bims-mibica 2026-02-15 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–02–15
twelve papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Single-Mitochondrion ATP Profiling Directs Discovery of Targetable OXPHOS Dependency in Cancers.
Metabolic permissiveness: how tissue context shapes cancer.
Dual-Targeting Bcl-2-Mediated apoptosis and synergistic Pathways: Combinatorial strategies to overcome therapeutic resistance in cancer.
Simulating tumor mitochondrial energetics through engineering-style energy metrics.
Intrinsic and niche-dependent metabolic regulation of haematopoietic stem cells and implications for leukaemogenesis.
RAD51 succinylation regulates homologous recombination and contributes to the chemosensitivity in cancer.
The bottleneck of fat burning.
FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response.
Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis.
Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.
Mitochondrial presequences are more than just address labels.
CD36 enhances sensitivity of triple negative breast cancer cells to palmitate-induced ferroptosis.

Adv Sci (Weinh). 2026 Feb 13. e13341

Single-Mitochondrion ATP Profiling Directs Discovery of Targetable OXPHOS Dependency in Cancers.

Xu Xiao, Cheng Lu, Hao Chen, Jing Zhou, Yunyun Hu, Haonan Di, Guoqiang Su, Xiaomei Yan.

  Mitochondrial adenosine triphosphate (mitoATP) serves as the primary bioenergetic currency for oxidative phosphorylation (OXPHOS)-driven malignancies, yet its precise organelle-level quantification remains challenging due to mitochondrial heterogeneity and cytosolic interference. Herein, we report MitoATP-nFCM, a nano-flow cytometry platform enabling single-mitochondrion ATP measurement via simultaneous fluorescence and side scatter detection. We uncover 1.7-1.9-fold higher ATP levels in isolated mitochondria from breast (MCF-7, MDA-MB-231) and colon (HCT-15, HCT-116) cancer cells than in their normal counterparts. Single-organelle analysis further reveals coordinated metabolic reprogramming in cancer mitochondria, featuring elevated membrane potential, increased ATP synthase expression, and reduced hexokinase 2 levels, demonstrating their OXPHOS-dominant bioenergetic phenotype that contrasts with classical Warburg-effect expectations. Furthermore, we establish a screening strategy to identify highly potent cancer-selective inhibitors targeting mitochondrial metabolism. We find that bedaquiline (ATP synthase inhibitor) outperforms oligomycin A in specificity, VLX600 (electron transport chain inhibitor) shows superior selectivity to rotenone/metformin, and CPI-613 (tricarboxylic acid cycle blocker) surpasses other glutaminase inhibitors. MitoATP-nFCM establishes a quantitative single-organelle platform that profiles elevated mitoATP levels in cancer cells and enables precision screening of OXPHOS-targeting inhibitors.

Keywords:  cancer vulnerability; mitochondrial ATP; mitochondrial metabolism; precision cancer therapy; single‐organelle analysis

DOI:  https://doi.org/10.1002/advs.202513341
Genes Dev. 2026 Feb 09.

Metabolic permissiveness: how tissue context shapes cancer.

Chrysanthi Moschandrea, Christian Frezza.

  An emerging paradox in cancer metabolism is that identical oncogenic mutations produce profoundly different metabolic phenotypes depending on tissue context, with many mutations exhibiting striking tissue-restricted distributions. Here we introduce metabolic permissiveness as the inherent capacity of a tissue to tolerate, adapt to, or exploit metabolic disruptions, providing a unifying framework for explaining this selectivity. We examine tissue-specific metabolic rewiring driven by canonical oncogenes (MYC and KRAS), tumor suppressors (p53, PTEN, and LKB1), and tricarboxylic acid (TCA) cycle enzymes (FH, SDH, and IDH), demonstrating that baseline metabolic architecture, nutrient microenvironment, redox buffering, and compensatory pathways determine whether mutations confer a selective advantage or metabolic crisis. We further discuss how the tumor microenvironment shapes metabolic adaptation and therapeutic vulnerability. This framework reveals shared principles of tissue-specific metabolic vulnerability in cancer and provides a mechanistic basis for precision metabolic therapies.

