bims-mibica 2026-08-30 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–08–30
sixteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Rebalancing mitochondrial dynamics restores succinate dehydrogenase activity and reduces succinate release in hepatocellular carcinoma.
Cheminformatic identification of small molecules targeting acute myeloid leukemia.
Dimethyl Fumarate Enhances Venetoclax-Induced Cell Death by Inhibiting Mitochondrial Respiration and Cell Cycle Control in Colorectal Cancer.
Age-Associated NAD+ Decline and Mitochondrial Dysfunction Predispose Cells to a Reversible Tumor-Permissive Metabolic State.
Mitochondrial Cristae as Separate Compartments: Linking Organization and Function.
The molecular mechanisms of crista formation: how mitochondria give themselves breathing room.
The molecular basis of mitochondrial crista formation by the MIC10 complex.
USP16 promotes osteosarcoma progression by stabilizing ESRRA to enhance mitochondrial oxidative phosphorylation.
Oxidative Phosphorylation and Fatty Acid Oxidation Are Central to Mitochondrial Metabolism Rewiring in CML Stem/Progenitor Cell Survival.
Phosphoglycerate mutase 5 regulates lipid metabolism and mitochondrial homeostasis in hepatocellular cancer cells.
Mitochondrial NAD+ determines the metabolic capacity for liver regeneration.
Circulating cell-free mitochondrial DNA as a redox-associated marker of mitochondrial homeostasis disruption during gastric carcinogenesis.
Oxaloacetate damages mitochondria by perturbing MIC60-dependent membrane remodeling.
Mitochondria as central regulators of cancer progression and antitumor immunity.
Genome-wide CRISPR screens identify an RXR-MYLIP-LDLR axis regulating BH3 mimetic sensitivity in peripheral T-cell lymphomas.
The Dysregulation of the Integrated Stress Response in Leukemic Stem Cells as a Marker of Treatment Sensitivity in Acute Myeloid Leukemia.

J Biomed Sci. 2026 Aug 27. pii: 86. [Epub ahead of print]33(1):

Rebalancing mitochondrial dynamics restores succinate dehydrogenase activity and reduces succinate release in hepatocellular carcinoma.

Jing-Yiing Wu, Tzu-Ching Chang, Mei-Jen Chen, Shih-Han Cho, Jun-Yang Liou, Cheng-Chin Kuo, Kenneth K Wu.

   BACKGROUND: Dysregulated mitochondrial dynamics in cancer cells perturbs mitochondrial function and metabolism and promotes cancer progression. Its impacts on the electron transport chain, oxidative phosphorylation, redox balance, and glycolysis are well recognized. However, its influence on tricarboxylic acid (TCA) cycle activity is less clear. In this study, we hypothesized that excessive mitochondrial fragmentation suppresses the expression of succinate dehydrogenase (SDH), resulting in the accumulation and secretion of succinate.
METHODS: We tested this hypothesis in human hepatocellular carcinoma (HCC) cell model, murine xenograft tumor model, human HCC tumor tissues, and serum samples from patients with HCC. Genetic suppression and pharmacological inhibition of dynamin-related protein 1 (Drp1) were employed to examine their effects on SDH expression and succinate levels. The effects of Mdivi-1, a pharmacological inhibitor of Drp1-mediated mitochondrial fission, were evaluated in the xenograft tumor model, and the impact of succinate on mitochondrial dynamics was assessed in Huh7 cells.
RESULTS: The results reveal imbalance of mitochondrial fission and fusion proteins and increase in mitochondrial fragmentation which was associated with reduced expression of SDH and increased succinate. Succinate dehydrogenase B subunit (SDHB) mRNA levels were reduced in human HCC tumor tissues, and higher SDHB expression was associated with improved overall and relapse-free survival. Serum succinate levels were increased in patients with HCC. Genetic suppression and pharmacological inhibition of Drp1 resulted in restoration of SDH and reduction of succinate. Administration of Mdivi-1 reduced tumor growth and lung metastasis in the xenograft tumor model, which was associated with reduced p-Drp1 and increased SDHB. Addition of succinate to Huh7 cells enhanced Drp1-mediated mitochondrial fragmentation while succinate antibodies abrogated it. Overexpression of SDHB in Huh7 cells suppressed Drp1 activation and mitochondrial fragmentation through reduction of succinate. By contrast, SDHB silencing with SDHB siRNA enhanced Drp1 activation and mitochondrial fragmentation. These results suggest a positive feedback regulation of mitochondrial fragmentation by SDH/succinate.
CONCLUSIONS: These findings indicate that the mitochondrial fragmentation-SDH-succinate regulatory loop plays an important role in HCC growth and metastasis and may represent a potential target for new drug development.

