bims-mibica 2026-05-24 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–05–24
eleven papers selected by
Kelsey Fisher-Wellman, Wake Forest University

ICAM2 promotes endocrine resistance via dynein-mediated OXPHOS activation in ER-positive breast cancer.
The Natural Quassinoid Brusatol Enhances Venetoclax Efficacy and Overcomes Resistance in Myeloid Leukemias.
CPT1A loss promotes lung metastasis in immune-competent mice via a mechanism of mtDNA release and chronic activation of STING pathway.
Elevated NDUFAF2 expression correlates with poor prognosis and drives metabolic dependency in hepatocellular carcinoma.
Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite.
Phosphoglycerate mutase 5 regulates lipid metabolism and mitochondrial homeostasis in hepatocellular cancer cells.
Metabolic Reprogramming in Cancer Stem Cells.
Overcoming metabolic plasticity and microenvironmental rescue when targeting SLC25A1 in acute myeloid leukemia. Comment on: "SLC25A1 reprograms mitochondrial and fatty acid metabolism to promote the progression of acute myeloid leukemia".
Overcoming resistance in lung cancer: combined mitochondrial destabilization by lipophilic cations and doxycycline in hypoxic non-small cell lung carcinoma.
Mitochondria-Targeting Moieties Based on N-Tethered Pyridinium Cations.
Rapid Transcription Dynamics Confers Cytarabine Resistance in Acute Myeloid Leukemia.

Cell Death Dis. 2026 May 18.

ICAM2 promotes endocrine resistance via dynein-mediated OXPHOS activation in ER-positive breast cancer.

Si Chen, Shiyi Wu, Jiajie Hu, Bohan Liu, Yuting Liu, Siyue Yang, Fen Tang, Yiqing He, Qinqing Liu, Yiwen Liu, Yan Du, Guoliang Zhang, Qian Guo, Feng Gao, Cuixia Yang.

Acquired endocrine resistance in ER+ breast cancer (BC) involves metabolic reprogramming, yet key drivers are unclear. Multi-omics of endocrine-resistant BC revealed upregulated oxidative phosphorylation (OXPHOS) and identified intercellular adhesion molecule 2 (ICAM2) as a biomarker of high-OXPHOS cells. ICAM2-positive cells were significantly enriched in resistant tumors and predicted poor survival, and were functionally essential for maintaining resistance and promoting metastasis in vivo. Mechanistically, ICAM2 binds dynein light chain DYNLT3 and the mitochondrial complex I subunit MT-ND2, thereby facilitating dynein-mediated mitochondrial trafficking and further modulating the assembly of mitochondrial complex I. Disrupting this interaction through ICAM2 knockdown or dynein inhibition (Ciliobrevin D) effectively suppressed OXPHOS activity. Importantly, ERα inhibition alleviates the transcriptional repression of ICAM2 by ERα. Therapeutically, combining the complex I inhibitor IACS-10759 with fulvestrant potently inhibited both tumor growth and metastasis. Collectively, these findings reveal that ICAM2 drives endocrine resistance via dynein-dependent OXPHOS activation, revealing a targetable axis in refractory ER+ BC.In summary, we establish ICAM2 as a novel biomarker and driver of endocrine resistance in ER⁺ breast cancer. ICAM2⁺ cancer cells-enriched in treatment-resistant tumors-maintain elevated OXPHOS by assembling a functional complex with dynein and mitochondrial Complex I, thereby promoting mitochondrial trafficking. Disruption of this axis, either through ICAM2 depletion or Complex I inhibition, re-sensitizes tumors to therapy, revealing a targetable metabolic dependency in resistant disease.

DOI: https://doi.org/10.1038/s41419-026-08864-1
Cancer Sci. 2026 May 21.

The Natural Quassinoid Brusatol Enhances Venetoclax Efficacy and Overcomes Resistance in Myeloid Leukemias.

Shin-Ichiro Kawaguchi, Kazuya Sato, Junko Izawa, Norihito Takayama, Hiroko Hayakawa, Ken Suzaki, Susumu Goyama, Chiyoko Kato, Eiji Sakashita, Kaoru Tominaga, Hitoshi Endo, Yoshinobu Kanda.

