sensitivity to chemotherapies in human TNBC cell lines, PDX-derived spheroids, and in an in vivo PDX trial. These findings identify OXA1L-dependent mitochondrial translation and ETC formation as critical determinants of mitochondrial function that support TNBC chemoresistance, justifying further exploration of the clinical potential of repurposed antibiotics for TNBC.
DISCLOSURES: GVE is co-founder, Chief Scientific Officer, and an equity stakeholder of Nemea Therapeutics. G.V.E. formerly received sponsored research funding from Chimerix Inc. G.V.E. receives experimental compounds from the Lead Discovery Center of Germany and from Jazz Pharmaceuticals. MLB is a co-inventor at Nemea Therapeutics. MTL is a founder and limited partner in StemMed Ltd. and a manager in StemMed Holdings, its general partner. He is a founder and equity stakeholder in Tvardi Therapeutics Inc. Some PDX models, including BCM-4272 and BCM-7649, are exclusively licensed to StemMed Ltd., resulting in royalty income to MTL when used for commercial purposes. LED is a compensated employee of StemMed Ltd. Some PDX models, none of which are included in this study, are exclusively licensed to StemMed Ltd., resulting in royalty income to LED. All other authors have nothing to disclose.

DOI: https://doi.org/10.64898/2026.03.23.712647
Autophagy. 2026 Mar 31. 1-3

Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.

Polyxeni Papadea, Nils-Göran Larsson.

  Mammalian mitochondrial DNA (mtDNA) is transmitted asexually without recombination and accumulates mutations at a high rate, which eventually should cause a mutational meltdown. Two processes operating in the maternal germline, the genetic bottleneck and purifying selection, are counteracting this decline but the exact molecular mechanisms and their possible link remain incompletely understood. To address this, we investigated the role of autophagy and mtDNA copy number in shaping purifying selection during maternal mtDNA transmission. Using a carefully designed breeding strategy in mice expressing a proofreading-deficient mitochondrial DNA polymerase, we generated animals carrying random mtDNA mutations and simultaneously introduced moderately decreased or increased mtDNA copy number, or impaired autophagy. Mutation patterns in control animals closely resembled those observed in humans, showing strong purifying selection against non-synonymous mutations, particularly in oxidative phosphorylation (OXPHOS) genes. Our recent work provides new insight by identifying autophagy as a key mediator of germline purifying selection of mtDNA. Moreover, we demonstrate that mtDNA copy number directly influences the efficiency of purifying selection, revealing that these two processes are functionally interconnected.

Keywords:  Bottleneck; maternal transmission; mitochondria; mitophagy; mtDNA mutations

DOI:  https://doi.org/10.1080/15548627.2026.2650772
Nat Struct Mol Biol. 2026 Apr 01.

MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.

Stephen P Burr, Kathryn Auckland, Angelos Glynos, Abhilesh Dhawanjewar, Cameron Ryall, Wei Wei, Antony Hynes-Allen, Malwina Prater, Matylda Sczaniecka-Clift, Julien Prudent, Patrick F Chinnery, Jelle van den Ameele.

Mitochondria contain their own genome, mitochondrial DNA (mtDNA), which is under strict control by the cell nucleus. mtDNA occurs in many copies per cell and mutations often only affect a proportion of them, giving rise to heteroplasmy. mtDNA copy number and heteroplasmy level together shape the tissue-specific impact of mtDNA mutations, eventually giving rise to both rare mitochondrial and common neurodegenerative diseases. Here, we use MitoPerturb-Seq for CRISPR-Cas9-based, high-throughput single-cell interrogation of the nuclear genes and pathways that sense and control mtDNA copy number and heteroplasmy. We screened a panel of mtDNA maintenance genes in mouse cells with a heteroplasmic mtDNA mt-Ta mutation. This revealed both common and perturbation-specific aspects of the integrated stress response to mtDNA depletion caused by Tfam, Opa1 and Polg knockout. These responses are only partially mediated by ATF4 and cause cell-cycle stage-independent slowing of cell proliferation. MitoPerturb-Seq, thus, provides experimental insight into disease-relevant mitochondrial-nuclear interactions and may inform development of therapies targeting cell-type- and tissue-specific vulnerabilities to mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41594-026-01779-7
Haematologica. 2026 Apr 02.

Pharmacological blockade of rho kinase enhances venetoclax responses in translational models of acute myeloid leukemia.