Keywords:  Cancer metabolism; Dynamin-related protein 1; Hepatocellular carcinoma; Mitochondrial dynamics; Succinate; Succinate dehydrogenase

DOI:  https://doi.org/10.1186/s12929-026-01289-0
Leukemia. 2026 Aug 27.

Cheminformatic identification of small molecules targeting acute myeloid leukemia.

Megan R Daneman, Bernadetta Meika, Lois Armendariz, Elissa Tjahjono, Alexey V Revtovich, Leonid A Stolbov, Natthakan Thongon, Natalia Baran, Scott R Gilbertson, Vladimir V Poroikov, Natalia V Kirienko.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor prognosis and high relapse rates when treated with cytotoxic chemotherapeutics. Previously, we identified a family of small molecules that modulate mitochondrial function, referred to as PS127-family compounds. These drugs were selectively toxic to AML and were characterized by two predicted functions: apoptotic agonism and thioredoxin/glutathione reductase inhibition. Here, we uncovered a third critical predicted function, autophagic induction. Using a cheminformatic screen of ~4.2 million compounds for molecules with high predicted probability for all three functions, we found and validated hits that selectively killed AML cells, activated apoptosis, were dependent upon autophagic activation, and compromised glutathione metabolism by interfering with glutathione reductase, all of which are consistent with predictions. Compound treatment increased pools of cytosolic and mitochondrial ROS, decreased oxygen consumption, and reduced ATP synthesis. Structurally unrelated compounds caused the same phenotypes, validating our approach of screening for predicted function. Finally, we also observed strong synergy between these compounds and midostaurin and venetoclax, underscoring their therapeutic potential. Key phenotypes, including the compounds' impact on glutathione metabolism and synergy with doxorubicin and midostaurin, were confirmed in AML-patient-derived primary cells, validating the potential of these compounds for the development of future AML treatments.

DOI: https://doi.org/10.1038/s41375-026-03104-z
Life (Basel). 2026 Jul 28. pii: 1250. [Epub ahead of print]16(8):

Dimethyl Fumarate Enhances Venetoclax-Induced Cell Death by Inhibiting Mitochondrial Respiration and Cell Cycle Control in Colorectal Cancer.

Simon Wagner, Anne Schroeder, Sara Martina Steinmann, Claudia Kunst, Kirstin Pollinger, Manuela Gunckel, Elisabeth Aschenbrenner, Martina Müller, Karsten Gülow.

  Colorectal cancer (CRC) is a leading cause of cancer death, with resistance and apoptosis evasion-often via Bcl-2-representing major challenges. The redox-modulating drug dimethyl fumarate (DMF) has demonstrated efficacy in hematologic malignancies; however, its potential in solid tumors remains unclear. Here, we show that DMF, especially in combination with the Bcl-2 inhibitor venetoclax (ABT-199), induces apoptosis in HCT-116 CRC cells. DMF impairs mitochondrial respiration, causing membrane hyperpolarization, ATP depletion, autophagy, and cell cycle arrest. Combined treatment increases metabolic stress, reduces proliferation, and induces sustained G2 arrest with downregulation of cyclins and CDKs. These findings highlight a combined effect targeting redox balance and apoptosis in CRC. Given their clinical availability, DMF and ABT-199 represent a promising combination for further preclinical evaluation.