  While venetoclax-based combinations have shown promising results in acute myeloid leukemia (AML), the remission duration is generally short, warranting strategies to further improve efficacy and overcome resistance. Here, we show that the natural quassinoid brusatol induces cell-cycle arrest and apoptosis in multiple AML cell lines while enhancing venetoclax efficacy irrespective of inherent or acquired resistance. Mechanistically, brusatol increased p53 protein expression, leading to upregulation of its target genes/proteins, including CDKN1A (p21) and BBC3 (PUMA). Genetic deletion of TP53 attenuated brusatol-induced apoptosis and its synergy with venetoclax, supporting p53 activation as a central mechanism underlying the anti-leukemia response. Furthermore, the combination synergistically decreased mitochondrial membrane potential and respiratory activity, causing accumulation of reactive oxygen species in AML cells. Although brusatol and venetoclax exhibited limited effects individually, their combination markedly reduced leukemia burden and significantly prolonged survival in three independent cell line-derived xenograft models, including venetoclax-resistant and -refractory models. Notably, brusatol increased normal leukocyte and platelet counts while reducing leukemic infiltration in both bone marrow and extramedullary sites. These findings provide mechanistic insight into the synergistic effects of the brusatol-venetoclax combination, supporting further evaluation of this therapeutic strategy in myeloid leukemias.

Keywords:  CDKN1A; acute myeloid leukemia; brusatol; mitochondria; p53; venetoclax

DOI:  https://doi.org/10.1111/cas.70423
bioRxiv. 2026 May 05. pii: 2026.05.01.722261. [Epub ahead of print]

CPT1A loss promotes lung metastasis in immune-competent mice via a mechanism of mtDNA release and chronic activation of STING pathway.

Xiaoyong Wang, Shu-Ting Chou, Yoonha Hwang, Jin Chen, Deanna N Edwards.

The metastatic progression of breast cancer involves complex interactions between tumor cells and immune cells, including T cells that exert cytotoxic pressure to limit metastasis. Tumor cells reprogram their metabolism to evade immune surveillance, a critical step to achieving metastatic outgrowth. Using an unbiased CRISPR screen targeting metabolism-related genes and a clinically relevant spontaneous metastasis mouse model, we identified CPT1A, the rate-limiting enzyme in fatty acid β-oxidation, as a suppressor of immune-dependent metastasis. Loss of CPT1A enhances lung metastasis in immunocompetent mice, but not Rag1 KO mice that lack mature lymphocytes. Loss of CPT1A triggers cytosolic mitochondrial DNA (mtDNA) release via the mPTP pore. Cytosolic mtDNA release triggers a STING-dependent inflammatory response, creating an environment that impairs CD8+ T cell function, promoting metastatic outgrowth. Among breast cancer patients, low CPT1A expression correlates with poor survival when CD8+ T cell infiltration is high. These findings reveal an extrinsic role for CPT1A in immune-tumor dynamics and suggest therapeutic opportunities targeting inflammation in metastatic breast cancer.

DOI: https://doi.org/10.64898/2026.05.01.722261
Biol Direct. 2026 May 16.

Elevated NDUFAF2 expression correlates with poor prognosis and drives metabolic dependency in hepatocellular carcinoma.

Peiting Zeng, Jingshu Wang, Wenhua Lu, Zizhen Li, Amin Huang.

  Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic options for advanced and immunotherapy-resistant cases. Mitochondrial oxidative phosphorylation (OXPHOS) has emerged as a key metabolic dependency in a subset of HCCs, yet the molecular regulators of this vulnerability remain poorly understood. Here, we report that NDUFAF2, a core assembly chaperone for mitochondrial Complex I, is significantly overexpressed across multiple human cancers, particularly in HCC, where elevated expression correlates with poor overall survival, progression-free interval, and disease-specific survival in large-scale TCGA and CPTAC cohorts. At the transcriptomic and proteomic levels, NDUFAF2 upregulation was consistently observed in primary HCC tissues compared with paired normal liver samples, and correlated with advanced histological grade, pathological stage, high AFP levels, and vascular invasion. Bioinformatic pathway analyses identified OXPHOS as the dominant biological process associated with NDUFAF2 expression. Mechanistically, stable NDUFAF2 knockdown in two independent HCC cell lines (HCC-LM3 and SNU-449) resulted in profound mitochondrial dysfunction, including reduced oxygen consumption rate, impaired ATP production, increased reactive oxygen species (ROS) accumulation, and compensatory upregulation of glycolytic genes. These metabolic defects ultimately led to suppressed cell proliferation in vitro. Preliminary correlative analyses further suggested weak associations between NDUFAF2 expression and immunosuppressive features in the tumor microenvironment, although these trends remain hypothesis-generating and require experimental validation. Collectively, our findings establish NDUFAF2 as a pivotal regulator of mitochondrial bioenergetics and malignant progression in HCC, identifying it as a promising prognostic biomarker and a potential target for metabolic therapy in OXPHOS-dependent liver cancers.

