bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–08–16
eleven papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Polyunsaturated fatty acid sequestration protects against mitochondrial dysfunction-induced ferroptosis.
  2. Succinate and its carrier Sfc1 mediate metabolic control of mitochondrial protein import by the TIM23 translocase.
  3. Novel noscapine derivative induces AML differentiation by dual-engaging DHODH and mitochondrial lipids to trigger a metabolic-epigenetic-transcriptional cascade.
  4. Beyond BCL-2: What drives venetoclax resistance in acute myeloid leukemia?
  5. MCART1 (SLC25A51) deficiency exacerbates mitochondrial dysfunction during MPP+-induced complex I stress.
  6. Investigating POLG-driven modulation of cancer stemness: a pilot study in breast cancer cells.
  7. LZTFL1 rewires NADPH-glutathione metabolism to amplify ferroptosis.
  8. DRP1-mediated mitochondrial fragmentation is a druggable vulnerability in multiple myeloma.
  9. Adaptation of OXPHOS biogenesis to cellular requirements.
  10. A high-resolution circulating metabolic atlas of lung adenocarcinoma progression supports early and accurate diagnosis.
  11. The emerging metabolic role and treatment target of CPT1A in CRC.
  1. EMBO Rep. 2026 Aug 14.
    Polyunsaturated fatty acid sequestration protects against mitochondrial dysfunction-induced ferroptosis.
    Guillermo Puertas-Frías, María José Saucedo-Rodríguez, Kristýna Čunátová, Lukáš Alán, Patrik Hrbáč, Michal Knězů, Soňa Koníčková, Jakub Schimmer, Monika Krakovková, Marek Vrbacký, Tomáš Čajka, Ondřej Kuda, Erika Fernández-Vizarra, Massimo Zeviani, Hana Hansíková, Tomáš Honzík, Josef Houštěk, Petr Pecina, Tomáš Mráček, Alena Pecinová.
      Impaired energy production is a hallmark of mitochondrial oxidative phosphorylation (OXPHOS) defects. However, secondary metabolic disturbances also represent an important trigger for pathologies originating from OXPHOS aberrations. Here we show that cells with OXPHOS deficiencies accumulate triacylglycerols enriched in polyunsaturated fatty acids (PUFAs), which are stored in lipid droplets. Sequestration of PUFAs is a critical component of a broader stress response, which also includes downregulation of cellular desaturases and upregulation of glutathione peroxidase 4 (GPX4). We demonstrate that this mechanism represents a physiologically relevant protective strategy, manifesting in cells under hypoxia and in immortalised fibroblasts derived from patients with primary mitochondrial complex IV deficiency. As a proof of principle, we observe elevated PUFA-enriched triacylglycerols in the plasma of patients with Myoclonic Epilepsy with Ragged Red Fibres (MERRF). Our findings reveal a novel protective mechanism against ferroptosis, which preserves membrane integrity when mitochondrial respiration is compromised.
    DOI:  https://doi.org/10.1038/s44319-026-00898-y
  2. Cell Rep. 2026 Aug 14. pii: S2211-1247(26)00935-6. [Epub ahead of print]45(8): 117857
    Succinate and its carrier Sfc1 mediate metabolic control of mitochondrial protein import by the TIM23 translocase.
    Koyeli Das, Rituparna Samanta, Tamar Ziv, Johannes M Herrmann, Bella Kalderon, Ophry Pines.
      Tim23 is an essential component of the mitochondrial inner membrane translocase and Sfc1 is a carrier that exchanges succinate for fumarate across that membrane. Sfc1 and succinic acid availability regulate dual targeting of fumarase and aconitase by facilitating mitochondrial import of their newly synthesized precursors, as shown by pulse-chase experiments. Here, we show that Sfc1 associates with Tim23 in vivo, and succinate modulates this association, which in turn affects mitochondrial protein import. Physical interaction between Tim23 and Sfc1 was proven by co-immunoprecipitation, bimolecular fluorescence complementation (BiFC) and biotin-based proximity labeling (TurboID). Proximity labeling and structural modeling-informed mutagenesis allowed us to dissect the carrier activity of Sfc1 from its function as a TIM23 regulator. We performed Rosetta-MP docking of Sfc1 and Tim23 to envisage the interface. Thus, our findings show that metabolites can regulate mitochondrial import and adjust the segregation of key metabolic enzymes between the cytosol and mitochondria.