Keywords:  Venetoclax (ABT-199); apoptosis; autophagy; cell cycle; dimethyl fumarate (DMF); metabolism

DOI:  https://doi.org/10.3390/life16081250
Biology (Basel). 2026 Aug 21. pii: 1443. [Epub ahead of print]15(16):

Age-Associated NAD+ Decline and Mitochondrial Dysfunction Predispose Cells to a Reversible Tumor-Permissive Metabolic State.

Bibi Amina, Zainab Nasir, Rida Nasir Butt, Ashar Alban Chanan-Khan, Safee Ullah Chaudhary.

  Age-associated mitochondrial decline reduces NAD+ availability, impairs oxidative phosphorylation (OXPHOS), and leads to accumulation of reactive oxygen species (ROS) thereby reshaping cellular metabolism. However, the regulatory logic coupling mitochondrial aging to metabolic dysregulation resulting in tumorigenic cell-fate transitions has not been modeled systematically. In this work, we propose a Boolean biomolecular network model of mitochondrial aging and integrate it with metabolic, cell-cycle, and apoptotic biomolecular networks comprising 94 nodes and 370 edges. We then examined how NAD+ decline, hypoxia and extracellular ROS shifts the balance between OXPHOS and glycolysis. To this end, the consolidated network model underwent dynamical analysis to elucidate the system-level outcomes as well as its molecular triggers. In particular, we investigated whether the metabolic phenotypes are reversible and how cancer-driver perturbations act in the absence of extracellular pyruvate. The model recapitulates a quiescent, OXPHOS-leaning baseline and predicts that progressive NAD+ decline lowers OXPHOS propensity (0.686 to 0.186) while raising glycolysis (0.256 to 0.426). Hypoxia and extracellular ROS synergize glycolytic and hybrid oxidative-glycolytic (W/O) states. Furthermore, these two triggers, together with elevated mitogenic signaling, give rise to a hyperproliferative, glycolytic, and apoptosis-resistant cellular state. Interesting, this state is conditionally reversible wherein receptor tyrosine kinase (RTK) inhibition redirects this cell fate toward apoptosis and collapses the W/O state. Cancer-driver analysis further indicates that, without extracellular pyruvate, VHL loss and RAS, PI3K, or AKT activation preferentially stabilizes glycolytic and hybrid states. Age-resolved TCGA-BRCA analysis provided expression-level support for the predicted remodeling, with declining OXPHOS-associated expression and concurrent OXPHOS/glycolysis activity in older Basal-like tumors. Together, our results show that mitochondrial aging is a priming condition whose tumor-permissive metabolic output is gated by microenvironmental and nutrient inputs. The model provides a novel framework for evaluating age-associated metabolic reprogramming and predicting early tumorigenic cell fates.

Keywords:  Warburg effect; aerobic glycolysis; metabolic plasticity; metabolic reprogramming; mitochondrial aging; tumorigenesis

DOI:  https://doi.org/10.3390/biology15161443
Curr Issues Mol Biol. 2026 Aug 04. pii: 792. [Epub ahead of print]48(8):

Mitochondrial Cristae as Separate Compartments: Linking Organization and Function.

Alexander V Panov, Semen V Nesterov, Lev S Yaguzhinsky.

