bims-mibica 2026-03-29 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–03–29
twenty papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Cancer mtDNA mutations: metabolic plasticity and therapeutic promise?
Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.
Functional cooperation between the B-cell receptor and NOTCH1 in regulating metabolic reprogramming in chronic lymphocytic leukemia.
Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity.
Synergistic Anti-Tumor Activity of LRPPRC Inhibition and Dasatinib Through Dual Oxidative Phosphorylation Disruption.
UFMylation of Pyruvate Dehydrogenase Regulates Mitochondrial Metabolism.
Bortezomib Restores Venetoclax Sensitivity in Acute Myeloid Leukemia Cell Lines with Intrinsic and Acquired Resistance.
Mitochondrial NADP(H) integrates redox and metabolism.
A Mitochondrial Plasma Proteomic Signature Identifies Metastatic Chromophobe Renal Cell Carcinoma.
Autophagy and Lipid Metabolism as a Therapeutic Target for Overcoming Drug Resistance in Acute Myeloid Leukemia.
Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.
The E3-ome gene-centric compendium reveals the human E3 ligase landscape.
Targeting glioblastoma mitochondrial metabolism with S-Gboxin induces cytotoxicity under conditions of the tumor microenvironment.
Malic enzyme 2 suppresses PINK1-Parkin-mediated mitophagy by stabilizing ATAD3A via competitive interaction with TRIM25.
Melanoma resists chemotherapy through an adaptive mitochondrial response.
Palmitate-induced mitochondrial damage restricts histone acetylation in CD8 T cells to impair antitumor immunity.
The pyruvate branch point controls lymphoid cancer cell dissemination.
mtDNA-Depleted Mitochondria Form Sites of Contact with the Nucleus and Alter the Cellular Epigenome.
Dynamic switching of apoptosis-modulating BIM heterodimers in response to BH3 mimetics in xenograft models of hematologic malignancies.
Aberrant oxidative metabolism selects for TET2 -deficient hematopoietic stem and progenitor cells.

Trends Mol Med. 2026 Mar 24. pii: S1471-4914(26)00033-X. [Epub ahead of print]

Cancer mtDNA mutations: metabolic plasticity and therapeutic promise?

Ersong Shang, Omar Aftab, Abbienaya Dayanamby, Laura C Greaves.

  Mitochondria, once viewed mainly as cellular powerhouses, are now recognised as key regulators of cancer metabolism, redox balance, and immune interactions. While early models emphasised a switch to aerobic glycolysis, many tumours exhibit metabolic plasticity and retain oxidative phosphorylation capacity. Mitochondrial DNA (mtDNA) mutations are common across cancers, yet their roles in carcinogenesis and therapy response remain unclear. Emerging base-editing technologies now enable modelling of these mutations, allowing the exploration of their impact on tumourigenesis, which may differ depending on mutation type, heteroplasmy, and tissue origin. mtDNA alterations also shape immune responses within the tumour microenvironment and therefore may influence treatment sensitivity. This review integrates recent advances on mtDNA's role in cancer biology and explores therapeutic opportunities for targeting mitochondrial metabolism.

Keywords:  DNA, mitochondrial; genes, neoplasm; neoplasms; oxidative phosphorylation; tumour microenvironment

DOI:  https://doi.org/10.1016/j.molmed.2026.02.003
Blood. 2026 Mar 24. pii: blood.2025031552. [Epub ahead of print]

Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.

Silvia Sighinolfi, Laura Cassina, Maria Rosa Lidonnici, Stefano Beretta, Davide Stefanoni, Mariangela Storto, Christina Mayerhofer, Trine A Kristiansen, David T Scadden, Ivan Merelli, Alessandra Boletta, Annamaria Aprile, Giuliana Ferrari.

Iron is an essential element for most cellular processes and recent evidence highlighted its role in regulating the function of hematopoietic stem cells (HSCs). Abnormal iron levels impact HSC quiescence and self-renewal, however, the mechanism by which iron overload (IO) influences HSC function is still unknown. Here, we show that intracellular IO impairs mitochondrial fitness and bioenergetics, inducing metabolic rewiring. In thalassemic mice, as a model of chronic IO, HSCs accumulate mitochondria with elevated reactive oxygen species (mtROS), low membrane potential and reduced oxidative phosphorylation (OXPHOS). Mitochondrial defects are confirmed in other two models of IO, sickle cell disease and iron-loaded wild-type mice, and in vivo iron reduction rescues HSC mitochondria. IO HSCs are highly proliferating and in presence of damaged mitochondria rely on glycolysis for energy production. Notably, restoration of mitochondrial function by targeting in vivo mtROS improved the quiescence and self-renewal of IO HSCs. Our results unravel the critical interplay between iron, ROS and mitochondrial activity in HSCs, revealing that IO shapes HSC metabolic programs.

DOI: https://doi.org/10.1182/blood.2025031552
Leukemia. 2026 Mar 23.

Functional cooperation between the B-cell receptor and NOTCH1 in regulating metabolic reprogramming in chronic lymphocytic leukemia.