    Keywords:  CP: cell biology; CP: metabolism; Tim23; aconitase; dual targeting; fumarase; glyoxylate shunt; metabolic signaling; metabolites; mitochondrial protein import; succinate-fumarate carrier; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.celrep.2026.117857
  3. Acta Pharm Sin B. 2026 Aug;16(8): 5363-5382
    Novel noscapine derivative induces AML differentiation by dual-engaging DHODH and mitochondrial lipids to trigger a metabolic-epigenetic-transcriptional cascade.
    Shuting Shen, Defeng Li, Youping Zhang, Shiwei Li, Lei Li, Wenhao Shen, Yujie Ma, Wenhao Zhang, Rong Tao, Wei Wang, Biao Jiang, Fang Bai, Chuanxu Liu, Yongqiang Zhang, Qianqian Yin.
      Acute myeloid leukemia (AML) is a heterogeneous and devastating hematologic malignancy characterized by differentiation blockage and immature progenitor accumulation, positioning differentiation therapy as a promising therapeutic strategy. However, clinical success is largely confined to acute promyelocytic leukemia (APL) and isocitrate dehydrogenase (IDH)-mutated AML, leaving most AML subtypes with unmet needs. Herein, novel noscapine derivative ES428 is discovered that induces AML differentiation and exhibits potent anti-AML efficacy across diverse AML cell lines, primary patient samples, as well as cell line- and patient-derived xenograft models. Target deconvolution with combinatorial strategies identifies dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in de novo pyrimidine synthesis, as the direct functional target. Integration of molecular dynamics simulations and comprehensive structure-activity relationship studies elucidates ES428's unique mechanism via simultaneous engagement with DHODH and mitochondrial membrane lipids. This dual-engagement underpins ES428's enhanced target engagement, efficacy, and selectivity in physiologically relevant mitochondrial membrane environment, potentially through stabilizing ES428-DHODH interaction in situ and facilitating ES428's selective mitochondrial localization. Furthermore, ES428 triggers a mechanistic cascade linking decreased pyrimidine synthesis, reduced O-linked N-acetylglycosylation (O-GlcNAcylation), EP300/CREBBP catalytic inhibition, and transcriptional reprogramming. Our findings identify promising lead candidates, establish a novel DHODH-targeting strategy, and provide important mechanistic insights to advance differentiation therapies for myeloid malignancies.
    Keywords:  Acute myeloid leukemia; De novo pyrimidine synthesis; Differentiation therapy; EP300/CREBBP; Noscapine derivative; Novel DHODH inhibitor; Protein‒lipid dual engagement; Transcriptional reprogramming
    DOI:  https://doi.org/10.1016/j.apsb.2026.05.019
  4. Cancer Cell. 2026 Aug 10. pii: S1535-6108(26)00313-2. [Epub ahead of print]44(8): 1525-1532
    Beyond BCL-2: What drives venetoclax resistance in acute myeloid leukemia?
    Anna Skwarska, Marina Konopleva.
      The BCL-2 inhibitor venetoclax has transformed outcomes for older or frail patients with acute myeloid leukemia (AML), and its resistance mechanisms are becoming better defined, including compensatory and lineage-associated switches toward MCL-1 or BCL-xL dependence, oncogenic signaling activation, blast phenotype, and differentiation stage. Additional putative mechanisms-such as emerging BAX mutations, mitochondrial structure remodeling, integrated stress response, and metabolic adaptations, including enhanced amino acid uptake and fatty acid oxidation to sustain oxidative phosphorylation-require further validation.
    DOI:  https://doi.org/10.1016/j.ccell.2026.07.004
  5. Free Radic Biol Med. 2026 Aug 10. pii: S0891-5849(26)01024-5. [Epub ahead of print]255 763-773
    MCART1 (SLC25A51) deficiency exacerbates mitochondrial dysfunction during MPP+-induced complex I stress.
    Shiliang Wang, Peixin Sun, Yue Zhang, Jinlun Kylian Zhang, Xurui Shen, Hanting Yang.