  Traditional bioenergetic paradigms historically relied on classical equilibrium thermodynamics to calculate mitochondrial kinetics, often overlooking the non-equilibrium processes dictated by complex structural architecture. Recent discoveries fundamentally challenge these outdated views by demonstrating that the inner mitochondrial membrane is strictly segregated into distinct functional domains, where individual cristae operate as autonomous, ultra-confined nanocompartments, where the transport of metabolites and protons is tightly controlled by ultrastructure-assisted electric and entropic effects. Compartmentalization prevents proton dissipation, allows for the rapid generation of a localized proton motive force optimized for efficient ATP synthesis and provides robust functional redundancy against localized membrane damage. Furthermore, recognizing cristae as isolated microspaces resolves the long-standing paradox of mitochondrial nicotinamide adenine dinucleotide transhydrogenase (TH). We describe a multi-stage transport pipeline-the TH-isocitrate dehydrogenase axis-wherein matrix-generated reducing equivalents are exported into the cytoplasm via an irreversible isocitrate/α-ketoglutarate loop. This universal pipeline continuously supplies uncommitted NADPH for biosynthesis, systemic antioxidant defense and detoxification. We also highlight the role of compartmentalization in ATP transport and utilization processes. Consequently, disruptions to cristae compartmentalization emerge as primary pathogenic drivers in ischemic, neurodegenerative, and cardiovascular diseases.

Keywords:  NADPH transport; NADPH-isocitrate dehydrogenases; cellular bioenergetics; microcompartmentalization; mitochondrial cristae; nonequilibrium thermodynamics; proton motive force; transhydrogenase

DOI:  https://doi.org/10.3390/cimb48080792
Biochem Soc Trans. 2026 Sep 23. 54(9): 1155-1167

The molecular mechanisms of crista formation: how mitochondria give themselves breathing room.

Lilia Colina-Tenorio, Martina Bohuslavová, Alexander W Bruce, Hassan Hashimi.

  Cristae are mitochondrial subcompartments that give the organelle its distinctive appearance. More significantly, mitochondria are the proverbial powerhouses as cristae house the molecular machinery underlying cellular respiration, a process that converts carbon sources into ATP by chemiosmosis. The form of cristae is invariably connected to their bioenergetic function. Here, we review our current understanding of the molecules underpinning crista formation. Not surprisingly, respiratory chain multiprotein complexes are involved in crista formation, with F1FO-ATP synthase dimers being eminent membrane sculptors. But crista formation also requires factors that are not directly part of the respiratory chain. The most ancient is the MICOS complex, which delineates the subcompartment and acts as a hub for crista biogenesis. The mitochondrial inner membrane (IM), from which cristae emerge, is remodelled by different dynamin-related proteins in animals and fungi. Cardiolipin is an integral component of the membranous fabric of the IM. To begin to grasp general design principles underlying crista formation, we synthesize findings from canonical animal and yeast experimental models with those from diverse protists and other eukaryotes. However, how these molecules are orchestrated during crista formation remains a hidden piece in our understanding of how cells differentiate in specialized forms. We highlight the few knowns about crista formation in a handful of organisms to guide research into the many unknowns about how complex subcompartments represented by mitochondrial cristae are formed.

Keywords:  ATP synthase; MICOS; cristae; dynamin-related protein; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1042/BST20260167
Sci Adv. 2026 Aug 28. 12(35): eaee8657

The molecular basis of mitochondrial crista formation by the MIC10 complex.

Chelsea M Brown, Tsjerk A Wassenaar, Zachary Freyberg, Siewert J Marrink.

Mitochondrial cristae are essential for respiration, yet the molecular basis of how the high curvature of these membrane folds is maintained remains unclear. Using structure prediction tools and multiscale simulations, we examined the role of the MIC10 subcomplex of the mitochondrial contact site and cristae organizing system (MICOS). We found that the MIC10 proteins Mic10, Mic26, and Mic27 strongly recruit cardiolipin at conserved positive loop motifs, driving oligomerization of these subunits and resulting in the stabilization of curvature in model membranes. Reconstruction of the full MIC10 complex in a realistic crista junction setup shows its capability to maintain membrane bending, while intrinsically disordered regions may form a permeability barrier between cristae and the intermembrane space. These findings provide a mechanistic model for cristae curvature formation and suggest how MICOS components cooperate with cardiolipins to maintain mitochondrial architecture.

