bims-medica 2026-02-01 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–02–01
twenty-two papers selected by
Brett Chrest, Wake Forest University

Clinical Impact of Ketogenic Diet.
A metabolic basis for motor deficits in mice lacking BCKDK.
Mitochondrial succinate transport is required for cardiac ischemia/reperfusion injury.
OGDHL promotes prostate cancer progression and regulates neuroendocrine marker expression and nucleotide abundance.
The Function and Mechanism of OXCT1 in Tumor Progression as a Critical Ketone Body Metabolic Enzyme.
Comparison of changes in blood cells and hemostatic biomarkers in mouse xenograft models of acute myeloid leukemia and acute promyelocytic leukemia.
Acute ketone monoester ingestion increases monocyte lysine β-hydroxybutyrylation and plasma β-hydroxybutyrate amino acid conjugates in humans.
Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance.
Lactic Acid in Tumour Biology.
Off-target effects of mitochondrial oxidative phosphorylation inhibitors are common and can compromise the viability of cultured cells.
Carnivore Diet: A Scoping Review of the Current Evidence, Potential Benefits and Risks.
A Combined SIRT5 Activation and SIRT3 Inhibition Prevents Breast Cancer Spheroids Growth by Reducing HIF-1α and Mitophagy.
Mitochondrial protein carboxyl-terminal alanine-threonine tailing promotes human glioblastoma growth by regulating mitochondrial function.
Hematologic complications in patients exposed to poly-ADP ribose polymerase inhibitors.
Label-Free Electrochemical Detection of K-562 Leukemia Cells Using TiO2-Modified Graphite Nanostructured Electrode.
Restoration of Interaction Between Fatty Acid Oxidation and Electron Transport Chain Proteins In Vitro by Addition of Recombinant VLCAD.
Coenzyme Q10 supplementation raises plasma levels without improving mitochondrial function in older adults.
N-3 PUFAs Enhancing Chemotherapy Efficacy in Acute Myeloid Leukemia While Safeguarding Healthy Cells.
Hypomethylating agents plus venetoclax versus intensive chemotherapy in acute myeloid leukemia with chromosome 5 and 7 abnormalities.
The Role of Mitochondrial Ion Channels in the Evolution of Anticancer Drug Resistance.
Real-World Utilization of Midostaurin in Combination with Intensive Chemotherapy for Patients with FLT3 Mutated Acute Myeloid Leukemia: A Multicenter Study.
Energy-Rich Molecules and Group Transfer Potentials in Energetic Coupling Reactions.

Nutrients. 2026 Jan 13. pii: 245. [Epub ahead of print]18(2):

Clinical Impact of Ketogenic Diet.

Valentina Guarnotta.

During the last century, the ketogenic diet (KD) has gradually shifted from a specialized dietary therapy used almost exclusively in pediatric epilepsy to a metabolic intervention explored across several areas of clinical medicine [...].

DOI: https://doi.org/10.3390/nu18020245
J Nutr Biochem. 2026 Jan 24. pii: S0955-2863(26)00017-3. [Epub ahead of print] 110275

A metabolic basis for motor deficits in mice lacking BCKDK.

Lingyi Zhu, Isha Kinjawadekar, Caleb Prempeh, Inna A Nikonorova, Emily T Mirek, Esther M Lopez, William O Jonsson, Jordan L Levy, Lin Wang, Xiaoxuan Li, Yeva Shamailova, Timothy J Stanek, Elizabeth M Snyder, Piyawan Bunpo, Robert A Harris, Shawn M Davidson, Ronald C Wek, Tracy G Anthony.