Keywords:  cancer; metabolism; permissiveness

DOI:  https://doi.org/10.1101/gad.353516.125
Biochem Pharmacol. 2026 Feb 11. pii: S0006-2952(26)00133-4. [Epub ahead of print] 117802

Dual-Targeting Bcl-2-Mediated apoptosis and synergistic Pathways: Combinatorial strategies to overcome therapeutic resistance in cancer.

Jiongjia Cheng, Haiying Wang, Yuchi Zhang, Guangxiang Liu.

  Dysregulation of apoptosis pathways is a defining characteristic of cancer, that has established pro-apoptotic activation as a fundamental therapeutic strategy in oncology. The B-cell lymphoma-2 (Bcl-2) family proteins serves as master regulators of mitochondrial apoptosis, with anti-apoptotic members constituting critical checkpoints in cancer cell survival. Across diverse cancer types, overexpression of anti-apoptotic Bcl-2 proteins is a universal mechanism driving cancer cells to evade apoptosis and acquire resistance to chemotherapy. However, relying solely on agents that induce the downregulation of anti-apoptotic Bcl-2 proteins has proven inefficient for cancer treatment. Notably, the observed synergy between Bcl-2 inhibitors and other anti-tumor agents supports the development of dual-targeting regimens as promising therapeutic approaches. Here, we comprehensively review the recent progress in dual-targeted apoptotic modulation, focusing on strategies that concurrently inhibit anti-apoptotic Bcl-2 family proteins and synergistic pathways. Emerging evidence demonstrates that Bcl-2/B cell lymphoma extra large (Bcl-xL)/myeloid cell leukemia 1 (Mcl-1) inhibitors (e.g., venetoclax and the derivatives) combined with p53/murine double minute 2 (MDM2) disruptors, epigenetic modifiers (e.g., histone deacetylase inhibitors), autophagy modulators, or kinases inhibitors, achieve synergistic potency. These rationally designed combination therapies effectively suppress compensatory upregulation of alternative anti-apoptotic proteins overcome Bcl-2/Bcl-xL/Mcl-1-driven resistance and restore drug efficacy in apoptosis-deficient cancer subtypes. This paradigm shift offers substantial potential to advance precision oncology by establishing durable responses through simultaneous blockade of multiple survival axes, and carries tremendous promise in the next-generation evolution of cancer therapeutics.

Keywords:  Anti-apoptotic proteins; Apoptotic pathway; Bcl-2 family; Cancer treatment; Dual-targeted therapies

DOI:  https://doi.org/10.1016/j.bcp.2026.117802
Biosystems. 2026 Feb 05. pii: S0303-2647(26)00029-8. [Epub ahead of print]262 105719

Simulating tumor mitochondrial energetics through engineering-style energy metrics.

Arturo Tozzi.

  Cancer progression is linked to alterations in cellular energetics, where malignant cells reprogram their metabolism to sustain proliferation, resist stress and adapt to nutrient limitations. Recent work has shown that tumors actively remodel their microenvironment by acquiring functional mitochondria from surrounding stromal or immune cells. Mitochondrial transfer enhances tumor bioenergetics while simultaneously depleting immune cells of metabolic competence, thereby reinforcing both tumor growth and immune evasion. The energetic consequences in terms of throughput, efficiency and stored energy of these exchanges are not captured by conventional assays focused on oxygen consumption or glycolytic flux. We introduce a simulation-based framework for theoretical analysis of mitochondrial energetics that adapts engineering-style energy metrics to mitochondrial biology. Three theoretical, model-defined bioenergetic metrics are introduced: mitochondrial power density, expressing ATP production per unit mitochondrial volume; mitochondrial surface power density, relating ATP production to inner membrane area; and mitochondrial energy density, quantifying stored chemical free energy per unit volume. Using controlled in silico simulations of tumor and immune cell populations before and after modeled mitochondrial transfer, we examine how these descriptors vary under explicit simulation assumptions. Within our simulation framework, results indicate model-predicted differences between cell populations, with tumor-associated mitochondria occupying higher energetic throughput and immune-associated mitochondria exhibiting complementary reductions. Although exploratory and hypothesis-generating rather than validated biomarkers or clinical tools, our metrics provide a quantitative physical framework that may inform experimental studies of mitochondrial transfer and its energetic consequences, including efforts to disrupt pathogenic transfer and restore metabolic competence in immune cells.

