bims-mibica 2026-07-26 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–07–26
ten papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Cancer-Associated BCL-2 Mutants Reveal Mechanisms Towards Venetoclax Resistance.
Ex vivo pretreatment with venetoclax boosts the antileukemic efficacy of therapeutic γδ T cells in AML models.
SLC25A51 and mitochondrial NAD⁺ transport in acute myeloid leukemia: mechanisms, therapeutic potential, and translational perspectives.
Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival.
Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.
Deciphering LonP1's Role in Glioblastoma: An Alternative Mechanism of Treatment Resistance.
G3BP2 confers venetoclax resistance by stabilizing ELF1-mediated MCL1 transcription in acute myeloid leukemia.
Direct coupling of human TOM and TIM22 complexes drives mitochondrial carrier import.
Newly diagnosed acute myeloid leukemia in Fit patients: 2026 treatment algorithms.
DHODH is a synthetic lethal target in PIK3CA-mutant colorectal cancer.

Adv Sci (Weinh). 2026 Jul 24. e76693

Cancer-Associated BCL-2 Mutants Reveal Mechanisms Towards Venetoclax Resistance.

Jonas Aufdermauer, Ian de de Ridder, Mahjoobeh Ehsani, Marasim Khan, Justin Kale, Lukas P Frenzel, David Andrews, Spyridoula Karamanou, Ana J Garcia-Saez, Geert Bultynck.

  BCL-2 is an anti-apoptotic protein frequently upregulated in cancer, enabling cell survival despite oncogenic stress. This BCL-2 dependence sensitizes tumor cells to venetoclax, an FDA-approved drug used against chronic lymphocytic leukemia. Yet, treatment-induced mutations in BCL-2 frequently result in resistance. While mutations G101V and D103Y were reported to disrupt BCL-2 interaction with venetoclax, it remains unclear how other mutations cause resistance. Here, we performed a comprehensive comparison of frequently occurring cancer-associated BCL-2 mutations inside and outside the venetoclax binding site. We find that, besides disrupting venetoclax interaction, G101V and D103Y also increased the sequestration and inhibition of pro-apoptotic proteins, revealing a double effect of these mutations. We also define V156D, A113G, R129L, and R139H as previously uncharacterized BCL-2 mutations conferring venetoclax resistance. Remarkably, V156D reduces venetoclax binding allosterically, without altering pro-apoptotic protein inhibition. Other BCL-2 mutants, like A113G, R129L, and R139H, do not exhibit alterations in venetoclax binding, but venetoclax cannot efficiently release their pro-apoptotic partners from inhibitory complexes in cells. Finally, sonrotoclax binds with high affinity to all venetoclax-resistant BCL-2 mutants, yet its efficacy against these BCL-2 mutants in cells was heterogeneous. Our findings uncover diverse mechanisms that reduce venetoclax efficacy with the potential to inform anticancer treatment.

Keywords:  B‐cell lymphoma‐2; apoptosis; cancer; resistance mutations; venetoclax

DOI:  https://doi.org/10.1002/advs.76693
J Clin Invest. 2026 Jul 23. pii: e202932. [Epub ahead of print]

Ex vivo pretreatment with venetoclax boosts the antileukemic efficacy of therapeutic γδ T cells in AML models.

Xingchi Chen, Lin Zhang, Bingbing Yan, Yinqiang Sui, Weiwei Ma, Hui Zhao, Yining Wang, Kepeng Yang, Jiewen Ma, Baolin Tang, Yonghui Zhang, Xiaoyu Zhu.