Keywords:  Liver hepatocellular carcinoma; NDUFAF2; Oxidative phosphorylation; Prognostic biomarker; Tumor metabolism

DOI:  https://doi.org/10.1186/s13062-026-00827-y
Nature. 2026 May 20.

Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite.

Ram P Chakrabarty, Jonathan G Van Vranken, Yuki Aoi, Taylor A Poor, Gregory S McElroy, Karthik Vasan, Shimaa H A Soliman, Marta Iwanaszko, Rogan A Grant, Benjamin C Howard, Colleen R Reczek, Anjali D Chandel, Michael Kahl, Zhaofa Xu, Kathryn A Helmin, Qiushi Jin, Dongmei Wang, Peng Gao, Jenna L E Blum, Zachary L Sebo, Feng Yue, Yongchao C Ma, Shawn M Davidson, Steven P Gygi, Samuel E Weinberg, Benjamin D Singer, SeungHye Han, Ali Shilatifard, Navdeep S Chandel.

L-2-Hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals because the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH) oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation1. In humans, a lack of L2HGDH activity leads to L-2-HG accumulation and causes L-2-hydroxyglutaric aciduria2. Thus, L-2-HG is often classified as a toxic metabolite2-5. However, whether L-2-HG has any physiological function is unclear. Here we investigate whether L-2-HG qualifies as a physiological signalling metabolite by testing three criteria: regulated levels, defined molecular targets and a measurable physiological function. We report that an increase in mitochondrial NADH/NAD+ ratio drives malate dehydrogenase 2 (MDH2) to reduce 2-OG into L-2-HG. Moreover, L2HGDH oxidizes L-2-HG back to 2-OG in the mitochondrial matrix without requiring a functional electron transport chain. Through proteome integral solubility alteration assays, we show that the KDM4 family of H3K9 demethylases are L-2-HG-responsive targets. L-2-HG represses the nascent transcription of specific genes in mouse embryonic stem cells and increases H3K9me3 (a repressive histone mark) at these loci. In vivo, early embryonic L2HGDH overexpression in mice systemically reduces L-2-HG levels, impairs postnatal growth, causes mortality and produces selective functional and histological renal vulnerabilities. In postnatal kidneys, this reduction in L-2-HG causes H3K9me3 loss at L1MdTf retrotransposons and their derepression, which coincides with the activation of the integrated stress response and inflammation pathways. Our findings establish mitochondrial L-2-HG as a physiological signalling metabolite and indicate that metabolites previously regarded as toxic may also have crucial physiological functions.

DOI: https://doi.org/10.1038/s41586-026-10564-x
bioRxiv. 2026 May 05. pii: 2026.05.01.718031. [Epub ahead of print]

Phosphoglycerate mutase 5 regulates lipid metabolism and mitochondrial homeostasis in hepatocellular cancer cells.

Praveen Kumar Guttula, Ganesan Muthusamy, Chin-Chi Liu, Priscilla Devora, Emi Sasaki, Tyler Butsch, Hasand Gandhi, James Moran, Manas Ranjan Gartia, Andrea N Johnston.

The mitochondrial membrane protein phosphoglycerate mutase 5 (PGAM5) is a protein of interest in the complex transition from hepatic steatosis to hepatocellular carcinoma. PGAM5 is a serine/threonine/histidine phosphatase that plays a role in mitochondrial biogenesis, mitophagy, and multiple cell death pathways. Increased expression of PGAM5 in hepatocellular carcinoma is correlated with reduced patient survival. In this study, we demonstrate that loss of PGAM5 alters the bioenergetic landscape of liver cancer by promoting mitochondrial oxidant injury and suppressing the glycerophospholipid and lysophospholipid pathways, leading to accumulation of the bioactive phospholipid lysophosphatidylcholine. Additionally, PGAM5 deletion downregulates fatty acid biosynthesis, resulting in reduced cellular diacylglycerol concentrations through two probable mechanisms: attenuated long chain fatty acid uptake and suppressed de novo synthesis. These findings underscore the broad impact of a single phosphatase on mitochondrial function and provide a rationale for therapeutically targeting PGAM5 to disrupt lipid metabolism in hepatocellular carcinoma.

DOI: https://doi.org/10.64898/2026.05.01.718031
Cancer Treat Res. 2026 ;195 155-174

Metabolic Reprogramming in Cancer Stem Cells.

Gaurav Ranjan, Srijani Dasgupta, Uttam Kumar Mishra, Priyashree Sunita, Shakti Prasad Pattanayak.