Upendarrao Golla, Riya Bhalodia, Charyguly Annageldiyev, Satyam Patel, Vishnu Sravan Bollu, Su-Fern Tan, Myles C Cabot, David J Feith, Thomas P Loughran, Ross L Levine, Shin Mineishi, Hong Zheng, Kentaro Minagawa, Jeremy Hengst, Giselle L Saulnier Sholler, Dhimant Desai, Sinisa Dovat, Kelsey H Fisher-Wellman, David F Claxton, Arati Sharma.

Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy requiring concomitant targeting of critical cellular survival pathways due to resistance and frequent relapse with monotherapies. Venetoclax (VEN), a BCL-2 inhibitor, is one such promising clinical agent best utilized in combination therapies due to transient responses and acquired resistance. Given the involvement of the Rho/ROCK pathway in VEN activity, we combined Rho-associated coiled-coil-containing protein kinase inhibitors (ROCKi))with VEN to achieve superior antileukemic activity. The ROCKi (Fasudil, DJ4, GSK269962A) synergized with VEN to enhance cytotoxicity in both VEN-sensitive and VEN-resistant cell lines in vitro. Among the three ROCKi, GSK269962A (GSK) was best-tolerated in combination with VEN and effectively inhibited leukemia growth across multiple AML cell line-derived xenograft models in vivo. The GSK+VEN combination exhibited additive to synergistic cytotoxicity in primary AML patient cells ex vivo and enhanced antileukemic activity in a patientderived xenograft model. Additionally, the GSK+VEN combination significantly decreased the clonogenicity of primary AML cells, relatively sparing normal cells. Functional assays demonstrated enhanced apoptosis (Annexin V, caspase-3/7), elevated reactive oxygen species, and mitochondrial depolarization in both VENsensitive and VEN-resistant AML cells following combination treatment. Mechanistically, GSK augmented venetoclax responses by downregulating anti-apoptotic proteins (BCL2, MCL1) and inducing pro-apoptotic mediators (NOXA, MCL1 short isoforms), including in VEN-resistant AML cells. Together, these findings across multiple preclinical AML models demonstrate synergistic antileukemic activity and support combining VEN with ROCKi as a promising therapeutic strategy for AML.

DOI: https://doi.org/10.3324/haematol.2025.289041
Curr Biol. 2026 Apr 01. pii: S0960-9822(26)00310-6. [Epub ahead of print]

Specialized high-capacity mitochondria fuel cell invasion.

Isabel W Kenny-Ganzert, Lena P Basta, Lianzijun Wang, Qiuyi Chi, Laura C Kelley, Caitlin Y Su, Jake Leyhr, Katherine S Morton, Joel N Meyer, David R Sherwood.

  Cell invasion through basement membrane (BM) is energetically intensive. How cells produce high ATP levels to power invasion is understudied. By endogenously tagging 20 mitochondrial proteins, we identified a specialized mitochondrial subpopulation within the C. elegans anchor cell (AC) that localizes to the BM breaching site and generates elevated ATP levels to fuel invasion. These electron transport chain (ETC)-enriched high-capacity mitochondria are compositionally unique, harboring increased protein import machinery and dense cristae enriched with ETC components. High-capacity mitochondria emerge at the time of AC specification and depend on the AC pro-invasive transcriptional program. Finally, we show that netrin signaling through an Src kinase directs microtubule polarization, facilitating metaxin adaptor complex-dependent ETC-enriched mitochondrial trafficking to the AC invasive front. Our studies reveal that an invasive cell produces high ATP levels by generating and localizing high-capacity mitochondria. This might be a common strategy used by other cells to meet the energetically demanding processes.

Keywords:  ATP; basement membrane; cell invasion; cell specification; electron transport chain; live imaging; mitochondria; mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.cub.2026.03.023
Cell Rep. 2026 Mar 28. pii: S2211-1247(26)00263-9. [Epub ahead of print]45(4): 117185

Targeting systemic and tumor metabolic balances with ketogenic diets enhance efficacy of therapy in FLT3-ITD acute myeloid leukemia.

Léa Goupille, Alexandre Boudet, Laura Lauture, Ambrine Sahal, Guillaume Gautier-Renard, Emeline Chu-Van, Anvi Laetitia Nguyen, Céline Chollet, Coralie Alcazar, Isabelle Bernard, François Vergez, Véronique de Mas, Christian Récher, Tony Kaoma, Paolo Gallipoli, Vilma Dembitz, Irene Basili, Flavia Bernardi, Olivier Ayrault, Carine Joffre, Florence Castelli, Benoit Colsch, Nathalie Bourgès-Abella, Fanny Granat, Jean-Emmanuel Sarry.