  Branched-chain α-amino acids (BCAAs) support protein synthesis and their oxidation is restrained by branched-chain α-keto acid dehydrogenase kinase (BCKDK). We previously observed that in the brains of Bckdk knockout (KO) mice, BCAAs fall while glutamate is preserved and other amino acids rise. We asked why this profile emerges and how it affects skeletal muscle versus brain during nutrient stress. Motor behavior, protein synthesis and nutrient signaling were compared in the skeletal muscle and brains of wildtype (WT) and Bckdk KO male mice. In addition, nitrogen delivery into brain from BCAAs was assessed using stable isotope tracing and mass spectrometry imaging. Bckdk KO showed normal grip strength but poor beam traversal and reduced wheel running during protein restriction. In skeletal muscle, leucine or protein-feeding stimulated and fasting suppressed mechanistic target of rapamycin complex 1 (mTORC1) signaling in both genotypes. Fasting reduced muscle protein synthesis in both strains without activating the integrated-stress response (ISR). In contrast, Bckdk KO brains exhibited ISR activation during fasting, and up-regulation of Atf4 and its target genes, including Slc7a5 mRNA. Tracer studies revealed lower serum [15N]-BCAA enrichment and diminished incorporation of BCAA-derived nitrogen into brain glutamate in Bckdk KO mice, despite unchanged total glutamate. Thus, in the nongrowing adult constitutive BCKDH activation limits BCAA-derived nitrogen delivery to brain and alters AA transporters as part of an adaptive ISR during nutrient scarcity. This creates a vulnerability in brain not observed in skeletal muscle. These data provide a metabolic basis for poor motor performance in Bckdk KO mice.

Keywords:  BCAAs; BCKDK; ISR; MALDI imaging; glutamate; neuromuscular coordination; stable isotope tracing; transamination

DOI:  https://doi.org/10.1016/j.jnutbio.2026.110275
Cardiovasc Res. 2026 Jan 28. pii: cvag031. [Epub ahead of print]

Mitochondrial succinate transport is required for cardiac ischemia/reperfusion injury.

Laura Pala, María Torres-López, Stuart T Caldwell, Joyce Valadares, Emily M Smith, Katherine L Hammond, Olga Sauchanka, Jiro Abe, Thomas Krieg, Richard C Hartley, Michael P Murphy, Hiran A Prag.

   BACKGROUND: Succinate accumulates significantly during myocardial ischemia, and its rapid oxidation upon reperfusion is a critical driver of ischemia/reperfusion (I/R) injury. The transport of succinate across the mitochondrial inner membrane, particularly by the dicarboxylate carrier (DIC; SLC25A10), is hypothesized to play a crucial role in mediating these pathological succinate dynamics. However, tools to test this hypothesis by modulating mitochondrial succinate transport in biological systems are lacking.
METHODS AND RESULTS: C57BL/6J mice, isolated Wistar Rat heart mitochondria, bovine heart mitochondrial membranes, C2C12 mouse myoblasts and primary adult cardiomyocytes were used as in vitro and in vivo models. Butylmalonate prodrugs were synthesized and tested. Isolated mitochondria were used to assess succinate-dependent respiration and reactive oxygen species (ROS) production. Cells were treated with succinate dehydrogenase (SDH) inhibitors or exposed to anoxia and butylmalonate esters. Mouse hearts were subjected to in vivo left anterior descending coronary artery ligation. Succinate and butylmalonate levels were measured by targeted liquid chromatography-tandem mass spectrometry, and infarct size by TTC (2,3,5-triphenyl-2H-tetrazolium chloride) staining.Knockdown of DIC, but not of the oxoglutarate carrier OGC, in C2C12 cells prevented succinate accumulation by SDH inhibition and anoxia. The only extant DIC inhibitor butylmalonate, is limited by poor cell permeability. We synthesized diacetoxymethyl butylmalonate (DAB), which efficiently delivers butylmalonate intramitochondrially in isolated heart mitochondria and cells. DAB inhibited succinate-dependent respiration and ROS production. DAB prevented succinate accumulation in cells treated with SDH inhibitors. DAB delivered butylmalonate to cardiac mitochondria when administered to mice in vivo and reduced infarct size by perturbing mitochondrial succinate transport.
CONCLUSIONS: The DIC is a key node in the cellular distribution of succinate, controlling its transport between mitochondria and the cytosol. These findings highlight the potential of DIC as a promising therapeutic target for conditions where succinate elevation contributes to pathogenesis, such as cardiac I/R injury.