  Ex vivo engineering strategies for adoptive αβ T-cell therapies increasingly use pharmacological modulation to improve survival, expansion, and antitumor activity. Short-term exposure to the BCL-2 inhibitor venetoclax during αβ T-cell manufacturing enhances apoptotic priming and effector persistence, suggesting a route to strengthen other T-cell lineages. γδ T cells share cytotoxic properties with αβ T cells but recognize targets independently of major histocompatibility complex (MHC) and show low alloreactivity, supporting off-the-shelf use in acute myeloid leukemia (AML). Whether such conditioning benefits γδ T cells was unknown. Here, we show that ex vivo venetoclax pretreatment enhances the antileukemic efficacy of therapeutic γδ T cells and chimeric antigen receptor (CAR) γδ T cells. Venetoclax-pretreated γδ T cells displayed increased cytotoxicity and proliferation with reduced exhaustion, yielding superior control of AML blasts and xenografts. These functional gains coincided with elevated mitochondrial content and a fatty acid oxidation metabolic profile. In vivo, venetoclax-pretreated γδ T cells achieved durable disease suppression, and the same conditioning improved CAR γδ T-cell efficacy. Together, these results show that short-term BCL-2 inhibition enhances γδ T-cell cytotoxicity and persistence. Incorporating venetoclax pretreatment into γδ T-cell manufacturing may improve therapeutic efficacy and inform next-generation γδ T-cell therapies for AML.

Keywords:  Cancer immunotherapy; Hematology; Immunology; Immunotherapy; Leukemias

DOI:  https://doi.org/10.1172/JCI202932
Hum Cell. 2026 Jul 19. pii: 111. [Epub ahead of print]39(8):

SLC25A51 and mitochondrial NAD⁺ transport in acute myeloid leukemia: mechanisms, therapeutic potential, and translational perspectives.

Chunmeng Rong, Ruixiu Chen, Hanqi Lou, Yongming Xia, Shiwei Duan.

  Acute myeloid leukemia (AML) remains a highly lethal hematologic malignancy characterized by metabolic reprogramming, therapeutic resistance, and poor survival, particularly in older patients. Nicotinamide adenine dinucleotide (NAD⁺) metabolism has emerged as a central driver of AML progression, and recent studies have identified solute carrier family 25 member 51 (SLC25A51) as the primary mitochondrial NAD⁺ transporter in mammalian cells. SLC25A51 regulates mitochondrial redox balance, oxidative phosphorylation, and tricarboxylic acid (TCA) cycle activity, thereby sustaining leukemic proliferation and survival. Structural studies have elucidated its six-transmembrane helix architecture, salt-bridge-mediated transport mechanism, and stabilization by cardiolipin binding. Functional investigations demonstrate that SLC25A51 overexpression correlates with poor prognosis, while its depletion disrupts mitochondrial metabolism, induces apoptosis, and suppresses AML progression in vivo. Therapeutically, pharmacologic inhibition of SLC25A51 with fludarabine, or its combination with hypomethylating agents, such as 5-azacytidine, enhances antileukemic efficacy by perturbing metabolic and epigenetic regulation. Moreover, SLC25A51 expression may serve as a predictive biomarker for mitochondrial-targeted therapies, such as complex I inhibitors. Future translational research should focus on developing selective inhibitors, optimizing combination strategies with demethylating agents and BCL-2 inhibitors, and validating its prognostic significance in clinical cohorts. Collectively, SLC25A51 represents a promising metabolic target with potential to overcome therapeutic resistance and improve patient outcomes in AML. Furthermore, this review discusses its potential implications across distinct genetic subtypes of AML (e.g., mutations in TP53, NPM1, and RAS), thereby highlighting key directions for future translational research.

Keywords:  Acute myeloid leukemia (AML); Metabolic reprogramming; Mitochondrial NAD⁺ transport; SLC25A51; Targeted therapy

DOI:  https://doi.org/10.1007/s13577-026-01428-7
JCI Insight. 2026 Jul 22. pii: e199182. [Epub ahead of print]11(14):

Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival.

David Alsina, Diana Rubalcava-Gracia, Kristina Bubb, Rodolfo Garcia-Villegas, Akos Vegvari, Roberta Filograna, Florian A Rosenberger, Camilla Koolmeister, Nils-Göran Larsson.