  FMS-like tyrosine kinase 3 (FLT3) mutations in acute myeloid leukemia (AML) are associated with adverse prognosis. FLT3 inhibitors (FLT3i) improve therapeutic response; however, diverse resistance mechanisms, such as adaptations in lipid metabolism, have been identified. We hypothesized that a lipid-rich ketogenic diet (KD) might alter both host and tumoral lipid metabolism, enhancing responses to FLT3i. In FLT3-mutated AML mouse models, 3 weeks of lard- or plant-based KD improved the efficacy of FLT3i by 2-fold reduction of engraftment and tumor burden. KD increased ketone bodies and lipid accumulation in plasma, liver, and AML cells and also induced a polyunsaturated fatty acid:monounsaturated fatty acid (PUFA:MUFA) imbalance. KD impacted pentoses, hexoses, and amino acid metabolism, enhancing sugar phosphates and vitamins in the host. Mechanistically, KD rewired anabolism toward fatty acid oxidation and glycine-utilizing pathways, modulated the expression of FLT3 signaling pathways and lipid biosynthesis, and promoted tumor cell differentiation. In conclusion, this study shows that KD reduces FLT3i resistance, offering a promising therapeutic solution.

Keywords:  CP: cancer; CP: metabolism; FLT3-ITD mutations; acute myeloid leukemia; ketogenic diet; metabolism; therapy resistance

DOI:  https://doi.org/10.1016/j.celrep.2026.117185
bioRxiv. 2026 Mar 27. pii: 2026.03.25.714193. [Epub ahead of print]

Suppression of de novo lipogenesis and dietary PUFA supplementation inhibit prostate cancer progression.

Silvia D Rodrigues, Caroline Fidalgo Ribeiro, Giuseppe N Fanelli, Isadora Ferreira Teixeira, Hubert Pakula, Pier Vitale Nuzzo, Filippo Pederzoli, Fabio Socciarelli, Sara Bleve, Jeanne Jiang, Jonas Dehairs, Guilherme Henrique Tamarindo, Giorgia Zadra, Lisa M Butler, Stephen R Plymate, David W Goodrich, Johannes V Swinnen, David M Nanus, Massimo Loda.

Prostate cancer progression is characterized by dysregulated lipid metabolism, with fatty acid synthase (FASN), the rate-limiting step in de novo lipogenesis (DNL), resulting in significant accumulation of saturated lipids. Here, we investigate whether pharmacologic FASN inhibition creates a metabolic state that increases reliance on exogenous polyunsaturated fatty acids (PUFAs). Inhibition of FASN profoundly alters membrane phospholipid composition, driving compensatory incorporation of PUFAs into membrane phospholipids, thus increasing susceptibility to lipid peroxidation and oxidative damage. Combined FASN inhibition and PUFA exposure increased reactive oxygen species, induced mitochondrial hyperpolarization, and enhanced lipid peroxidation in both hormone-sensitive and castration-resistant prostate cancer models. Marked inhibition of human and murine prostate cancer organoids is achieved ex vivo . In genetically engineered, DNL-reliant Hi-Myc mice, a diet enriched in PUFAs significantly inhibited invasive carcinoma compared to a saturated fat-enriched diet. Environmental PUFAs modulate and enhance the therapeutic efficacy of FASN-targeted strategies. These findings set the stage for pharmacologic and dietary intervention in prostate cancer patients.

DOI: https://doi.org/10.64898/2026.03.25.714193
Cell Death Discov. 2026 Mar 31.

Protein lactylation: a metabolic signal driving cancer therapy resistance.

Silvia D'amico, Sara Giovannini, Gerry Melino, Angelo Peschiaroli, Francesca Bernassola.

Unlike normal cells, which primarily rely on oxidative phosphorylation, cancer cells reprogram their metabolism by preferentially utilizing glycolysis even in the presence of oxygen to generate ATP. As a result, cancer cells and the tumor microenvironment typically accumulate high levels of lactate. Although initially considered a mere byproduct of glucose metabolism, lactate has recently emerged as an important metabolic intermediate involved in many intracellular pathways and protein modifications. Lysine lactylation is indeed a newly identified, metabolism-linked post-translational modification in which lactate is covalently bound to specific lysine residues. This review provides an overview of the current understanding of how lysine lactylation mechanistically contributes to therapeutic resistance in tumor cells. Remarkably, protein lactylation is emerging as a promising druggable approach for overcoming therapy resistance. Hence, here, we also highlight new strategies that target lactylation with pharmacological inhibitors to counteract drug resistance in cancer.