Keywords:  SLC25A10; Succinate; butylmalonate; ischemia/reperfusion injury; mitochondrial dicarboxylate carrier; mitochondrial transport; myocardial infarction

DOI:  https://doi.org/10.1093/cvr/cvag031
Mol Cancer Res. 2026 Jan 27.

OGDHL promotes prostate cancer progression and regulates neuroendocrine marker expression and nucleotide abundance.

Matthew J Bernard, Andrea Gallardo, Angel Ruiz, Johnny A Diaz, Nicholas M Nunley, Rachel N Dove, Shile Zhang, Ernie Lee, Kylie Y Heering, Grigor Varuzhanyan, Sachi Bopardikar, Takao Hashimoto, Raag Agrawal, Chad M Smith, Blake R Wilde, Nedas Matulionis, Helen M Richards, Sandy Che-Eun S Lee, Marina N Sharifi, Joshua M Lang, Shuang G Zhao, Owen N Witte, Michael C Haffner, David B Shackelford, Paul C Boutros, Heather R Christofk, Andrew S Goldstein.

As cancer cells evade therapeutic pressure and adopt alternate lineage identities not commonly observed in the tissue of origin, they likely adopt alternate metabolic programs to support their evolving demands. Targeting these alternative metabolic programs in distinct molecular subtypes of aggressive prostate cancer may lead to new therapeutic approaches to combat treatment-resistance. We identify the poorly studied metabolic enzyme Oxoglutarate Dehydrogenase-Like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme Oxoglutarate Dehydrogenase (OGDH), as an unexpected regulator of tumor growth, treatment-induced lineage plasticity, and DNA Damage in prostate cancer. While OGDHL has been described as a tumor-suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation. Loss of OGDHL reduces nucleotide synthesis, induces accumulation of the DNA damage response marker ƔH2AX, and alters Androgen Receptor inhibition-induced plasticity. Our data suggest that OGDHL has minimal impact on TCA cycle activity, and that mitochondrial localization is not required for its regulation of nucleotide metabolism. Finally, we demonstrate that OGDHL expression is tightly correlated with neuroendocrine differentiation in clinical prostate cancer, and that knockdown of OGDHL impairs growth of cell line models of neuroendocrine prostate cancer. These findings underscore the importance of investigating poorly characterized metabolic genes as potential regulators of distinct molecular subtypes of aggressive cancer. Implications: OGDHL emerged as an unexpected metabolic dependency associated with lineage plasticity and neuroendocrine differentiation, implicating poorly studied metabolic enzymes as potential targets for treatment-resistant prostate cancer.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-0913
Biomolecules. 2025 Dec 19. pii: 4. [Epub ahead of print]16(1):

The Function and Mechanism of OXCT1 in Tumor Progression as a Critical Ketone Body Metabolic Enzyme.

Wen Qin, Wenwei Hu, Yiting Geng.

  3-Ketoacid CoA-transferase 1 (OXCT1) is a homodimeric mitochondrial matrix enzyme essential for ketone body metabolism. It catalyzes the reversible transfer of coenzyme A from succinyl-CoA to acetoacetate, playing a central role in extrahepatic ketone body catabolism. Accumulating evidence indicates that OXCT1 is dysregulated in various cancers, where it functions as an oncogene, driving tumor progression by modulating proliferation, metastasis, apoptosis, autophagy, and drug resistance. Its overexpression is associated with aggressive tumor behavior, metabolic adaptation, and poor clinical outcomes. This review systematically summarizes the molecular structure, biological functions, and regulatory mechanisms of OXCT1, highlighting its multifaceted roles in tumorigenesis and progression. Furthermore, we discuss its potential as a diagnostic biomarker, prognostic indicator, and therapeutic target, providing novel insights for developing OXCT1-based anticancer strategies.

Keywords:  OXCT1; drug resistance; ketone body metabolism; metabolic reprogramming; tumor

DOI:  https://doi.org/10.3390/biom16010004
Res Pract Thromb Haemost. 2026 Jan;10(1): 103319

Comparison of changes in blood cells and hemostatic biomarkers in mouse xenograft models of acute myeloid leukemia and acute promyelocytic leukemia.

Sierra J Archibald, Ana T A Sachetto, Xingru Zhu, Radhika Gangaraju, Nigel Mackman, Yohei Hisada.