  Cancer stem cells (CSCs) are a subset of tumor cells that exhibit self-renewal, differentiation potential, and resistance to conventional therapies. One of the characteristic traits of CSCs is their metabolic flexibility, with the ability to adapt energy production and biosynthesis in the context of low oxygen, limited nutrients, and therapy-driven stress. This adaptability allows them to survive, advances tumor development, and results in relapse after treatment.CSCs can switch between glycolysis and oxidative phosphorylation (OXPHOS) dynamically in different biological contexts. CSCs mainly produce ATP and synthesize nucleotides, amino acids, and lipids through glycolysis in hypoxia. OXPHOS is important for the maintenance of quiescent cells, for reducing reactive oxygen species (ROS) production, and supports long-term survival and tumor initiation. In addition to glucose, CSCs utilize lipid and amino acid metabolism. Fatty acid oxidation provides energy during stress, while glutamine, serine, and glycine support biosynthesis, redox homeostasis, and epigenetic control, collectively enhancing survival and therapy resistance. CSCs also rely on lipid and amino acid metabolism, in addition to glucose. Fatty acid oxidation is a source of energy during stress, and glutamine-, serine-, and glycine-derived metabolic products contribute to promoting biosynthesis for redox homeostasis, epigenetic regulation, and survival/therapy resistance. The tumor microenvironment (TME) dictates CSCs' metabolism through cross talk with fibroblasts, immune cells, and components of the extracellular matrix. Metabolic interplay, e.g., reverse Warburg effect, allows CSC to consume stromal metabolites, facilitating the promotion of tumor and resistance to therapy. Targeting of CSC metabolism, via glycolytic and mitochondrial inhibitors, lipid metabolism originated blockers, or amino acids modulators can perturb the survival of CSCs and increase tumor sensitivity to classical therapies. In this aspect, the application of combinatorial therapy was able to provide additional benefit by addressing both proliferative and quiescent CSC.In conclusion, metabolic reprogramming underpins CSC survival, drives therapy resistance, and promotes tumor progression. Exploiting these metabolic adaptations provides a promising strategy for achieving long-lasting and effective cancer therapies.

Keywords:  Cancer stem cells; Glycolysis; Metabolic reprogramming; Metabolic targeting; Reverse Warburg effect; Tumor microenvironment

DOI:  https://doi.org/10.1007/978-3-032-21861-2_8
Haematologica. 2026 May 21.

Overcoming metabolic plasticity and microenvironmental rescue when targeting SLC25A1 in acute myeloid leukemia. Comment on: "SLC25A1 reprograms mitochondrial and fatty acid metabolism to promote the progression of acute myeloid leukemia".

Ruijie Li, Zhenghe Liu, Xuan Wu.

Not available.

DOI: https://doi.org/10.3324/haematol.2026.301161
Front Pharmacol. 2026 ;17 1797291

Overcoming resistance in lung cancer: combined mitochondrial destabilization by lipophilic cations and doxycycline in hypoxic non-small cell lung carcinoma.

Mabel Catalán, Denny Vidal, Alfredo Molina-Berríos, Javiera Carrasco-Rojas, Rodrigo López-Muñoz, Gisella Vásquez, Ivonne Olmedo, José A Jara.

   Introduction: Lung cancer remains the leading cause of cancer-related mortality worldwide. Drug resistance is a major limitation of current therapies, prompting the search for new treatment strategies. Lung tumors frequently develop a hypoxic microenvironment associated with aggressive behavior and unfavorable clinical outcomes. Tumor-initiating cells (TICs), also known as cancer stem cells, and hypoxia-driven metabolic adaptations contribute significantly to therapy resistance. Mitochondrial destabilization has emerged as a promising invariant target in TICs. Triphenylphosphonium (TPP+)-conjugated hydroxybenzoates selectively accumulate in the mitochondrial matrix, driven by membrane potential, disrupting organelle function. Additionally, doxycycline inhibits mitochondrial biogenesis and reduces mitochondrial mass. Here, we evaluate a therapeutic strategy combining TPP+-conjugated lipophilic cations with doxycycline to target mitochondrial vulnerability in non-small cell lung cancer.
Methods: TPP+ lipophilic cations conjugated to benzoate derivatives, alone or combined with doxycycline, were evaluated for their ability to disrupt mitochondrial function, reduce cell viability, and induce apoptosis in two lung cancer cell lines under normoxic and hypoxic conditions.
Results: Our results demonstrate that these compounds exhibit cytotoxicity in lung cancer cells, particularly under hypoxic conditions, consistent with mitochondrial functional impairment. Combinations of TPP+C10/doxycycline and GA-TPP+C10/doxycycline exhibited synergistic cytotoxicity in both normoxia and hypoxia, and increased apoptotic cell death compared to monotherapies.
Conclusion: Targeting mitochondrial functions using mitochondria-directed compounds, particularly in combination with doxycycline, represents a promising therapeutic approach for lung cancer. This strategy may be especially effective in hypoxic microenvironments, where conventional therapies often fail. Further in vivo validation is warranted to support the translational potential of this approach.