Amelia Fascì, Francesco Edoardo Vallone, Nahal Nabelsi, Elodie Viry, Ilenia Sana, Alessia Morabito, Silvia Seghezzi, Noemi Anna Pesce, Matteo Rovere, Nadia Bertola, Chloé Duculty, Silvia Ravera, Samir Mouhssine, Marta Muzio, Paolo Ghia, Candida Vitale, Marta Coscia, Etienne Moussay, Gianluca Gaidano, John Allan, Richard R Furman, Jerome Paggetti, Tiziana Vaisitti, Silvia Deaglio.

Mutations in NOTCH1, which occur in ~10% of Chronic Lymphocytic Leukemia (CLL) patients at diagnosis, are typically associated with unmutated (UM) B-cell receptor (BCR) subsets and define patients with earlier treatment need. Using primary CLL cells classified as NOTCH1 wild-type (CLL/NWT) or mutated (CLL/NM), both with UM-BCR, we show that BCR stimulation activates the NOTCH1 pathway, upregulating metabolic programs and mitochondrial biogenesis, selectively in CLL/NM. These cells display enhanced basal respiration and glycolysis, driven by higher mitochondrial mass, and further increase metabolic activity upon BCR triggering. To directly implicate NOTCH1 mutations, we engineered an MEC-1 model to generate wild-type (MEC-1/NWT) or mutated (MEC-1/NM) clones in a UM-BCR background. Here, NOTCH1 hyperactivation promoted mitochondrial metabolism through TFAM-dependent transcriptional control. Gene expression profiling, metabolic assays, and stable isotope tracing confirmed that MEC-1/NM cells rely on oxidative metabolism, with increased glutamine dependency and strengthened anabolic pathways, leading to augmented proliferation compared to MEC-1/NWT. Importantly, CLL/NM cells exhibit a marked vulnerability to glutamine deprivation. Combined inhibition of glutamine utilization and BCL2 triggered rapid apoptosis, providing a rationale for tailored therapeutic strategies in NOTCH1-mutated CLL. Representation of the molecular mechanism behind the metabolic reprogramming. BCR and NOTCH1 drive a dual metabolic reprogramming of glucose and glutamine pathways. In NOTCH1-mutated cells, both glucose and glutamine uptake are positively increased and even more upon BCR stimulation. Glucose is preferentially used to fuel the pentose phosphate pathway, and glutamine the TCA cycle. Concurrently, NICD accumulation, driven by BCR signaling, promotes TFAM expression and mitochondrial biogenesis. The resulting increase in mitochondrial mass underpins enhanced ATP production, oxygen consumption, and ROS generation, establishing a glutamine-dependent mitochondrial phenotype. This dependency sensitizes NOTCH1-mutated cells to glutamine blockade, which selectively induces apoptosis, further enhanced by combination with BCL-2 inhibition.

DOI: https://doi.org/10.1038/s41375-026-02912-7
EMBO J. 2026 Mar 24.

Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity.

Mitsuhiro Nishigori, Serina Hirata, Hidetaka Kosako, Takeshi Ichinohe, Hendrik Nolte, Jan Riemer, Thomas Langer, Takumi Koshiba.

  Mitochondrial proteases regulate dynamic properties of organelle morphology and ensure functional plasticity at the cellular level. The metalloprotease OMA1 mediates constitutive and stress-inducible processing of its mitochondrial substrates, although only a few of its direct functional targets have been characterized. Using in vitro and in vivo multiproteomic and biochemical approaches, we here demonstrate that the membrane-anchored intermembrane space (IMS) protein AIFM1 serves as a mitochondrial stress-responsive OMA1 substrate. Under stress conditions, OMA1 cleaves AIFM1 in the IMS with slower kinetics than its conventional substrate, the dynamin-like GTPase OPA1. OMA1-mediated dislocation of cleaved AIFM1 from the mitochondrial inner membrane reduces its interaction with oxidative phosphorylation subunits, thereby decreasing respiratory activity and impairing cell growth. Furthermore, we reveal that under steady-state conditions AIFM1 broadly safeguards the mitochondrial proteome by mediating the import of proteins, particularly respiratory complex I subunits, via the TIM23 complex. Similar changes to the mitochondrial proteome occur in the lungs of virally infected mice, accompanied by stress-inducible AIFM1 processing. These findings identify OMA1 as a key integrator of mitochondrial stress and cellular energetics through AIFM1 remodeling.

Keywords:  AIFM1; Mitochondrial Stress; OMA1; OXPHOS Activity; Proteolysis

DOI:  https://doi.org/10.1038/s44318-026-00734-y
Pharmaceuticals (Basel). 2026 Mar 12. pii: 472. [Epub ahead of print]19(3):

Synergistic Anti-Tumor Activity of LRPPRC Inhibition and Dasatinib Through Dual Oxidative Phosphorylation Disruption.

Jing Chen, Lu Gao, Yuxin Liang, Wei Zhou, Yong Wang, Xiaojia Wang, Xiaohong Fang, Xiying Shao.