   Background: Leukemia patients have an increased risk of both thrombosis and bleeding due to a dysregulated hemostatic system. Levels of coagulation and fibrinolysis activation markers are increased, whereas levels of platelets and fibrinogen are decreased in leukemia patients. Mouse models can be used to study the pathways that contribute to coagulopathy in leukemia.
Objectives: To measure blood cells and hemostatic biomarkers in a mouse xenograft model of acute myeloid leukemia (AML) and compare them with a mouse xenograft model of acute promyelocytic leukemia (APL).
Methods: We established a mouse xenograft model of AML by injecting HL-60-Luc2 cells into NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ mice and monitored the growth of leukemic cells by measuring luciferase expression. Levels of blood cells and hemostatic biomarkers were measured in leukemic mice. The parameters of the AML model were compared with those of the APL model using NB4-Luc cells.
Results: AML mice exhibited an increase in white blood cells, an increase in a marker of coagulation activation (thrombin-antithrombin complexes), an increase in a marker of fibrinolysis activation (plasmin-antiplasmin complexes), and a decrease in platelets and fibrinogen compared with control mice. No increase in white blood cell counts was observed in APL mice. APL mice had significantly higher levels of thrombin-antithrombin complexes compared with AML mice.
Conclusion: These leukemia mouse models can be used to understand how the hemostatic system is dysregulated in leukemia.

Keywords:  coagulation; fibrinogen; fibrinolysis; leukemia; platelet

DOI:  https://doi.org/10.1016/j.rpth.2025.103319
Am J Physiol Cell Physiol. 2026 Jan 28.

Acute ketone monoester ingestion increases monocyte lysine β-hydroxybutyrylation and plasma β-hydroxybutyrate amino acid conjugates in humans.

Alexis Marcotte-Chénard, Roderick E Sandilands, Alexandre Abílio Teixeira, Seth F McCarthy, Maria Dolores Moya-Garzon, Emily Goldberg, Jonathan Z Long, Hashim Islam, Jonathan P Little.

  Endogenous ketosis during fasting can induce beta-hydroxybutyrylation of lysine residues on proteins (known as Kbhb) in human immune cells and increase circulating beta-hydroxybutyrate (BHB) amino acid conjugates, both of which are hypothesized to have functional physiological consequences. It remains unknown if similar modifications occur with acute consumption of an exogenous ketone monoester (KME) supplement ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate), which robustly increases circulating BHB. Thirteen healthy adults (7 females; 6 males, age: 28±7 y) consumed 0.750 g per kg body mass KME with blood samples collected before and after 2 h, coinciding with peak plasma BHB concentration. Monocytes (CD14+) were isolated by negative immunomagnetic selection for Kbhb assessment by immunoblotting. Plasma BHB-amino acid conjugates were quantified by mass spectrometry. Blood BHB concentration significantly increased after KME consumption (P< 0.0001), peaking at 2 h (5.0 ± 0.8 mmol/L). Compared to baseline, monocyte Kbhb was significantly increased after 2 h (~70% increase; P= 0.004). Plasma BHB-amino acid conjugates, including BHB-phenylalanine, -leucine, -valine and -methionine were also increased at 2 h (P< 0.0001). Changes in capillary blood BHB and BHB-amino acid concentrations were positively correlated (r≥ 0.58; P≤ 0.046), suggesting a dose-dependent increase. Acute high-dose KME ingestion increases monocyte lysine Kbhb and plasma BHB amino acid conjugates in healthy humans, highlighting the possible immunodulatory and systemic signaling effects of raising BHB through exogenous ketone supplementation.

Keywords:  BHB-phe; Kbhb; beta-hydroxybutyrate; blood pressure; ketosis

DOI:  https://doi.org/10.1152/ajpcell.00896.2025
Nat Aging. 2026 Jan 29.

Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance.

Masahiro Wakita, Koyu Ito, Kaho Fujii, Dai Sakamoto, Takumi Mikawa, Sho Sugawara, Xiangyu Zhou, Jeong Hoon Park, Hideka Miyagawa, Daisuke Motooka, Emi Ogasawara, Naotada Ishihara, Akiko Takahashi, Hiroshi Kondoh, Eiji Hara.