      Mitochondrial NAD+ homeostasis, sustained by the inner membrane transporter MCART1, is critical for oxidative metabolism and stress resilience. Inhibition of complex I by 1-methyl-4-phenylpyridinium (MPP+) triggers metabolic collapse and mitochondrial dysfunction, yet whether MCART1 provides a protective gatekeeping function against the MPP+ toxin remains unclear. Here, we show that loss of MCART1 exacerbates mitochondrial dysfunction under physiological conditions, and that MCART1 contributes to maintaining membrane potential, preventing ATP depletion, and suppressing ROS accumulation in MPP+-treated neuronal cells. We identify key NAD+-binding residues within the predicted substrate-binding pocket. Mutation of these residues uncouples MPP+ resistance from constitutive NAD+ transport, defining a structural determinant required for the stress-responsive gatekeeping function of MCART1. These findings establish that MCART1 acts as a conditionally indispensable protector of mitochondrial integrity during complex I poisoning, and reveal that failure of this NAD+ influx pathway drives metabolic collapse in the MPP+ toxin model relevant to Parkinson's disease.
    Keywords:  MCART1 / SLC25A51; Mitochondrial NAD(+) homeostasis; Mitochondrial dysfunction; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.022
  6. Aging (Albany NY). 2026 Aug 08. 18(1): 940-969
    Investigating POLG-driven modulation of cancer stemness: a pilot study in breast cancer cells.
    Chiara Chinigò, Conor J Sugden, Marco Fiorillo, Anna Rita Cappello, Federica Sotgia, Michael P Lisanti.
      Mitochondria have emerged as key regulators of breast cancer stem cell (CSC) biology. Mitochondrial metabolic pathways, including oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis, are frequently altered during tumorigenesis, highlighting their role in breast cancer pathogenesis. Since breast CSCs are highly dependent on mitochondrial metabolism, targeting mitochondrial DNA (mtDNA) replication may represent a strategy to impair CSC maintenance. Mitochondrial DNA polymerase-γ (POLG), composed of a catalytic subunit encoded by POLG1 and an accessory subunit encoded by POLG2, is essential for mtDNA replication and repair. In this pilot study, we investigated whether targeting POLG could modulate breast CSC activity. Genetic knockdown of POLG1 and POLG2 in MCF-7 cells resulted in mtDNA depletion, reduced mitochondrial protein expression, impaired energy production, and loss of stemness-related features. To pharmacologically target POLG, we tested Alovudine, a nucleoside reverse transcriptase inhibitor known to act as an off-target POLG inhibitor. In MCF-7 cells, Alovudine reduced clonogenic potential, decreased mitochondrial DNA-encoded protein levels, and lowered oxygen consumption. To further validate these findings, we employed the independent POLG inhibitor Zalcitabine (ddC) in additional breast cancer models. ddC impaired mitochondrial respiration, reduced mammosphere formation, and modulated SOX2 and NANOG expression. Preliminary Kaplan-Meier analyses in a cohort of 458 breast cancer patients showed that high POLG1 expression correlates with worse clinical outcomes, including relapse-free and overall survival. Taken together, these findings suggest that POLG supports mitochondrial function and CSC maintenance, highlighting its potential as a therapeutic target and prognostic biomarker in breast cancer.
    Keywords:  POLG; breast cancer; cancer metabolism; cancer stem cells; mitochondrial DNA
    DOI:  https://doi.org/10.18632/aging.206406
  7. Mol Cell. 2026 Aug 04. pii: S1097-2765(26)00504-6. [Epub ahead of print]
    LZTFL1 rewires NADPH-glutathione metabolism to amplify ferroptosis.
    Xiangfei Xue, Xiao Zhang, Qianjun Zhou, Lifang Ma, Yiran Yang, Wanxin Guo, Xin Xu, Yongjie Wang, Jiangtao Cui, Yikun Wang, Shiyu Qiu, Zhixin Yin, Manyuan Wang, Yuanyuan Ling, Yongchun Yu, Rui Kang, Guido Kroemer, Yongxia Qiao, Lutao Du, Daolin Tang, Jiayi Wang.