  Background/Objectives: Mitochondrial Oxidative Phosphorylation (OXPHOS) is a critical metabolic dependency in many cancers. Targeting OXPHOS through Leucine-Rich PPR Motif-Containing Protein (LRPPRC) degrader-mediated OXPHOS Complex Biogenesis Inhibition (OCBI) has demonstrated promising anti-tumor activity. However, rational combination strategies to enhance therapeutic efficacy remain undefined. This study aims to identify FDA-approved drugs that synergize with LRPPRC inhibition and elucidate the underlying mechanism. Methods: We conducted a high-throughput screen of 1376 FDA-approved compounds using LRPPRC isogenic cancer cell models to identify agents that synergize with LRPPRC degrader-based OCBI therapy. The synergistic effects of the candidate compound were validated in multiple cancer cell lines with either genetic ablation or pharmacological inhibition of LRPPRC. Mechanistic studies were performed to investigate the impact on OXPHOS gene expression from both nuclear and mitochondrial genomes. Results: The clinically approved multi-kinase inhibitor Dasatinib was identified as a robust synergistic candidate, exhibiting heightened sensitivity in cancer cells with either LRPPRC knockout or pharmacological inhibition. Mechanistically, Dasatinib selectively suppressed nuclear-encoded OXPHOS genes, whereas LRPPRC inhibition preferentially impaired mitochondrial DNA-encoded OXPHOS genes, resulting in a coordinated dual-genome blockade of OXPHOS. Conclusions: This study uncovers a previously unrecognized synergistic anti-tumor effect between LRPPRC inhibition and Dasatinib, mediated by complementary suppression of nuclear- and mitochondrial genome-encoded OXPHOS pathways. These findings provide a strong mechanistic and translational rationale for combination therapies targeting LRPPRC-high tumors.

Keywords:  Dasatinib; LRPPRC; combination therapy; high-throughput screening; synergistic inhibition

DOI:  https://doi.org/10.3390/ph19030472
bioRxiv. 2026 Mar 18. pii: 2026.03.18.712693. [Epub ahead of print]

UFMylation of Pyruvate Dehydrogenase Regulates Mitochondrial Metabolism.

Phong T Nguyen, Zheng Wu, Dohun Kim, Tamaratare Ogu, Siyu Yin, Varun Sondhi, Feng Cai, Trevor S Tippetts, Annie Jen, Evgenia Shishkova, Ling Cai, Dennis Dumesnil, Margaret Cervantes, Hongli Chen, Prashant Mishra, Joshua J Coon, Gerta Hoxhaj, Min Ni, Ralph J DeBerardinis.

The ubiquitin-fold modifier 1 (UFM1) post-translational modification (PTM), or UFMylation, regulates protein homeostasis and is essential for human development. Yet the roles of the de-UFMylase, UFM1-specific peptidase 2 (UFSP2), which removes UFM1 from UFMylated proteins, remain poorly characterized. Here, we demonstrate that UFMylation and UFSP2 regulate mitochondrial metabolism. Quantitative proteomics in UFSP2-deficient cells revealed the accumulation of many proteins previously unknown to be impacted by UFMylation. These included components of the mitochondrial ribosome, electron transport chain (ETC), and pyruvate dehydrogenase (PDH) complex. Functional analyses demonstrated that excessive UFMylation in UFSP2-deficient cells increases mitochondrial respiration, glucose oxidation in the tricarboxylic acid (TCA) cycle, and PDH enzymatic activity. We identified dihydrolipoamide S-acetyltransferase (DLAT), the E2 component of PDH, as a direct UFMylation substrate, with lysine 118 (K118) as the primary conjugation site. Mutating K118 to arginine (K118R) abolished DLAT UFMylation and reduced pyruvate oxidation, identifying this modification as an activator of PDH. These findings reveal a UFMylation-based regulatory mechanism that controls mitochondrial function by inducing utilization of pyruvate as a TCA cycle fuel.

DOI: https://doi.org/10.64898/2026.03.18.712693
Mol Cancer Ther. 2026 Mar 26.

Bortezomib Restores Venetoclax Sensitivity in Acute Myeloid Leukemia Cell Lines with Intrinsic and Acquired Resistance.

Chengxi Li, Yu-Hsuan Chang, Minori Maki, Ikuko Omori, Naru Sato, Susumu Goyama, Toshio Kitamura, Yutaka Enomoto.