  Mitochondrial gene expression is essential for oxidative phosphorylation that generates the bulk of the cellular ATP, and mitochondrial dysfunction is a common cause of human metabolic diseases. Recently, the first pathogenic variants in the only known mitochondrial RNA polymerase (POLRMT) were described in patients presenting with a wide variety of clinical manifestations, including hypotonia, short stature, and developmental delay. Here, we modeled two human pathogenic POLRMT variants by creating the corresponding substitutions in mice: the dominant S582F and the recessive R984C variant. Mice homozygous for the R984C variant showed perinatal lethality without apparent embryonic developmental defects, a finding consistent with a failure to adapt to the metabolic transition to oxidative metabolism at birth. Mice carrying the S582F variant were viable and exhibited decreased mitochondrial transcript levels due to impaired de novo transcription. However, mtDNA levels and in organello mtDNA replication remained normal, which recapitulates the molecular phenotypes observed in patients. Altogether, our findings indicate that the conserved arginine near the active site is essential for POLRMT function, while the serine in the intercalating hairpin of the N-terminal domain is required for near-genome length transcription but not primase activity. This study highlights genotype-phenotype differences and provides new insights into POLRMT function.

Keywords:  Cell biology; Metabolism; Mitochondria; Mouse models

DOI:  https://doi.org/10.1172/jci.insight.199182
Nat Metab. 2026 Jul 23.

Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.

Deborah Y Moss, Connor N Brown, Andrew M Shaw, Christopher McCann, Nikita Lewis, Matilda Downs, Rebecca Wurelly, Ciara Cunningham, Aaron Philips, Niamh Doherty, Sarah Gallagher, William J McDaid, Andrew Roe, Aisling Y Coughlan, Brenton Cavanagh, Callum Ormsby, Fiammetta Falcone, Rachel McCole, Scott Monteith, Emily Rogan, Sudhir B Malla, Alexandra J Emerson, Letitia Mohammed-Smith, Shaun Sharkey, Aoife Leonard, Peter F Gallagher, Arindam Banerjee, Sandra Van Schaeybroeck, Sufyan Pandor, Brian Quinn, Brett Greer, Christopher Elliott, Sarah Maguire, Aideen E Ryan, Philip D Dunne, Mary Mallon, Stephanie Craig, Omar Aftab, Laura C Greaves, Bryan P Marzullo, Daniel A Tennant, Vicky Coyle, Ian G Mills, Owen Sansom, Tríona Ní Chonghaile, Daniel B Longley, Simon S McDade, Melissa J LaBonte, Emma M Kerr.

Therapy resistance is attributed to over 80% of cancer deaths per year, emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. As an antimetabolite, 5FU imposes substantial metabolic stress, forcing cells that survive treatment to rapidly adapt. We explored acute 5FU-driven changes in mitochondria, the organelle critical for coordinating metabolic stress responses. Here we demonstrate in a range of CRC models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Furthermore, we show that targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.

DOI: https://doi.org/10.1038/s42255-026-01578-w
Am J Physiol Cell Physiol. 2026 Jul 21.

Deciphering LonP1's Role in Glioblastoma: An Alternative Mechanism of Treatment Resistance.

Shashi Jain, Dahlia A Ordaz, Javier Lepe, Naomi Lomeli, James Pham, Bhaskar Das, Daniela A Bota.

  Temozolomide (TMZ) remains the standard-of-care chemotherapy for glioblastoma, yet resistance severely limits its clinical efficacy. To identify alternative pathways, we developed TMZ resistant (TR) and MGMT inhibitor O6 benzylguanine (O6-BG)-resistant (OTR) glioblastoma models that differ in MGMT status, but both show elevated expression compared with parental cells, implicating LonP1 in the resistant phenotype. Functional analyses showed that LonP1 drives metabolic reprogramming toward oxidative phosphorylation (OXPHOS) and supports survival under therapeutic stress. To establish LonP1's causal role, we genetically overexpressed LonP1 in glioma lines, which conferred robust TMZ resistance, whereas LonP1 downregulation via inducible shRNA or pharmacologic inhibition restored TMZ sensitivity, reduced cell viability, and compromised mitochondrial integrity and OXPHOS capacity. Remarkably, our findings confirm LonP1 as a strong contributor to de novo TMZ resistance in treatment-naïve tumor cells and to maintain/enhance resistance in established resistant models. However, the initial rescue experiment partially supports the specificity of the LonP1-dependent phenotype. Together, our data identify LonP1 as a potential therapeutic target to overcome TMZ resistance and provide a rationale for developing LonP1 directed interventions as adjuncts to standard TMZ therapy with the potential to improve glioblastoma. Additional in vivo orthotopic or PDX-based models will be required to define the full translational relevance of LonP1 in glioblastoma outcomes and delay or reverse chemoresistance.