DOI: https://doi.org/10.1126/sciadv.aee8657
Biochem Biophys Res Commun. 2026 Aug 24. pii: S0006-291X(26)01237-4. [Epub ahead of print]834 154473

USP16 promotes osteosarcoma progression by stabilizing ESRRA to enhance mitochondrial oxidative phosphorylation.

Zhonglun Liu, Xuan Liu, Yifan Gao, Bolun Song.

  Osteosarcoma is a highly aggressive primary bone malignancy, yet the underlying mechanisms driving its metabolic reprogramming remain incompletely understood. In this study, we identified ubiquitin-specific protease 16 (USP16) as a critical oncogenic driver in osteosarcoma. Bioinformatics analysis showed that USP16 was markedly upregulated in osteosarcoma tissues and predicted poor patient prognosis. Functional assays revealed that USP16 depletion significantly suppressed osteosarcoma cell proliferation and colony formation in vitro, as well as subcutaneous xenograft tumor growth in vivo, accompanied by the downregulation of cell cycle regulators. Conversely, USP16 overexpression promoted cell proliferation. Seahorse extracellular flux analysis demonstrated that USP16 depletion drastically impaired mitochondrial oxygen consumption rate (OCR) and oxidative phosphorylation (OXPHOS) parameters. Mechanistically, USP16 sustained mitochondrial respiration by deubiquitinating and stabilizing estrogen-related receptor alpha (ESRRA). Crucially, ectopic expression of ESRRA in USP16-knockout cells effectively rescued the suppressed cell proliferation and mitochondrial respiratory defects, whereas pharmacological inhibition of OXPHOS abolished USP16-induced hyperproliferation. Collectively, our findings demonstrate that USP16 drives osteosarcoma progression by orchestrating ESRRA-mediated mitochondrial OXPHOS, highlighting the USP16/ESRRA deubiquitination axis as a promising therapeutic target.

Keywords:  ESRRA; Mitochondrial respiration; Osteosarcoma; Oxidative phosphorylation; USP16

DOI:  https://doi.org/10.1016/j.bbrc.2026.154473
Pathophysiology. 2026 Aug 06. pii: 56. [Epub ahead of print]33(3):

Oxidative Phosphorylation and Fatty Acid Oxidation Are Central to Mitochondrial Metabolism Rewiring in CML Stem/Progenitor Cell Survival.

Jelena Milenkovic, Dijana Stojanovic, Branka Djordjevic, Sanja Velickovic, Vladana Stojiljkovic, Milica Veljkovic, Maja Milojkovic.

  Background/Objectives: Quiescent leukemia stem cells (LSCs) are self-renewing, pluripotent cells that present a major obstacle to the successful curative treatment of chronic myeloid leukemia (CML). LSCs function independently of BCR::ABL1 signaling and persist following tyrosine kinase inhibitor treatment. The mechanisms enabling LSC survival are a central focus of current CML research. This review details the complex relationship between signaling pathways and discusses recent advancements in energy metabolism research within the pathogenesis of CML. Discussion: Energy metabolism is critical to the biology of CML LSCs. These cells depend on oxidative phosphorylation (OXPHOS) and mitochondrial homeostasis, utilizing fatty acid oxidation as their primary ATP source. Research highlights significant alterations in signaling networks, marked by a dynamic interplay among dominant pathways within the CML clone. While TGF-β-FOXO signaling maintains the self-renewal capacity of quiescent LSCs, proliferating mature CML cells rely heavily on glycolysis and the PI3K/Akt pathway. Furthermore, unique metabolic traits of LSCs underscore the impact of leukemic cell-microenvironment interactions in fostering a permissive niche. Conclusions: Fatty acid oxidation is critical to the survival and self-renewal of CML LSCs. This adaptation of mitochondrial function is closely linked to signaling alterations and entails an adjustment of mitochondrial respiration alongside stimulated OXPHOS. Emerging research unveils many potential targets within metabolic signaling that can be exploited to overcome these survival mechanisms, highlighting the disruption of mitochondrial energy support as a promising strategy to selectively eradicate CML LSCs.