Venetoclax, a selective BCL-2 inhibitor, effectively induces apoptosis in a wide range of malignancies. Venetoclax-based regimens, combined venetoclax with either hypomethylating agents or low-dose cytarabine, have markedly improved treatment outcomes in elderly patients with acute myeloid leukemia (AML). However, approximately one-third of patients exhibit intrinsic resistance to these regimens, and the majority of initial responders eventually develop acquired resistance. Therefore, intrinsic and acquired resistance to venetoclax-based regimens remains a major barrier to achieving durable clinical responses in AML patients. In this study, we aimed to identify effective treatment strategies to overcome venetoclax resistance. Among drugs tested in this study, we found that bortezomib, a proteasome inhibitor, showed potent synergy with venetoclax in inducing apoptosis in a wide range of AML cell lines, irrespective of RAS or TP53 mutation status. Mechanistically, bortezomib upregulates pro-apoptotic proteins such as NOXA, BIM, and PUMA, which neutralize MCL1 and promote apoptosis. Notably, NOXA upregulation plays a critical role in the efficacy of the combination of venetoclax and bortezomib. Moreover, bortezomib resensitized AML cell lines with acquired resistance to venetoclax, further supporting its role in overcoming therapeutic resistance. Importantly, the combination of bortezomib and venetoclax significantly prolongs the survival of mice inoculated with venetoclax-resistant AML cell line harboring BAX mutations, which are commonly observed in relapsed AML following venetoclax-based regimens and confer resistance to venetoclax by inhibiting BAX-dependent apoptotic pathway. Collectively, this study provides a rationale for venetoclax-bortezomib combination as a potential strategy to overcome venetoclax resistance in certain AML subsets.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0986
Trends Endocrinol Metab. 2026 Mar 25. pii: S1043-2760(25)00267-X. [Epub ahead of print]

Mitochondrial NADP(H) integrates redox and metabolism.

Ren Zhang, Kezhong Zhang.

  The compartmentalization of NAD(H) and NADP(H) is fundamental to cellular metabolism, enabling precise coordination of redox balance, biosynthetic reactions, and energy homeostasis. Within mitochondria, NADP(H) has long been viewed as a redox buffer supporting antioxidant defense and reductive biosynthesis. Emerging evidence, however, reveals that mitochondrial NADP(H) also drives oxidative metabolism and metabolic flexibility. Loss of the mitochondrial NAD kinase, which phosphorylates NAD(H) to generate mitochondrial NADP(H), disrupts NADP(H)-dependent pathways that sustain oxidative metabolism and systemic energy balance. These advances reposition mitochondrial NADP(H) as an integrative regulator that links redox homeostasis with energy metabolism across cellular and systemic levels, with broad implications for metabolic disease.

Keywords:  NAD(H); NADK2; NADP(H); fatty acid oxidation; mitochondria; redox

DOI:  https://doi.org/10.1016/j.tem.2025.12.003
Cancers (Basel). 2026 Mar 23. pii: 1032. [Epub ahead of print]18(6):

A Mitochondrial Plasma Proteomic Signature Identifies Metastatic Chromophobe Renal Cell Carcinoma.

Clara Steiner, Tiegang Han, Steven Safi, Wafaa Bzeih, Hadi Mansour, Eddy Saad, Jessica F Williams, Michelle S Hirsch, Vinay K Giri, Liliana Ascione, Yehonatan Elon, Adam P Dicker, Yan Tang, Toni K Choueiri, Elizabeth P Henske, Wenxin Xu.

   BACKGROUND: Chromophobe renal cell carcinoma (ChRCC) is characterized by the accumulation of abnormal mitochondria, a high rate of mitochondrial DNA (mtDNA) mutations, and altered oxidative metabolism. There are no existing circulating biomarkers to distinguish metastatic ChRCC from clear cell renal cell carcinoma (ccRCC).
METHODS: High-throughput plasma proteomic profiling using the SomaScan platform was performed in 18 ChRCC (including 16 metastatic ChRCC) and 197 metastatic ccRCC patients. Data were harmonized to generate a unified 7K-protein matrix.
RESULTS: Differential expression analysis was performed using limma (version 3.62.2). Of 7272 quantified human plasma proteins, 209 were differentially expressed between ChRCC and ccRCC. Upregulated proteins in ChRCC included essential β-oxidation enzymes such as ECH1 (enoyl-CoA hydratase 1) and ECI1 (enoyl-CoA delta-isomerase 1), suggesting increased long-chain fatty acid degradation. Creatine and energy-buffering pathways were also represented, with increased CKMT1A (Creatine Kinase, Mitochondrial 1A) in ChRCC. KIM-1 (Kidney Injury Molecule-1) and leptin were lower in ChRCC, consistent with the known upregulation of these proteins in ccRCC. Pathway enrichment analyses revealed an overrepresentation of mitochondrial protein degradation, fatty acid β-oxidation, and respiratory electron transport in ChRCC, suggesting that ChRCC sheds a unique mitochondrial signature into the peripheral circulation. A bootstrap-based LASSO logistic regression restricted to upregulated mitochondrial proteins in ChRCC vs. ccRCC consistently selected ECI1 and CKMT1A. The LASSO model achieved an AUROC of 0.964.
CONCLUSIONS: Compared to ccRCC, the plasma proteome of metastatic ChRCC is dominated by mitochondrial metabolic enzymes, revealing a systemic metabolic phenotype strikingly aligned with the known histologic accumulation of abnormal mitochondria in ChRCC cells.

Keywords:  LASSO; SomaScan; chromophobe renal cell carcinoma; metabolic reprogramming; mitochondria; proteomics

DOI:  https://doi.org/10.3390/cancers18061032
Life (Basel). 2026 Mar 06. pii: 428. [Epub ahead of print]16(3):

Autophagy and Lipid Metabolism as a Therapeutic Target for Overcoming Drug Resistance in Acute Myeloid Leukemia.