Keywords:  Cristae morphology; Immune evasion; Metabolic profiling; Oxidative phosphorylation; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.biosystems.2026.105719
Nat Cell Biol. 2026 Feb 11.

Intrinsic and niche-dependent metabolic regulation of haematopoietic stem cells and implications for leukaemogenesis.

Ayşegül Erdem, Claudia Morganti, Haruhito Totani, Nick van Gastel, Keisuke Ito.

Haematopoietic stem cells (HSCs) rely on precisely coordinated metabolic programs to preserve their functionality, adapt to environmental cues, and sustain lifelong haematopoiesis. Here we analyse recent advances in understanding the metabolic landscape of HSCs, emphasizing how their intrinsic bioenergetic programs facilitate quiescence, self-renewal and differentiation. We also summarize the dynamic metabolic interactions with the bone marrow microenvironment, including stromal cells, osteoblasts, endosteal cells and adipose tissue, highlighting how they support proper HSC fate. In addition, we discuss how alterations in metabolic homeostasis in healthy and aged HSCs are linked to haematological disorders, particularly leukaemogenesis. We discuss metabolic dysregulation in leukaemic cells that maintains malignant persistence by mimicking certain intrinsic-extrinsic key HSC metabolic features, while simultaneously activating distinct metabolic pathways to support their growth and survival. Understanding the complex role of metabolism in HSC biology will be essential to advance regenerative medicine and blood cancer prevention strategies.

DOI: https://doi.org/10.1038/s41556-026-01872-5
Mol Cell. 2026 Feb 11. pii: S1097-2765(26)00062-6. [Epub ahead of print]

RAD51 succinylation regulates homologous recombination and contributes to the chemosensitivity in cancer.

Zhe Wang, Mingpeng Jin, Linhui Zhai, Bingsong Huang, Xuan Jin, Xuanhe Wang, Ala Eddine Boudemia, Xiaoning Yang, Zhiting Wei, Yiming He, Jie Yang, Yunxuan Li, Xin Ding, Rui Li, Xuan Zhou, Wen Zheng, Yaobing Ouyang, Qianwen Wang, Yifei Song, Zhikai Zeng, Yu Li, Lu Lu, Jiaqi Liu, Yunhui Li, Lei Li, Ke Li, Chun-Long Chen, Zhenkun Lou, Minjia Tan, Jinhuan Wu, Yuping Chen, Jian Yuan.

Genomic instability and metabolic reprogramming are core hallmarks of cancer, yet how they are mechanistically interconnected remains unclear. Here, we demonstrate that succinyl-coenzyme A (CoA), a tricarboxylic acid (TCA) cycle metabolite and protein succinylation donor, modulates homologous recombination (HR) by regulating RAD51 succinylation. OXCT1 succinylates RAD51 at K285, whereas HDAC11 removes this modification. RAD51 succinylation disrupts BRCA2 interaction, impairs RAD51 foci formation, and suppresses HR. Upon DNA damage, ATM-dependent phosphorylation of HDAC11 enhances the interaction with RAD51, promoting RAD51 desuccinylation and inhibiting HR. In breast cancer models, elevated RAD51 succinylation correlates with reduced HR capacity and increased sensitivity to the PARP inhibitor olaparib, whereas diminished succinylation confers resistance. Moreover, a cell-penetrating peptide that disrupts the RAD51-HDAC11 interaction increases RAD51 succinylation and synergizes with chemotherapy. Collectively, our findings uncover a metabolic-epigenetic mechanism linking protein succinylation to HR and genomic stability and identify RAD51 succinylation as a predictive biomarker and therapeutic target in cancer.