Keywords:  Chemotherapy; Glioblastoma; LonP1; Oxidative Phosphorylation (OXPHOS); Oxidative Stress; Temozolomide Resistance; genetic LonP1 overexpression and knockdown models

DOI:  https://doi.org/10.1152/ajpcell.00145.2026
Leukemia. 2026 Jul 20.

G3BP2 confers venetoclax resistance by stabilizing ELF1-mediated MCL1 transcription in acute myeloid leukemia.

Zhixiang Chen, Yuanhua Cai, Yaping Wang, Xiaolin Lai, Xiongbin Yan, Xuechun Wang, Fuquan Tu, Wanting Wu, Huiyin Gao, Yi Zheng, Yingying Zeng, Yang Li, Jinggang Li, Lili Pan, Peiyao Wang, Wei Ji, Lin Xu, Shaoyuan Wang.

Venetoclax is a promising treatment for acute myeloid leukemia (AML) patients, but resistance occurs following the upregulation of MCL1. The RNA-binding protein G3BP2 is upregulated in various solid tumors, and targeting G3BP2 has been shown to restore chemosensitivity. However, the role of G3BP2 in AML development and venetoclax resistance remains unknown. Herein, an integrated analysis revealed that G3BP2 confers venetoclax resistance and correlates with poor outcomes in AML. G3BP2 deficiency inhibits AML proliferation and induces apoptosis in AML cells and xenograft mice. G3BP2 expression aligns with MCL1 levels across AML cohorts, and the regulatory effect of G3BP2 on MCL1 was validated in AML cells. Notably, G3BP2 and MCL1 do not interact directly; instead, G3BP2 interacts with ELF1 mRNA to increase its stability. The transcription factor ELF1 binds to the MCL1 promoter to induce its expression, which can be attenuated by G3BP2 inhibition. Furthermore, C108-mediated inhibition of G3BP2, in combination with venetoclax, has anticancer effects in primary AML cells and in patient-derived xenografts (PDX). C108 increases the therapeutic efficacy of venetoclax and their combination prolongs overall survival (OS) in AML model mice. These findings identify G3BP2 as a regulator of venetoclax resistance through ELF1-mediated MCL1 transcription, suggesting new therapeutic strategies.

DOI: https://doi.org/10.1038/s41375-026-03063-5
Nat Struct Mol Biol. 2026 Jul 23.

Direct coupling of human TOM and TIM22 complexes drives mitochondrial carrier import.

Xiaolong Liu, Hongjun Cai, Hao Wang, Xueyin Zhou, Yutong Zhang, Shuai Liu, Jiajun Zhu, Long Li.

Metabolite carriers that control essential metabolite transport are imported into mitochondria through the TOM and TIM22 complexes. How TOM and TIM22 coordinate in human mitochondria has remained largely unknown. Here we show that human TOM and TIM22 assemble into a supercomplex that seamlessly couples carrier translocation across the outer and inner membranes, unlike in yeast where the two complexes appear to function separately. Cryo-electron microscopy structures of the human TOM-TIM22 supercomplex reveal unpaired carrier transmembrane segments traversing the TOM channel along a hydrophobic path and exiting through an unexpected lateral groove outside the channel. The membrane-bound small Tim subunits provide the substrate entry site for TIM22, while a membrane-exposed groove of TIM22 serves as the exit for carrier insertion into the inner membrane. These findings provide insights into the human carrier translocation pathway at molecular resolution and establish the TOM-TIM22 supercomplex as a central organizing unit of mitochondrial carrier import.

DOI: https://doi.org/10.1038/s41594-026-01849-w
Blood Cancer J. 2026 Jul 18.