DOI: https://doi.org/10.1038/s41420-026-03050-w
EMBO Mol Med. 2026 Mar 31.

Bcl-xL blockade targets neutrophils and synergizes with chemotherapy in lung squamous cell carcinoma.

Abdullah Mayet, Beatrice Parma, Déborah Lécuyer, Amaury Defruit, Sarika Rana, Anita Bodac, Pieter Demetter, Sébastien Denanglaire, Abbie S Ireland, Mariana Brandão, Thierry Berghmans, Fabienne Andris, Stanislas Goriely, Jean Yannis Perentes, Trudy G Oliver, Etienne Meylan.

  Tumor-associated neutrophils (TANs) represent a large fraction of immune cells in tumors, but how their regulation and function vary in distinct cancer subtypes remains unknown. In KrasLSL-G12D/WT; p53fl/fl mouse models of lung adenocarcinoma (LUAD), TANs have an increased lifespan compared to normal neutrophils. Specifically, TANs upregulate the anti-apoptotic protein Bcl-xL, whose blockade by a BH3 mimetic selectively kills ageing TANs and diminishes tumor growth. Here, we have addressed this issue in lung squamous cell carcinoma (LUSC) using the Rosa26LSL-Sox2-IRES-GFP; Nkx2-1fl/fl; Lkb1fl/fl mouse model, where we demonstrate increased TAN survival with a rise in Bcl-xL similarly to LUAD. However, unlike in LUAD, inhibiting Bcl-xL alone was insufficient to alter tumor progression in LUSC. After carboplatin and paclitaxel treatment, a combination chemotherapy used in human LUSC, we detected increased neutrophils in circulation, spleen and tumors, and increased Bcl-xL in neutrophils and TANs. Bcl-xL blockade decreased the pool of Bcl-xL-high TANs and synergized with chemotherapy. Altogether, our results suggest distinct outcomes for targeting TANs in different tumor types and reinforce the concept of repurposing BH3 mimetics against cancer.

Keywords:  Bcl-xL; Lung Squamous Cell Carcinoma; Mouse Models of Lung Cancer; Tumor-associated Neutrophils

DOI:  https://doi.org/10.1038/s44321-026-00401-z
bioRxiv. 2026 Mar 28. pii: 2026.03.27.714789. [Epub ahead of print]

Mitochondrial ATP production promotes T cell differentiation and function by regulating chromatin accessibility.

Charles Ng, Tak Shun Fung, Dayi Li, Korbinian N Kropp, Luis F Somarribas Patterson, Alexandria Markovitz, Daniel N Weinberg, Olivia Jones, Ji-Young Kim, Guoan Zhang, Richard Koche, Mara Monetti, Huayuan Tang, Yun He, Zhengshuang Xu, Xin Cai, Ziqi Yu, Geetha Bhagavatula, Sean P Colgan, Ya-Hui Lin, Zhuoning Li, Elizabeth M Steinert, Christopher A Klebanoff, Santosha A Vardhana, Navdeep S Chandel, Lin Wu, Craig B Thompson.

Immune elimination of chronic infection or cancer requires cytotoxic CD8 + T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process and T cells subjected to chronic antigen exposure have compromised effector function despite high rates of glycolysis. Here we report the ability of the short-chain α-hydroxy acid, D-α-hydroxybutyrate, to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation, even in glucose-replete media. This conversion suppresses both AMPK phosphorylation and the integrated stress response (ISR) in activated T cells while significantly elevating the level of the phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induction of CD8-effector gene transcription was coupled to bioenergetics by enhanced ATP-dependent remodeling of chromatin accessibility at effector gene loci. DAHB enhanced CD8 + T cell antitumor activity both in vitro and in vivo, and DAHB treatment of transferred T cells led to persistent in vivo antitumor effects. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.

DOI: https://doi.org/10.64898/2026.03.27.714789
Cancer Lett. 2026 Mar 26. pii: S0304-3835(26)00220-X. [Epub ahead of print]647 218457

Melanoma cells release dysfunctional mitochondria to the tumor microenvironment and circulation in association with tumor progression.

Nicolás Georges-Calderón, Camila Fuentes, Yessia Hidalgo, Felipe Grunenwald, José Corrales-Bermúdez, Aliosha I Figueroa-Valdés, Mirliana Ramírez-Pereira, Gloria Arriagada, Fernando J Bustos, Constanza Ahumada-Marchant, Mercedes López, Francisca Alcayaga-Miranda.