DOI: https://doi.org/10.1016/j.molcel.2026.01.020
Science. 2026 Feb 12. 391(6786): 659-660

The bottleneck of fat burning.

Angela M Ramos-Lobo, Pierre Maechler.

A mitochondrial transport protein promotes carnitine synthesis in mice when fat consumption is needed.

DOI: https://doi.org/10.1126/science.aef2173
Cancer Res. 2026 Feb 09.

FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response.

Moumita Banerjee, Yekaterina Y Zaytseva, Ellen M Reusch, Dana L Napier, Sumati Hasani, Piotr Rychahou, Tadahide Izumi, Dennis A Cheek, Jing Li, Robert M Flight, Hunter N B Moseley, Heidi L Weiss, William McCulloch, B Mark Evers, Tianyan Gao.

Altered lipid metabolism is a potential targetable metabolic vulnerability in colorectal cancer (CRC). Fatty acid synthase (FASN), the rate limiting enzyme of de novo lipogenesis, is an important regulator of CRC progression, but the FASN inhibitor TVB-2640 showed only modest efficacy in reducing tumor burden in pre-clinical studies, suggesting combination strategies might be required to prolong patient survival. Here, by using samples from a window trial of TVB-2640 treatment in CRC patients, we found that FASN inhibition induced DNA damage but impaired the DNA damage response (DDR). In colon cancer cell lines and patient-derived organoids, FASN inhibition potentiated chemotherapy-induced double-strand DNA breaks (DSBs) and apoptotic cell death by altering histone acetylation levels. In addition, FASN inhibitor treatment blocked DDR by decreasing ATM expression and CHK2 phosphorylation. Mechanistically, FASN inhibition attenuated activation of the DDR pathway by attenuating BRCA1 and ATM recruitment to -H2AX foci in an acetylation-dependent manner. Moreover, FASN inhibition mediated DNA repair deficiency induced synthetic lethality with PARP inhibition in CRC cells. Importantly, combining FASN inhibition with the chemotherapeutic drug irinotecan synergistically decreased xenograft tumor growth and delayed tumor relapse, which was potentiated by the PARP inhibitor olaparib as maintenance treatment. Taken together, this study describes a therapeutic strategy in which FASN inhibitors can be utilized to delay tumor recurrence after chemotherapy, which is a major challenge in patients with CRC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1917
Cell Metab. 2026 Feb 06. pii: S1550-4131(26)00007-0. [Epub ahead of print]

Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis.

Fenfen Ji, Pingmei Huang, Qiming Zhou, Lok Hin Ko, Qinyao Wei, Charis Cheuk-Lok Chan, Danyu Chen, Huarong Chen, Wei Kang, Alvin Ho-Kwan Cheung, Cillian H Cheng, Jianming Shen, Yasi Pan, Ying Jiao, Lin Zhu, Tat Wai Chik, Peisi Xie, Xiao Liang, Onno Kranenburg, Zongwei Cai, Jun Yu, Chi Chun Wong.

  The role of metabolic compartmentalization in cancer metastasis is unexplored. Here, we identified that compartmentalized branched-chain amino acid (BCAA) metabolism modulates colorectal cancer (CRC) metastasis. Cytosolic BCAA transaminase (BCAT1) promotes epithelial-to-mesenchymal transition (EMT) and cancer spread of CRC cells, whereas the mitochondrial isoform (BCAT2) exerted opposite effects. The location of BCAT is critical, as mitochondria-targeted BCAT1 and cytosolic BCAT2 demonstrated opposite functions in EMT and cell migration, compared with their wild-type counterparts. Mechanistically, cytosolic BCAT promotes nitrogen flux from BCAA to glutamate, aspartate, and uridine monophosphate (UMP), whereas mitochondrial BCAT activity diverts nitrogen flux via glutamate dehydrogenase (GDH) to give NH3. UMP binds to vimentin and protects it against ubiquitination-proteasome degradation. Dietary BCAA restriction or blockade of UMP biosynthesis impaired cancer spread of BCAT1-high CRC, and BCAT1-to-BCAT2 expression ratio is an independent prognostic factor in CRC and pan-cancer cohorts, highlighting translational relevance of BCAA metabolic compartmentalization in cancer metastasis.