Keywords:  cancer treatment; doxycycline; drug combination; lipophilic cations; non-small cell lung carcinoma; targeting mitochondria

DOI:  https://doi.org/10.3389/fphar.2026.1797291
Angew Chem Int Ed Engl. 2026 May 20. e7158257

Mitochondria-Targeting Moieties Based on N-Tethered Pyridinium Cations.

Ivan Džajić, Natalija Trunkelj, Jernej Repas, Maša Kandušer, Lara Smrdel, Stane Pajk, Lovro Žiberna, Irena Mlinarič-Raščan, Bostjan Markelc, Tim Bozic, Masa Omerzel, Tanja Jesenko, Maja Cemazar, Katja Kološa, Bojana Žegura, Miha Virant, Matic Lozinšek, Hai M Nguyen, Joshua A Nasburg, Heike Wulff, Maxime Gueguinou, Valerije Vrček, Veronica Carpanese, Ildiko Szabo, Luis A Pardo, Tihomir Tomašič, Lucija Peterlin Mašič, Andrej Emanuel Cotman.

  Mitochondria-targeting moieties (MTMs) are molecular fragments designed to deliver covalently tethered functional cargo to mitochondria, providing a modular strategy for chemical biology tools, imaging agents, and mitochondria-targeted therapies. Phosphonium- or nitrogen cation-based MTMs are not inert vectors and exhibit intrinsic bioactivity on mitochondrial and cellular levels to various extents. Here, we systematically evaluated a panel of N+-based cations to determine how structural features influence subcellular distribution and inherent bioactivity. Live-cell imaging of fluorescent dye conjugates revealed that 3,5-diphenylpyridinium (DPPy+) exhibits cellular uptake and mitochondrial targeting comparable to the benchmark triphenylphosphonium (TPP+), whereas conjugates with unsubstituted pyridinium preferentially accumulate in lysosomes. Profiling of inert cargo derivatives showed that DPPy+ has lower intrinsic activity on mitochondrial membrane potential and oxidative phosphorylation, as well as on cellular respiration and viability than TPP+. The combination of efficient mitochondrial delivery and low intrinsic bioactivity translated to bioactive cargo: a Kv1.3 inhibitor conjugate with DPPy+ induced apoptosis in cancer cell lines and demonstrated improved cancer selectivity relative to the TPP+ conjugate in pancreatic organoid models. These results position lipophilic pyridinium cations as effective TPP+ surrogates with enhanced biocompatibility for mitochondria-targeted therapeutic and diagnostic agents, while revealing the structure-dependent competing lysosomal accumulation of permanent nitrogen cations.

Keywords:  cancer; cations; fluorescent probes; medicinal chemistry; mitochondria

DOI:  https://doi.org/10.1002/anie.7158257
Blood Cancer Discov. 2026 May 18.

Rapid Transcription Dynamics Confers Cytarabine Resistance in Acute Myeloid Leukemia.

Goichi Tatsumi, Rajni Kumari, Yutaro Suzuki, Shuting Li, Russell Scharf, Samuel J Taylor, Sriram Sundaravel, Amit Verma, Justin C Wheat, Ulrich Steidl.

Chemotherapy resistance remains a critical challenge in the treatment of patients with cancer, including acute myeloid leukemia (AML). While genetic alterations can contribute to resistance, the role of rapid-adaptive non-genetic mechanisms, particularly transcription dynamics, remains poorly understood. Here, we demonstrated that short-term treatment of AML cells with the widely used chemotherapeutic cytarabine (AraC) leads to the rapid emergence of a cell population with significant RNA induction and increased AraC resistance in cell lines and primary patient samples. Mechanistically, transcriptomic and targeted high-resolution analysis of transcription dynamics using single-molecule RNA FISH revealed rapid induction of transcriptional dynamics and upregulation of key transcription factors (TFs) - which we term "AraC rapid response TFs". Functionally, short-term pre- and co-treatment with RNA transcription inhibitors suppressed chemotherapy-induced RNA induction and prevented resistance acquisition in vitro and in vivo. Furthermore, CRISPR-mediated suppression of TFs PU.1 and GATA1 significantly attenuated AraC resistance. Our findings reveal a role of rapid-adaptive transcriptional dynamics in AML chemotherapy resistance.

DOI: https://doi.org/10.1158/2643-3230.BCD-25-0317