Cellular senescence contributes to aging and disease, and senolytic drugs that selectively eliminate senescent cells hold therapeutic promise. Although over 20 candidates have been reported, their relative efficacies remain unclear. Here we systematically compared 21 senolytic agents using a senolytic specificity index, identifying the Bcl-2 inhibitor ABT263 and the BET inhibitor ARV825 as most effective senolytics across fibroblast and epithelial senescence models. However, even upon extended treatment with these most potent senolytics, a proportion of senescent cells remained viable. We found that senolytic resistance was driven by maintenance of mitochondrial integrity through V-ATPase-mediated clearance of damaged mitochondria. Imposing mitochondrial stress via metabolic workload enhanced the senolytic efficacies of ABT263 and ARV825 in vitro, and in mouse models, ketogenic diet adoption or SGLT2 inhibition similarly potentiated ABT263-induced and ARV825-induced senolysis, reducing metastasis and tumor growth. These findings suggest that mitochondrial quality control is a key determinant of resistance to ABT263-induced and ARV825-induced senolysis, providing a possible framework for rational combination senotherapies.

DOI: https://doi.org/10.1038/s43587-025-01057-z
Metabolites. 2026 Jan 15. pii: 75. [Epub ahead of print]16(1):

Lactic Acid in Tumour Biology.

Cristina Cruz, Ignasi Barba.

  Lactic acid accumulates in the tumour microenvironment (TME) at concentrations reaching up to 40 mM. Initially, lactic acid was considered merely a metabolic by-product of aerobic glycolysis, a phenomenon commonly referred to as the Warburg effect and observed in the majority of tumours. Recent evidence, however, has demonstrated that lactic acid is not merely a waste product; rather, it plays a pivotal role in tumour biology. High plasma lactic acid levels correlate with increased metastatic potential and lower survival rates. Elevated lactic acid levels in the TME have been shown to suppress antitumour immune responses, facilitate both metastasis and cellular senescence, and might modulate gene expression through novel epigenetic mechanisms such as histone lactylation. This review aims to summarize current knowledge on the multifaceted impact of elevated lactic acid in the TME on tumour progression and biology.

Keywords:  Warburg effect; cancer; immune function; lactate; lactic acid; tumour microenvironment

DOI:  https://doi.org/10.3390/metabo16010075
Mitochondrial Commun. 2025 ;3 99-108

Off-target effects of mitochondrial oxidative phosphorylation inhibitors are common and can compromise the viability of cultured cells.

Natalya Kozhukhar, Mikhail F Alexeyev.

  Mitochondrial respiratory chain inhibitors (MRCIs) are indispensable for studying cellular bioenergetics and its effects on various cellular processes. However, their off-target (those not mediated by respiratory chain inhibition) effects remain incompletely understood, even though their comprehension is crucial for the accurate interpretation of experimental outcomes. Here, we use four isogenic cell line pairs, which either have mitochondrial DNA (mtDNA) or lack it (ρ+ or ρ0 cells, respectively), to assess the possible off-target effects of widely used MRCIs antimycin A, oligomycin A, rotenone, and carbonyl cyanide m-chlorophenylhydrazone (CCCP). We examined clonogenic growth of ρ0 cells and ρ+ cells under conditions that either require the functional respiratory chain or do not. Unexpectedly, ρ0 cells were sensitive to rotenone and antimycin A, even though these cells lack functional complex I and complex III, respectively, suggesting a nonspecific effect of these drugs. Furthermore, ρ0 cells were more sensitive to CCCP than their ρ+ counterparts. Intriguingly, the loss of the clonogenic potential in ρ+ 143B cells could not be precisely correlated to the decrement of the mitochondrial inner membrane potential. These findings underscore the significance of off-target effects of MRCIs, which must be carefully considered when designing, conducting, and interpreting experiments involving these inhibitors.