Seyed Mohammadreza Bolandi, Mahdi Pakjoo, Briandy Fernandez-Marrero, Amir Reza Boskabadi, Erfan Mohammadi Sephavand, Jamshid Sorouri Khorashad, Saeid Ghavami, Anna M Eiring.

  Acute myeloid leukemia (AML) remains a therapeutically challenging malignancy due to high relapse rates driven by leukemic stem cells (LSCs) and adaptive resistance mechanisms. Emerging evidence positions autophagy as a central regulator of AML pathobiology, exerting context-dependent effects that suppress leukemogenesis during disease initiation yet sustain LSC survival and chemoresistance in established AML. Mechanistically, autophagy integrates mitochondrial quality control, lipid droplet turnover, and metabolic rewiring to support oxidative phosphorylation, particularly under hypoxic bone marrow conditions. Lipophagy-driven fatty acid oxidation has emerged as a key metabolic vulnerability distinguishing LSCs from normal hematopoietic stem cells. Furthermore, non-coding RNAs critically modulate autophagy networks, reinforcing therapy resistance. Preclinical and clinical studies demonstrate that both inhibition and activation of autophagy may yield therapeutic benefit depending on genetic context, mutational landscape, and disease stage. We propose that integrating multi-omics approaches, particularly lipidomics, with artificial intelligence and machine learning will enable precise identification of autophagy-dependent AML subsets. Rational, biomarker-guided modulation of autophagy may overcome resistance while preserving normal hematopoiesis, offering a path toward personalized metabolic targeting in AML.

Keywords:  acute myeloid leukemia (AML); autophagy; cancer drug resistance; leukemia stem cells (LSCs); lipid metabolism; non-coding RNAs

DOI:  https://doi.org/10.3390/life16030428
Autophagy. 2026 Mar 22. 1-2

Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.

Julia A Thayer, Derek P Narendra.

  Mutations in PINK1 and PRKN/parkin are the leading recessive causes of Parkinson disease (PD). Together PINK1 and PRKN form a mitophagy pathway for clearing damaged mitochondria from the cell. It was unclear, however, whether diverse forms of mitochondrial damage activate the PINK1-PRKN pathway through a unified mechanism. Recently, we demonstrated that loss of mitochondrial membrane potential (MMP) leads to the stabilization and activation of PINK1 under a wide range of mitochondrial stressors, including mitochondrial protein misfolding. Mechanistically, we suggest that the MMP is required at a key step of PINK1 import into mitochondria, in which PINK1 is transferred between the translocases of the outer and inner mitochondrial membranes. Consistent with this model, retention of active PINK1 of the outer membrane requires the translocase of the outer mitochondrial membrane (TOMM) complex, whereas import of PINK1 from the outer to inner membrane requires the TIMM23 (translocase of inner mitochondrial membrane 23) complex. Notably, chronic disruption of the TIMM23 complex is sufficient to stabilize active PINK1 in the TOMM complex, phenocopying MMP loss. Together, our findings suggest PINK1 primarily senses catastrophic drops in a mitochondrion's MMP: a dead-end for the mitochondrion's continued biogenesis.

Keywords:  Autophagy; PARK2; PARK6; mitochondria unfolded protein response; mitochondrial quality control

DOI:  https://doi.org/10.1080/15548627.2026.2646238
Cell. 2026 Mar 20. pii: S0092-8674(26)00116-9. [Epub ahead of print]

The E3-ome gene-centric compendium reveals the human E3 ligase landscape.

Ngee Kiat Chua, Tania J González-Robles, Cameron J Reddington, Jane Dudley-Fraser, Richard W Birkinshaw, Jiru Han, Ashleigh Solano, Soon Wei Wong, Tomasz Kochańczyk, Joshua J Peter, Mark A Nakasone, Florian Aust, Jacob Munro, Yeh Huei Tong, Julie Iskander, Waruni Abeysekera, Alex Garnham, Hannah Huckstep, Matthew E Ritchie, Ingrid Wertz, Sarah Hymowitz, Sharad Kumar, Ron C Conaway, Gilbert G Privé, Alex N Bullock, Jeffrey J Babon, Rachel E Klevit, Sonja Lorenz, Alessio Ciulli, Eric S Fischer, Nicolas H Thomä, Radosław P Nowak, Brenda A Schulman, Michael Rapé, Katrin Rittinger, Julia K Pagan, Melanie Bahlo, Joel P Mackay, Peter D Mace, Christopher D Lima, Ronald T Hay, David Komander, Bernhard C Lechtenberg, Claudio A P Joazeiro, Michele Pagano, Kay Hofmann, Rebecca Feltham.