Keywords:  autophagy; free fatty acid; leukemia stem cell; lysophospholipids; oxidative phosphorylation; transforming growth factor beta

DOI:  https://doi.org/10.3390/pathophysiology33030056
Cell Signal. 2026 Aug 22. pii: S0898-6568(26)00491-2. [Epub ahead of print]148 112833

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 transition from hepatic steatosis to hepatocellular carcinoma. Increased expression of PGAM5 in hepatocellular carcinoma correlates with reduced patient survival. Herein we demonstrate that loss of PGAM5 promotes mitochondrial oxidant injury and suppresses the glycerophospholipid and lysophospholipid pathways, leading to accumulation of the bioactive phospholipid lysophosphatidylcholine. Additionally, PGAM5 deletion reduces diacylglycerol concentrations by attenuating long-chain fatty acid uptake and suppressing its synthesis. These findings underscore the broad impact of a single phosphatase on mitochondrial function and provide a rationale for therapeutically targeting PGAM5 in hepatocellular carcinoma.

Keywords:  Diacylglycerol; Lysophosphatidylcholine; Mitochondrial metabolism; Sphingolipid

DOI:  https://doi.org/10.1016/j.cellsig.2026.112833
J Hepatol. 2026 Aug 25. pii: S0168-8278(26)02843-6. [Epub ahead of print]

Mitochondrial NAD+ determines the metabolic capacity for liver regeneration.

Panu K Luukkonen.

DOI: https://doi.org/10.1016/j.jhep.2026.08.003
Free Radic Biol Med. 2026 Aug 24. pii: S0891-5849(26)01048-8. [Epub ahead of print]256 257-270

Circulating cell-free mitochondrial DNA as a redox-associated marker of mitochondrial homeostasis disruption during gastric carcinogenesis.

Tie Zhao, Justice Afrifa, Yingwei Xue, Jing Chen, Yunlong Li, Dong Wang, Ting Yang, Xiao Liang, He Zhang, Shuaihang Pang, Mengdi Cai, Wayne A Schroder, Songbin Fu, Jingcui Yu.

  Circulating cell-free mitochondrial DNA (ccf-mtDNA) is an emerging non-invasive marker across cancers. Yet, in gastric cancer (GC), its relationship to tissue mtDNA content, oxidative remodeling and somatic mtDNA variants, and thus its basis in mitochondrial homeostasis, remains poorly defined. We analyzed 169 individuals: 70 GC patients, 29 with precancerous gastric lesions and 70 healthy controls. MtDNA copy number was measured by quantitative PCR, and plasma biomarkers of oxidative damage (8-hydroxy-2'-deoxyguanosine, 8OH-dG; 4-hydroxynonenal, 4HNE) and of antioxidant capacity (glutathione peroxidase-1, GPX-1) were measured by ELISA. MtDNA variants were identified by next-generation sequencing. In MKN-28 GC cells, mitochondrial transcription factor A (TFAM) was manipulated with lentiviral vectors to alter mtDNA content. The results showed that GC progression was accompanied by higher ccf-mtDNA, shifts in plasma oxidative damage and antioxidant markers, and accumulation of mtDNA variants, alongside lower mtDNA content in cancers than in adjacent tissues. In GC cells, lowering mtDNA content by TFAM silencing promoted the malignant phenotype and increased intracellular superoxide-related fluorescence. By multiplex immunohistochemistry, tissue markers of mitochondrial maintenance and mtDNA release declined without a rise in caspase-3. D-loop variants already present at the precancerous stage suggest early mitochondrial changes, whereas predicted deleterious coding variants affecting respiratory chain components were observed in GC tissues. These findings support a redox-associated model of mitochondrial homeostasis that links impaired mitochondrial maintenance, mtDNA instability, and ccf-mtDNA accumulation, and provide a tissue-anchored mechanistic basis for the circulating mtDNA changes detected by plasma-based approaches in GC.