      Ferroptosis, a form of oxidative cell death, represents a therapeutic vulnerability for treating apoptosis-resistant cancers. Here, we identify leucine zipper transcription factor-like 1 (LZTFL1) as a key regulator of ferroptosis that rewires glutathione (GSH) metabolism. Mechanistically, LZTFL1 promotes oxidation of glucose-6-phosphate dehydrogenase (G6PD), thereby limiting NADPH production and impairing GSH regeneration. GSH depletion in turn enhances LZTFL1 translation via an AKT-mammalian target of rapamycin (mTOR)-eukaryotic initiation factor 4E (eIF4E) pathway, establishing a feedforward loop that amplifies ferroptosis. In vivo, the LZTFL1-formin homology 2 domain-containing 1 (FHOD1)-G6PD axis sensitizes multiple tumor models, including patient-derived xenografts, to ferroptosis, leading to enhanced lipid peroxidation, reduced GSH levels, suppressed tumor growth, and prolonged survival. LZTFL1 expression restores cisplatin sensitivity in resistant lung and ovarian cancer cells and predicts improved survival outcomes in patients with lung adenocarcinoma. Moreover, FDA-approved agents upregulate LZTFL1 and re-sensitize resistant tumors to cisplatin. These findings highlight LZTFL1 as a potential biomarker and a therapeutic target for enhancing ferroptosis-based cancer therapy.
    Keywords:  GSH metabolism; ferroptosis; lung cancer; oxidative modification
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.018
  8. Blood. 2026 Aug 03. pii: blood.2025030349. [Epub ahead of print]
    DRP1-mediated mitochondrial fragmentation is a druggable vulnerability in multiple myeloma.
    Maria Eugenia Gallo Cantafio, Noemi Puccio, Roberta Torcasio, Ilenia Valentino, Ludovica Ganino, Yuanyuan Jin, Anil Aktas Samur, Pierpaolo Murfone, Alessia Gallo, Mehmet K Samur, Nicola Cuscino, Cesarina Giallongo, Ida Daniela Perrotta, Alessia Ciarrocchi, Federico Tallarigo, Ernestina Marianna De Francesco, Davide Barbuto, Ross David Jansen-van Vuuren, Luka Jedlovčnik, Danchen Wu, Enrica Antonia Martino, Daniele Tibullo, Francesco Di Raimondo, Massimo Gentile, Antonino Neri, Stephen L Archer, Eugenio Morelli, Nikhil C Munshi, Giuseppe Viglietto, Mariateresa Fulciniti, Nicola Amodio.
      Mitochondrial dynamics is a key regulator of cellular homeostasis, orchestrating metabolic reprogramming that fuels tumor progression and treatment resistance. In multiple myeloma (MM), however, the functional relevance of mitochondrial remodeling has not been fully defined. Using ultrastructural analyses, we reveal that MM cells display a highly fragmented mitochondrial network, a phenotype further exacerbated in both cell lines and primary MM cells resistant to proteasome inhibitors. Transcriptomic profiling across multiple patient-derived datasets consistently demonstrated upregulation of DNM1L gene, which encodes the mitochondrial fission GTPase DRP1, particularly in relapsed and refractory MM, and revealed a significant association with inferior overall survival. Disrupting mitochondrial fission, either through genetic targeting of DNM1L or pharmacologic inhibition of DRP1 with the selective small molecule inhibitor Drpitor1a, resulted in pronounced mitochondrial dysfunction, impaired oxidative phosphorylation, and potent anti-myeloma activity in vitro, culminating in a hybrid cell death program with a predominant apoptotic component accompanied by ferroptotic features. These effects were recapitulated in vivo in a bortezomib-resistant xenograft model, where either DNM1L depletion or DRP1 inhibition produced similar outcomes. Mechanistically, the transcription factor c-MYC upregulated DNM1L expression, and DRP1-dependent mitochondrial fragmentation sustained MYC-driven oxidative metabolism and lipid synthesis. Altogether, these findings establish aberrant mitochondrial fission as a pathogenic hallmark of MM and highlight DRP1 inhibition as a promising therapeutic approach, especially for relapsed or refractory disease.
    DOI:  https://doi.org/10.1182/blood.2025030349
  9. Protein Sci. 2026 Sep;35(9): e70763
    Adaptation of OXPHOS biogenesis to cellular requirements.
    Sven Dennerlein, Peter Rehling.