Keywords:  BCAA; BCAT1; BCAT2; UMP; branched-chain amino acids; colorectal cancer; dietary restriction; metabolic compartmentalization; metastasis; uridine monophosphate

DOI:  https://doi.org/10.1016/j.cmet.2026.01.007
Nat Cell Biol. 2026 Feb 11.

Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.

Anna Bång-Rudenstam, Myriam Cerezo-Magaña, Marton Horvath, Hugo Talbot, Emma Gustafsson, Stevanus Jonathan, Chaitali Chakraborty, Itzel Nissen, Kelin Gonçalves de Oliveira, Axel Boukredine, Sarah Beyer, Julio Enriquez Perez, Maria C Johansson, Lena Kjellén, Emil Tykesson, Anders Malmström, Toin H van Kuppevelt, Karin Forsberg-Nilsson, Jeffrey D Esko, Silvia Remeseiro, Johan Bengzon, Valeria Governa, Mattias Belting.

Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1-replacing heparan sulfate with CS-thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.

DOI: https://doi.org/10.1038/s41556-026-01879-y
Protein Sci. 2026 Mar;35(3): e70491

Mitochondrial presequences are more than just address labels.

Erik Marcel Heller, Svenja Lenhard, Doron Rapaport, Johannes Herrmann.

  Most mitochondrial proteins are synthesized in the cytosol as precursor proteins with N-terminal presequences. These presequences serve as targeting signals that facilitate the binding to mitochondrial surface receptors and translocation across the mitochondrial membranes. However, recent studies showed that presequences can be more than address tags. They can contain degradation signals recognized by components of the ubiquitin-proteasome system, and therefore, serve as timers that determine the lifespan of newly synthesized precursor proteins. Moreover, presequences can interact with components of the cytosolic chaperone system to prevent or delay precursor folding. Finally, presequences of some dually localized proteins contain targeting information not only for mitochondria but also for other cellular destinations such as the nuclear lumen or chloroplasts in plant cells. Thus, presequences contain multifaceted information to endow mitochondrial precursor proteins with specific properties that are critical for the early steps of mitochondrial protein biogenesis.

Keywords:  Presequence; chaperones; mitochondria; proteasome; protein import; ubiquitin ligases

DOI:  https://doi.org/10.1002/pro.70491
Cell Death Dis. 2026 Feb 11.

CD36 enhances sensitivity of triple negative breast cancer cells to palmitate-induced ferroptosis.

Lara Closset, Jean-Philippe Foy, Lila Louadj, Elodie Pramil, Elisabetta Marangoni, Ivan Bieche, Michèle Sabbah.

Ferroptosis is a newly identified programmed cell death induced by iron-driven lipid peroxidation and implicated as a potential approach for tumor treatment. Breast tumors develop in a complex microenvironment whose main component is adipose tissue and gain aggressiveness through increased fatty acid uptake. Here, we demonstrated that palmitic acid (PA) induced ferroptosis in triple negative breast cancers (TNBC). We found that PA increases the protein expression levels of the long-chain fatty acid transporter CD36, leading to increased lipid uptake. Mechanistically, overexpression of CD36 increases lipid peroxidation, mitochondrial ROS production, the labile iron pool, and especially Fe2+ content. Additionally, we found increased expression of ferroptotic target genes (HMOX1, ACSL1, SAT1) and decreased of anti-ferroptotic genes (GPX4 and FSP1) in TNBC following PA exposure. Overexpression of CD36 did not induce ferroptosis in estrogen receptor positive breast cancer. Clinically, higher CD36 expression correlated with the luminal androgen receptor (LAR) subtype of TNBC, known to exhibit a higher sensitivity to ferroptosis. Altogether, these data provide evidence for an essential role of the CD36 protein in the ferroptotic process induced by the saturated fatty acid PA, opening potential new therapeutic approaches promoting ferroptosis in the most aggressive breast cancers.

DOI: https://doi.org/10.1038/s41419-026-08460-3