Keywords:  Cell-free mitochondrial DNA; D-loop variant; Gastric cancer; Mitochondrial DNA copy number; Oxidative stress; TFAM

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.046
PLoS Biol. 2026 Aug 28. 24(8): e3003649

Oxaloacetate damages mitochondria by perturbing MIC60-dependent membrane remodeling.

Jie Zhang, Qian Shan, Xin Wang, Meijiao Li, Yang Yang, Mei Duan, Ruofeng Tang, Junxiang Zhou, Fengyang Wang, Yuehui Shi, Kai Jiang, Chonglin Yang.

Mitochondria catabolize nutrients by generating sequentially-ordered organic acid intermediates that are oxidized through the tricarboxylic acid cycle. Pathogenic accumulation of metabolic organic acids manifests as devastating organic acidemias/acidurias and other severe diseases, but the underlying mechanisms are largely unknown. Using unbiased C. elegans genetic screening, we here reveal that mutations in the phosphoenolpyruvate carboxykinases PCK-1 and PCK-2 cause buildup of oxaloacetate, a key tricarboxylic acid cycle intermediate, leading to severe mitochondrial damage. Depletion of mitochondrial GOT-2.1 or GOT-2.2, which catalyze oxaloacetate conversion to aspartate, also causes oxaloacetate accumulation and defective mitochondria with disrupted cristae. We demonstrate that oxaloacetate binds the MICOS complex subunit CHCH-3/MIC19 and inhibits its function of promoting IMMT-1/MIC60-dependent membrane shaping and remodeling. In mammalian cells, aberrant OAA buildup similarly causes mitochondrial impairment through MIC19 and MIC60. These findings not only provide important mechanistic insights into mitochondrial damage in the context of defective oxaloacetate metabolism, but also suggest therapeutic strategies for oxaloacetate-related mitochondriopathies.

DOI: https://doi.org/10.1371/journal.pbio.3003649
Trends Endocrinol Metab. 2026 Aug 26. pii: S1043-2760(26)00176-1. [Epub ahead of print]

Mitochondria as central regulators of cancer progression and antitumor immunity.

Aurora Gomez-Duran, Inmaculada Martínez-Reyes.

  Mitochondria coordinate metabolic and signaling pathways that influence cancer progression across multiple stages of the disease. Beyond supporting tumor growth, mitochondria contribute to metastatic dissemination and shape interactions between tumor and immune cells through diverse outputs, including metabolite production, redox regulation, and mitochondrial genome dynamics. In this review, we discuss how mitochondrial functions sustain cancer cell proliferation, regulate pathways that facilitate metastatic progression, and influence antitumor immunity. We further highlight emerging roles for mitochondrial DNA variation, intercellular mitochondrial transfer, and mitochondrial dysfunction in immune cell exhaustion and senescence. Finally, we discuss how these advances are revealing therapeutic opportunities to target mitochondrial pathways and enhance the efficacy of current cancer immunotherapies.

Keywords:  antitumor immunity; cancer metabolism; metastasis; mitochondria; mitochondrial genetics

DOI:  https://doi.org/10.1016/j.tem.2026.07.005
Oncogene. 2026 Aug 25.

Genome-wide CRISPR screens identify an RXR-MYLIP-LDLR axis regulating BH3 mimetic sensitivity in peripheral T-cell lymphomas.

Keito Yokoyama, Masahiro Chiba, Norio Takei, Keito Suto, Takashi Ishio, Hideki Goto, Tomoyuki Endo, Marshall E Kadin, Michiyuki Maeda, Masashi Watanabe, Shigetsugu Hatakeyama, Takanori Teshima, Yibin Yang, Masao Nakagawa.