To define and systematically characterize the human E3 ubiquitin ligase (E3) landscape, we generated the E3-ome, a compendium of E3s encoded by the human genome. The E3-ome integrates experimental data, bioinformatics, and published research, revealing 672 high-confidence E3s. We standardized E3 classifications to create a unified framework for annotation and comparative analysis. The E3-ome identified several previously unrecognized domains, motifs, E3 candidates, and relationships, expanding the diversity of E3s. Furthermore, the E3-ome mapped the spatial and physiological organization of E3s across human tissues and cell types, revealing context-dependent E3s. Genetic analyses identified disease-associated variants across the E3-ome, linking E3s to diverse human pathologies. Together, these analyses define the human E3 landscape at high resolution and deliver a foundational resource to drive mechanistic and therapeutic discovery.

DOI: https://doi.org/10.1016/j.cell.2026.01.029
Cell Death Discov. 2026 Mar 27.

Targeting glioblastoma mitochondrial metabolism with S-Gboxin induces cytotoxicity under conditions of the tumor microenvironment.

Jan-Béla Weinem, Hans Urban, Benedikt Sauer, Tanja Buhlmann, Ann-Christin Hau, Stefan Liebner, Tillmann Rusch, Dmitry Namgaladze, Leander F Harwart, Jan-Hendrik Schröder, Maeve de Souza, Joachim P Steinbach, Stefan Legewie, Anna-Luisa Luger, Michael W Ronellenfitsch.

Glioblastoma (GB) is the most common primary malignant brain tumor in adults. Gboxin, a novel compound that targets oxidative phosphorylation via complex V inhibition, has shown promise in preclinical models of GB. We examined the efficacy of the pharmacokinetically optimized S-Gboxin under conditions replicating the GB microenvironment, including nutrient deprivation and hypoxia. We assessed cytotoxicity and growth-inhibitory effects of S-Gboxin in human GB cell lines, primary GB cultures, as well as immortalized and primary human astrocytes under different nutrient and oxygen deprivation scenarios. Oxygen consumption, cell migration, activation of the integrated stress response (ISR) as well as the relevance of the AMP-activated protein kinase (AMPK) were evaluated as variables under S-Gboxin treatment. S-Gboxin demonstrated cytotoxicity at low micromolar concentrations, with cell death enhanced under nutrient deprivation and hypoxia. S-Gboxin reduced cellular oxygen consumption and uncoupled mitochondria. Cytotoxicity was increased when mitochondrial fuels were the primary energy source. Additionally, S-Gboxin treatment resulted in elevated lactate production and glucose consumption. While the ISR marker ATF4 was induced by S-Gboxin in a dose-dependent manner, ISR inhibition with ISRIB did not affect its cytotoxicity. Conversely, S-Gboxin treatment combined with AMPK inhibition resulted in enhanced tumor cell death. Collectively, these findings demonstrate that S-Gboxin selectively targets cancer-specific metabolic vulnerabilities in GB cells. The synergistic action with AMPK inhibition suggests that this pathway contributes to maintain energy homeostasis in the presence of the drug. Therefore, S-Gboxin is a promising compound for GB therapy, especially in a combinatory approach with AMPK inhibition or other metabolic targeted therapies.

DOI: https://doi.org/10.1038/s41420-026-03072-4
Cell Death Dis. 2026 Mar 24.

Malic enzyme 2 suppresses PINK1-Parkin-mediated mitophagy by stabilizing ATAD3A via competitive interaction with TRIM25.

Qian Liu, Lei Su, Xiaoyun Wei, Shijie Lin, Lingkai Huang, Lige Hou, Yanhong Wang, Liubing Hu, Junyang Tan, Jing Qiao, Qinghua Zhou, Yi Ma, Wenjun Wang, Jianshuang Li.

Malic enzyme 2 (ME2), a pivotal enzyme related to the tricarboxylic acid (TCA) cycle, has been implicated in multiple cancers due to its overexpression and metabolic role in regulating the NADP+/NADPH balance. Malic enzyme 2 has been reported to regulate mitochondrial biogenesis and fusion; however, whether malic enzyme 2 participates in mitophagy regulation has remained unclear. Here, we reported that malic enzyme 2 depletion enhances PINK1-Parkin-mediated mitophagy. Mechanistically, ME2 competes with the E3 ubiquitin ligase TRIM25, disrupting its binding with ATPase family AAA domain-containing protein 3 A (ATAD3A), a mitochondrial protein crucial for the degradation of PINK1. Loss of malic enzyme 2 strengthens the TRIM25-ATAD3A interaction, resulting in ATAD3A ubiquitination and proteasomal degradation. The consequent PINK1 accumulation drives mitophagy activation. Hyperactivated mitophagy caused by malic enzyme 2 knockdown disrupts mitochondrial homeostasis, which suppresses the proliferative capacity of hepatoma cells. Moreover, pharmacological inhibition of mitophagy partially rescued the suppressed cell proliferation in the malic enzyme 2-knockdown cells. Our findings reveal a previously unrecognized role of malic enzyme 2 in mitochondrial quality control and highlight the ME2-ATAD3A-PINK1 axis as a potential regulatory node for mitophagy modulation.

DOI: https://doi.org/10.1038/s41419-026-08623-2
J Exp Clin Cancer Res. 2026 Mar 26.

Melanoma resists chemotherapy through an adaptive mitochondrial response.