      Metabolic cues regulate the formation of the mitochondrial OXPHOS machinery. These regulatory processes are tightly linked to mitochondrial translation, proteolytic degradation of unassembled subunits, and the formation of supercomplexes, creating checkpoints at which nutrient availability, oxygen tension, and signaling pathways remodel OXPHOS content and activity. In particular, the cytochrome c oxidase (COX) assembly pathway is regulated at multiple steps of its biogenesis in response to cellular demands. COX consists of mitochondrially encoded catalytic core subunits and nuclear-encoded accessory subunits whose coordinated expression, cofactor insertion, and incorporation into the COX enzyme result in optimized electron transport capacity. Consequently, COX assembly depends on numerous dedicated factors and protein isoforms, many of which are expressed in a tissue-specific manner. Through these metabolically regulated processes, cells tune oxidative phosphorylation efficiency, limit reactive oxygen species production, and support context-specific metabolic programs in development, adaptation, and disease.
    Keywords:  Cytochrome c Oxidase; OXPHOS; mitochondria
    DOI:  https://doi.org/10.1002/pro.70763
  10. Cell Rep Med. 2026 Aug 10. pii: S2666-3791(26)00408-8. [Epub ahead of print] 102991
    A high-resolution circulating metabolic atlas of lung adenocarcinoma progression supports early and accurate diagnosis.
    Shouzhi Yang, Yongxia Qiao, Tianxiang Chen, Wenjun Yu, Yuewei Zhao, Zhengying Gu, Xin Xie, Fanyu Meng, Hongwei Meng, Ayizekeranmu Yiming, Chunmeng Ding, Yang Li, Kexin Meng, Wanshan Liu, Jiao Wu, Juxiang Zhang, Yida Huang, Xiaoyu Xu, Rui Kang, Jiayi Wang, Kun Qian, Daolin Tang, Lin Huang.
      Early diagnosis of lung adenocarcinoma (LUAD), particularly at the adenocarcinoma in situ (AIS) stage, is critical for curative intervention. Profiling blood-based metabolic progression offers a systemic view of tumorigenesis to enable robust, noninvasive early detection. To achieve this, we profile 2,836 serum samples from predominantly female, never-smoking Chinese cohorts spanning normal lung to invasive carcinoma using an ultrafast nanoparticle-enhanced mass spectrometry platform. This integrated retrospective and prospective cohort design enables the construction of a comprehensive metabolic atlas, revealing conserved metabolic perturbations that arise at the pre-invasive stage and progress with histologic severity. Guided by these trajectories, we develop a ten-metabolite diagnostic assay that demonstrates reproducible performance across independent cohorts (area under the curve 0.900 for overall; 0.860 for pre-invasive disease). Notably, assay efficacy remains consistent after adjusting for demographic and lifestyle confounders. These findings identify metabolic rewiring as an early hallmark of LUAD, with potential utility in population-level early detection.
    Keywords:  biomarkers; early detection; lung adenocarcinoma; mass spectrometry; metabolomics; serum
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102991
  11. Front Cell Dev Biol. 2026 ;14 1881073
    The emerging metabolic role and treatment target of CPT1A in CRC.
    Xinyu Zhu, Ting Sun, Jintao Yuan, Fei Mao, Tao Jin, Chengxue Yi.
      Fatty acid oxidation is a major metabolic pathway responsible for fatty acid breakdown and energy production. Carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme in this process, catalyzes the conversion of acyl-coenzyme A into acyl-carnitine, enabling mitochondrial transport for oxidative metabolism. Emerging evidence indicates that dysregulated CPT1A contributes to metabolic disorders and cancer progression by driving metabolic reprogramming, modulating oxidative stress, and regulating protein modifications, including histone acetylation and lysine succinylation. Colorectal cancer (CRC), one of the leading causes of cancer-related mortality worldwide, has recently been linked to aberrant CPT1A activity. Studies demonstrate that CPT1A promotes CRC progression by regulating oncogenic signaling pathways, enhancing cancer stemness, supporting tumor proliferation and metastasis, and shaping the tumor microenvironment. Increasing evidence suggests that targeting CPT1A may be a promising therapeutic strategy for CRC. In this review, we summarize the biological functions of CPT1A, discuss its mechanistic role in CRC progression, and highlight its emerging potential as a metabolic and therapeutic target in CRC.
    Keywords:  cancer metabolic reprogramming; carnitine palmitoyltransferase 1a; colorectal cancer; fatty acid oxidation; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2026.1881073
This page is being maintained by Thomas Krichel. It was last updated on 2026‒08‒16 at 1:27.