BH3 mimetics are a promising class of drugs in hematologic malignancies, but their efficacy in peripheral T-cell lymphoma (PTCL) remains poorly understood. To identify genetic determinants of BH3 mimetic response, we performed a genome-wide CRISPR-Cas9 knockout screen in PTCL cell lines and identified MYLIP, an E3 ubiquitin ligase targeting the LDL receptor (LDLR), as a novel sensitizer to navitoclax. MYLIP deletion enhanced the cytotoxicity of navitoclax, venetoclax, and the BCL-XL-selective degrader DT2216 across multiple PTCL models. Mechanistically, MYLIP loss increased LDLR expression, promoted cholesterol uptake, and elevated apoptotic priming. Recombinant PCSK9, which facilitates LDLR degradation, reversed MYLIP knockout-induced sensitization, establishing a functional role for LDLR in BH3 mimetic response. We also identified the nuclear receptor RXRB as an upstream regulator of MYLIP; dual RXRA/RXRB depletion more effectively suppressed MYLIP, upregulated LDLR, and potentiated navitoclax cytotoxicity. In vivo, MYLIP-deficient xenografts showed enhanced tumor suppression with navitoclax treatment. Transcriptomic analyses of primary PTCL samples revealed reduced MYLIP expression in ALK-positive anaplastic large cell lymphoma and genetically defined subsets of nodal T follicular helper cell lymphomas. These findings uncover an RXR-MYLIP-LDLR axis that links cholesterol metabolism to apoptotic susceptibility, offering mechanistic insight into BH3 mimetic sensitivity in PTCL.

DOI: https://doi.org/10.1038/s41388-026-03970-y
Genes (Basel). 2026 08 14. pii: 954. [Epub ahead of print]17(8):

The Dysregulation of the Integrated Stress Response in Leukemic Stem Cells as a Marker of Treatment Sensitivity in Acute Myeloid Leukemia.

Giorgia Benedetta Dutti, Katia Mangialardi, Simona Rasola, Ludovico Sebastio, Francesco Tarantini, Cosimo Cumbo, Luisa Anelli, Antonella Zagaria, Nicoletta Coccaro, Angela Minervini, Giuseppina Tota, Immacolata Redavid, Maria Rosa Conserva, Pellegrino Musto, Francesco Albano.

  Acute myeloid leukemia (AML) persistence is sustained by leukemic stem cells (LSCs) that survive metabolic deprivation, oxidative stress, hypoxia, proteotoxic burden, and therapeutic pressure. The integrated stress response (ISR) has emerged as a central adaptive network in this process. Through phosphorylation of a subunit of eukaryotic initiation factor 2 (eIF2α) and selective translation of activating transcription factor 4 (ATF4), the ISR coordinates stress-responsive transcriptional programs that may either preserve cellular fitness or promote apoptotic commitment, depending on the intensity, duration, and biological context of activation. In AML, ATF4 occupies a critical position at the interface between stemness, metabolic adaptation, redox control, ferroptosis resistance, and treatment response. In primitive leukemic compartments, ISR-ATF4 signaling appears to support stress tolerance, amino acid metabolism, serine biosynthesis, autophagy, and leukemic persistence. At the same time, pharmacologic or sustained ISR activation may lower the apoptotic threshold by inducing pro-apoptotic mediators such as CHOP, PUMA, and NOXA, thereby modulating MCL-1 dependency and enhancing sensitivity to venetoclax-based strategies. Conversely, adaptive ISR signaling may promote resistance through mechanisms such as ATP-binding cassette subfamily B member 1 (ABCB1) enhancer activation and mitochondrial stress tolerance. This duality creates a therapeutic paradox: ISR-ATF4 signaling may need to be inhibited in adaptive, resistance-promoting states but amplified in apoptosis-permissive contexts. This review discusses the biological and therapeutic relevance of ISR-ATF4 dysregulation in AML and highlights the need for biomarkers capable of distinguishing adaptive ATF4 dependency from inducible apoptotic vulnerability.

Keywords:  ATF4; ISR; activating transcription factor 4; acute myeloid leukemia; integrated stress response

DOI:  https://doi.org/10.3390/genes17080954