Mehrdad Zarei, Semmer A Ali, Alexander W Loftus, Faith Nakazzi, Hallie J Graor, Om Prajapati, Sami O Abul-Khoudoud, John M Asara, Rui Wang, Jordan M Winter, Luke D Rothermel.



Keywords:  Chemosensitivity; Combination therapy; Complex I; ETC; Melanoma; Metabolic reprogramming; Mitochondria; OXPHOS; TCA cycle

DOI:  https://doi.org/10.1186/s13046-026-03685-8
Sci Immunol. 2026 Mar 27. 11(117): eaeb1459

Palmitate-induced mitochondrial damage restricts histone acetylation in CD8 T cells to impair antitumor immunity.

Silvia Tiberti, Sara Gennari, Martina Romeo, Ilir Sheraj, Mohamed Faisal Kassir, Juan Fernández-García, Carina B Nava Lauson, Roberta Noberini, Carlotta Catozzi, Tiziano Dallavilla, Mattia Ballerini, Alessia Loffreda, Simona G Codreanu, Stacy D Sherrod, Katrina L Leaptrot, Alexandra C Schrimpe-Rutledge, John A McLean, Martin H Schaefer, Simona Rodighiero, Tiziana Bonaldi, Sarah-Maria Fendt, Besim Ogretmen, Sara Sdelci, Luigi Nezi, Teresa Manzo.

Lipid accumulation in the tumor microenvironment is a hallmark of solid tumors, with increased palmitate (PA) availability fostering tumor progression. Although PA's direct effects on cancer cells are well described, its impact on CD8 T cells [cytotoxic T lymphocytes (CTLs)] remains unclear. Here, we show that PA irreversibly impairs CTL mitochondrial metabolism, leading to the loss of effector functions and compromised antitumor immunity. PA-induced mitochondrial dysfunction reduced histone acetylation and chromatin accessibility, suppressing transcription of genes involved in T cell replication and effector programs. We identified sphingosine kinase 2 (SPHK2) as a key mediator of PA-induced dysfunction, with pharmacological inhibition of SPHK2 restoring mitochondrial fitness, rescuing CTL effector function, and promoting antitumor activity. These findings uncover a distinct mechanism by which PA drives immune evasion in tumors and highlight SPHK2 as a potential therapeutic target to enhance T cell-based immunotherapies.

DOI: https://doi.org/10.1126/sciimmunol.aeb1459
bioRxiv. 2026 Mar 18. pii: 2026.03.16.712182. [Epub ahead of print]

The pyruvate branch point controls lymphoid cancer cell dissemination.

Hamidullah Khan, Steven John, Sushmita Roy, Mohd Farhan, Nguyet Minh Hoang, Patrick Buethe, Aman Prasad, Aman Nihal, David T Yang, Lixin Rui, Jing Fan, Stefan M Schieke.

Cancer cell dissemination critically determines clinical prognosis, yet metabolic dependencies and corresponding therapeutic targets during spread of lymphoid malignancies remain poorly understood. Here we show that the pyruvate branch point operates as a metabolic checkpoint for lymphoid cancer cell migration and disease dissemination through mitochondrial ROS (mROS)/HIF-1a signaling. Isolation of highly migratory mROS hi cells led us to identify selective metabolic requirements of malignant lymphocyte migration and disease dissemination. Highly migratory cells show a reprogrammed metabolic profile characterized by increased glucose uptake and reduced glucose-carbon entry into the TCA cycle. Reprogramming of the TCA cycle with downregulation of citrate synthase provide the mechanistic basis for decreased pyruvate oxidation leading to increased migration and disease dissemination through mROS/HIF-1a signaling. Our findings connect central carbon metabolism and migratory capacity of lymphoid cancer cells and identify the pyruvate branch point as a metabolic switch and potential therapeutic target in lymphoid cancer cell dissemination.

DOI: https://doi.org/10.64898/2026.03.16.712182
Contact (Thousand Oaks). 2026 Jan-Dec;9:9 25152564261428840

mtDNA-Depleted Mitochondria Form Sites of Contact with the Nucleus and Alter the Cellular Epigenome.

Richard Boulton-McDonald, Eva Sidlauskaite, Jiri Neuzil, Michelangelo Campanella.

  Mitochondrial sites of contact with the nucleus, hereafter referred to as Nucleus-Associated Mitochondria (NAM), are specialised domains that enable communication, influencing cellular function. Previous studies have shown that these contacts can be stabilised by protein scaffolds acting as tethers to promote retrograde signalling, particularly during apoptotic stress. This is facilitated via the mitochondrial protein TSPO. In this study, we have investigated a mitochondrial DNA (mtDNA)-depleted (ρ0) 4T1 cell model to further inform the role of NAM in retrograde communication between corrupted mitochondria and the nucleus. Our data report an increase in NAM frequency in mtDNA-depleted cells compared to the mtDNA-retaining parental 4T1 line. Using a combination of cellular assays, transmission electron microscopy, and epigenetic profiling, we have found that under conditions of mtDNA loss, mitochondria become enriched in TSPO, evading mitophagic clearance and are prone to forming stable contacts with the nucleus. This coincides with an extreme reduction in DNA methylation, as well as histone modifications associated with chromatin decondensation.