Newly diagnosed acute myeloid leukemia in Fit patients: 2026 treatment algorithms.

Naseema Gangat, Farhad Ravandi.

The introduction of venetoclax (a BCL2 inhibitor) and targeted therapies, including inhibitors of CD33, FLT3, IDH1, IDH2, and menin, has expanded treatment options for newly diagnosed acute myeloid leukemia (AML). In younger, fit patients, the primary goal remains long-term survival, which in most cases is secured through allogeneic stem cell transplant. Transplant in first complete remission is recommended for FLT-ITD, TP53 mutated, KMT2A rearranged, AML with other adverse genetic abnormalities, and is considered in most intermediate-risk patients. It is also recommended in relapsed/refractory disease or persistent measurable residual disease (MRD). The role of intensive chemotherapy, such as cytarabine (7) plus anthracycline (3), is limited to patients with core-binding factor AML, NPM1 mutation, CEBPA bZIP mutation and those with intermediate-risk disease. Intensive regimens such as FLAG-IDA and CLIA plus venetoclax have shown impressive long-term outcomes, but their use is not widespread. In FLT3 mutated AML, 7 + 3 plus an FLT3 inhibitor (midostaurin or quizartinib) remains a standard, with venetoclax-hypomethylating agent-FLT3 inhibitor triplets emerging as an alternative. Similarly, in IDH1/2 mutated AML, venetoclax-hypomethylating agent with or without IDH1/2 inhibitor combinations challenge intensive chemotherapy approaches. Patients with TP53 mutations or other adverse-risk features, where intensive chemotherapy is known to be less effective, should be referred for clinical trials. There remains ongoing debate regarding optimal management of fit patients with newly diagnosed AML without targetable mutations, as emerging data suggest that venetoclax- hypomethylating agents may be comparable to intensive chemotherapy in selected patients proceeding to transplant. Accordingly, treatment decisions should be individualized to maximize remission while minimizing toxicity.

DOI: https://doi.org/10.1038/s41408-026-01578-9
Cell Rep. 2026 Jul 24. pii: S2211-1247(26)00797-7. [Epub ahead of print]45(8): 117719

DHODH is a synthetic lethal target in PIK3CA-mutant colorectal cancer.

Jun Liang, Xi Liu, Ziyun Ni, Sen Zhang, Xiangli He, Lili Wang, Yukun Huang, Zhaomin Xu, Zhongyu Xu, Jiayi Qian, Lixue Lu, Naijipu Abuduaini, Jing Tian, Minghua Zeng, Qi Wang, Jing Sun, Qiong Xie, Yonghui Wang, Weiqiang Lu, Bo Feng, Bo Han, Jin Huang.

  Cancer cells acquire distinct metabolic and signaling dependencies driven by oncogenic mutations. Defining these mutation-specific liabilities can uncover therapeutic opportunities. Here, we identify dihydroorotate dehydrogenase (DHODH) as a selective metabolic dependency in PIK3CA-mutant colorectal cancer (CRC). DHODH sustains WDR77 O-GlcNAcylation and protein stability by promoting the generation of uridine diphosphate (UDP)-N-acetylglucosamine (UDP-GlcNAc), thereby maintaining PI3K-AKT signaling. Genetic or pharmacological inhibition of DHODH reduces WDR77 protein abundance, decreases phosphorylated AKT, and impairs cancer cell self-renewal and tumor initiation. Uridine supplementation restores WDR77 and AKT signaling, whereas O-GlcNAc transferase (OGT) depletion abrogates this rescue, establishing a UDP-dependent mechanism linking pyrimidine metabolism to signaling maintenance. Treatment with the DHODH inhibitor HL6 recapitulates the genetic phenotypes and suppresses tumor growth in xenograft, orthotopic, and patient-derived CRC models. This study demonstrates that the metabolic regulation of protein stability represents a critical mechanism underlying oncogene-specific dependencies in CRC.

Keywords:  CP: cancer; DHODH; O-GlcNAcylation; PIK3CA mutation; cancer stemness; colorectal cancer

DOI:  https://doi.org/10.1016/j.celrep.2026.117719