  Recent evidence establishes that melanoma cells actively uptake mitochondria from stromal cells; however, the mitochondrial release in a physiological context remains unstudied. Here, we show that melanoma cells release dysfunctional mitochondria into the extracellular space through a predominantly non-vesicular route. Using melanocyte Melan-a and melanoma B16-F1 and B16-F10 cell lines, we observed increased extracellular mitochondrial release in malignant cells. Electron microscopy revealed these mitochondria lacked cristae and were primarily free organelles. Membrane potential analysis confirmed their dysfunctional state. Mitophagy analysis using mtKeima showed that, under oxidative stress, melanoma cells failed to activate canonical mitophagy and instead upregulated mitochondrial release as an alternative MQC mechanism. Western blot analysis revealed a fission-biased mitochondrial network in melanoma cells, with elevated phospho-DRP1/DRP1 ratio, and a tendency to reduce MFN1 and OPA1. Together with PINK1/ATG7 downregulation and BNIP3/NIX upregulation, suggest a secretory mitophagy phenotype. Tumor-derived mitochondria were detected in both the tumor microenvironment and plasma of melanoma-bearing mice, with extracellular mitochondria levels correlating with tumor burden. Plasma from melanoma patients exhibited elevated levels of TOMM20+ mitochondria compared to healthy donors. Transcriptomic analysis of The Cancer Genome Atlas melanoma cohort revealed that high expression of MQC-related genes DRP1 and BNIP3L was associated with worse prognosis. Collectively, our findings uncover a tumor-intrinsic, non-canonical MQC pathway that releases dysfunctional mitochondria. This mechanism establishes a new paradigm of tumor-host systemic communication, wherein circulating tumor-derived mitochondria might actively influence disease progression. These findings open avenues for developing non-invasive biomarkers and therapeutic strategies targeting mitochondrial release.

Keywords:  Biomarkers; Extracellular mitochondria; Melanoma; Mitochondrial quality control; Secretory mitophagy

DOI:  https://doi.org/10.1016/j.canlet.2026.218457
Res Sq. 2026 Mar 25. pii: rs.3.rs-9077389. [Epub ahead of print]

Acid Ceramidase Inhibition Disrupts Ceramide Homeostasis and Induces Mitochondrial Apoptosis in IDH1-Mutant Oligodendroglioma.

Mioara Larion, Helena Muley, Faris Zaibaq, Meili Zhang, Dionne Davis, Michael Kruhlak, Samarth Mathur, Adrian Lita, Hua Song, Wei Zhang, Zalman Wong, Taylor Harmon, Lumin Zhang, Chen Cam-El Makranz, Aiguo Li, George Karadimov, Fengchao Lang, Christel Herold-Mende, Chunzhang Yang, Tyrone Dowdy.

Oligodendroglioma is genetically defined by mutations in isocitrate dehydrogenase 1 or 2 (IDH1/IDH2) and 1p/19q codeletion. We previously showed that in IDH1-mutant oligodendroglioma, the oncometabolite D-2-hydroxyglutarate biases the sphingosine-1-phosphate-to-ceramide rheostat toward ceramides. Taking advantage of this intrinsic metabolic vulnerability, we investigated whether further elevating ceramide levels through inhibition of acid ceramidase could exacerbate this imbalance and promote apoptotic cell death. Analysis of patient datasets demonstrated that acid ceramidase is expressed at higher levels in both low- and high-grade gliomas compared with normal tissue. Pharmacologic inhibition of acid ceramidase with SABRAC preferentially reduced viability in human IDH1-mutant oligodendroglioma cell lines. In these sensitive models, acid ceramidase inhibition markedly increased ceramide levels and induced coordinated sphingolipid remodeling. Subcellular imaging using a fluorescent ceramide analogue demonstrated increased ceramide localization to lysosomes and mitochondria following acid ceramidase inhibition. This was accompanied by cytochrome c redistribution, executioner caspase activation, and caspase-dependent apoptotic cell death, consistent with engagement of intrinsic mitochondrial apoptosis. Transcriptomic and biochemical analyses further revealed activation of endoplasmic reticulum stress and unfolded protein response signaling, including PERK- and IRE1α-associated programs, suggesting coordinated multi-organelle stress responses under sustained ceramide elevation. These mechanistic effects translated into a survival benefit in oligodendroglioma xenograft-bearing mice. Together, these findings suggest that IDH1-mutant oligodendroglioma harbors a pre-existing heightened sensitivity to ceramide stress and identify acid ceramidase as a therapeutically actionable target in this disease.

DOI: https://doi.org/10.21203/rs.3.rs-9077389/v1