Keywords:  NAM; TSPO; VDAC; contact sites; mitochondria

DOI:  https://doi.org/10.1177/25152564261428840
Mol Cancer Ther. 2026 Mar 17.

Dynamic switching of apoptosis-modulating BIM heterodimers in response to BH3 mimetics in xenograft models of hematologic malignancies.

Jeevan Prasaad Govindharajulu, Sharon Fluss, Melinda G Hollingshead, William Gillette, Dominic Esposito, Dianne L Newton, Luke H Stockwin, Li Chen, Shahanawaz Jiwani, Kelly Dougherty, Omozusi Andrews, Barry C Johnson, Yvonne A Evrard, Ralph E Parchment, James H Doroshow, Apurva K Srivastava.

This study tested the hypothesis that tumor cells can evade apoptosis following BH3 mimetic treatment by utilizing alternative Bim binding partners. Levels of Bim heterodimers with Mcl-1, Bcl-2 and Bcl-xL were measured in multiple hematologic cell line xenograft models (AMO-1, MV4-11, and RPMI-8226) following single-dose S63845 or venetoclax; Bak-Bax heterodimer and cleaved caspase-3 (cCasp3) levels were measured to demonstrate mitochondrial apoptosis. Anti-tumor efficacies of these agents were measured in vivo in mice bearing AMO-1 or MV4-11 xenografts and in vitro in patient-derived lymphoblastoid-like cells. Mechanism of combination activity of the CDC-like kinase (CLK) inhibitor cirtuvivint with venetoclax was determined in MV4-11 and KG-1a xenografts. S63845 decreased Mcl-1-Bim levels in AMO-1 and MV4-11 tumors by ~90% while unexpectedly decreasing Bcl-2-Bim and increasing Bcl-xL-Bim levels. Venetoclax decreased Bcl-2-Bim levels while increasing Mcl-1-Bim and Bcl-xL-Bim levels in MV4-11 tumors. The S63845+venetoclax combination decreased Mcl-1-Bim levels and demonstrated greater cell killing activity and pharmacodynamic effects than either single agent in multiple models including patient-derived lymphoblastoid-like cells. Cirtuvivint decreased Mcl-1 and Bim levels, combining with venetoclax to induce significantly greater Bak-Bax and cCasp3 responses than either single agent and induced regression of MV4-11 xenograft tumors. Our results elucidate quantitative pharmacodynamics of S63845, venetoclax, and cirtuvivint, an agent that is currently being evaluated with venetoclax to treat AML (NCT06484062). Compensatory increases in off-target Bim heterodimer levels in response to either S63845 or venetoclax offer a possible mechanism of clinical drug resistance.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0855
bioRxiv. 2026 Mar 02. pii: 2026.02.28.707294. [Epub ahead of print]

Aberrant oxidative metabolism selects for TET2 -deficient hematopoietic stem and progenitor cells.

Katia E Niño, Vera Adema, Alyx E Gray, Courtney M Cowan, Wolfgang E Schleicher, Mohsen Hosseini, Sierra N Bennett, Sweta B Patel, Steven Moreira, Etienne Danis, Feiyang Ma, Hsin-Ying Lin, Tracy N Young, Colin A Anderson, Devyani Sharma, Angelica Varesi, Marie-Dominique Filippi, Keisuke Ito, Meelad M Dawlaty, Gang Huang, Julie A Reisz, Stephanie Z Xie, Steven M Chan, Lin Tan, Guillermo Garcia-Manero, Kelly Chien, Irene Gañan Gomez, Angelo D'Alessandro, Simona Colla, Eric M Pietras.

The mechanism(s) driving selective expansion of mutant hematopoietic stem and progenitor cells (HSPC) in clonal hematopoiesis (CH) are incompletely understood. Here, we address the role of metabolism in selection for HSPC with loss of function mutations in TET2 . Loss of Tet2 in murine HSPC triggers overexpression of glycolysis and oxidative phosphorylation genes and increased oxidative metabolism via an enlarged mitochondrial network. However, Tet2 -deficient HSPC maintain a normal redox state. Strikingly, compound loss of the rate-limiting pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) triggers increased reactive oxygen species and impairs the fitness of Tet2 -deficient HSPC. We find that aberrant oxidative metabolism is also a feature of HSPC in human CH and clonal cytopenia of unknown significance (CCUS). Overall, our data point to aberrant metabolism as a critical and conserved driver of selection in TET2 -deficient CH and identify the PPP as a crucial compensatory pathway needed to maintain their selective advantage.
Statement of Significance: This study identifies oxidative metabolism as a critical driver of selection for TET2 -deficient HSPC in clonal hematopoiesis (CH). It also demonstrates that cellular redox state is a vulnerability that impairs their fitness. These insights establish targetable metabolic pathway(s) that could be exploited in the setting of TET2 mutant CH.

DOI: https://doi.org/10.64898/2026.02.28.707294