Keywords:  Antimycin A; Carbonyl cyanide m-chlorophenylhydrazone; Oligomycin A; Rho-0 cells; Rotenone

DOI:  https://doi.org/10.1016/j.mitoco.2025.12.001
Nutrients. 2026 Jan 21. pii: 348. [Epub ahead of print]18(2):

Carnivore Diet: A Scoping Review of the Current Evidence, Potential Benefits and Risks.

Almiera Lietz, Janina Dapprich, Tobias Fischer.

  Background: The Carnivore Diet (CD) is an almost exclusively animal-based dietary pattern that has gained increasing popularity on social media. Despite numerous health-related claims, a standardized definition is lacking, and scientific evidence regarding the long-term effects of this diet remains unclear. Methods: The literature search for this scoping review was conducted in accordance with PRISMA guidelines (PRISMA-ScR) using the databases PubMed, LIVIVO, Web of Science, and the Cochrane Library. Results: Nine human studies were included. Individual publications reported positive effects of the CD, such as weight reduction, increased satiety, and potential improvements in inflammatory or metabolic markers. At the same time, potential risks of nutrient deficiencies, particularly in vitamins C and D, calcium, magnesium, iodine, and dietary fiber, as well as elevated low-density-lipoprotein (LDL-) and total cholesterol (TC) levels, were identified, along with one case describing a deterioration in health status. Overall, the quality of evidence is very limited due to small sample sizes, short study durations, and the absence of control groups. Conclusions: The CD may offer short-term health benefits but carries substantial risks of nutrient deficiencies, reduced intake of health-promoting phytochemicals, and the development of cardiovascular disease. At this time, long-term adherence to a CD cannot be recommended.

Keywords:  LCHF; Lion Diet; cardiovascular risks; carnivore diet; ketogenic diet; microbiome; nutrient adequacy; plant-free diet; sustainability

DOI:  https://doi.org/10.3390/nu18020348
Pharmaceuticals (Basel). 2025 Dec 22. pii: 23. [Epub ahead of print]19(1):

A Combined SIRT5 Activation and SIRT3 Inhibition Prevents Breast Cancer Spheroids Growth by Reducing HIF-1α and Mitophagy.

Federica Barreca, Michele Aventaggiato, Mario Cristina, Luigi Sansone, Manuel Belli, Maria Beatrice Lista, Gaia Francisci, Sergio Valente, Dante Rotili, Antonello Mai, Matteo Antonio Russo, Marco Tafani.

  Background/Objectives: Metabolic reprogramming is an essential feature of tumors. Mitochondrial sirtuins SIRT3 and SIRT5 differently regulate glutamine metabolism with SIRT5 inhibiting glutaminase (GLS) and SIRT3 increasing glutamate dehydrogenase (GDH). Considering the important and interconnected role of glutamine, SIRT3 and SIRT5 for cancer growth and progression, our hypothesis is that a simultaneous modulation of SIRT3 and SIRT5 could represent a valid anti-tumoral strategy. Methods: wt and GLS1-silenced triple negative breast cancer spheroids were treated with 3-TYP, a selective SIRT3 inhibitor, and with MC3138, a new selective SIRT5 activator, both alone and in combination. The effects of such treatments on hypoxia, autophagy and mitophagy markers were determined by immunofluorescence and Western blot. Mitochondria morphology was studied by transmission electron microscopy (TEM) and mitochondrial ROS production by confocal analysis. Results: We observed that 3-TYP+MC3138 treatment decreased the size of spheroids by affecting HIF-1α, c-Myc, glutamine transporter SLC1A5 and autophagy (LC3II) and mitophagy (BNIP3) markers. Moreover, such treatments altered the morphology and conformation of the mitochondria. Finally, we also documented an increase in mitochondria reactive oxygen species (mtROS). Conclusions: The combined inhibition of SIRT3 and activation of SIRT5 greatly reduces the size of spheroids through the inhibition of hypoxic response, which is then followed by the alteration of the autophagic and mitophagic process and the toxic accumulation of mitochondrial ROS, representing a new anti-tumoral strategy.

Keywords:  autophagy; glutamine metabolism; mitophagy; sirtuins; triple negative breast cancer

DOI:  https://doi.org/10.3390/ph19010023
Elife. 2026 Jan 29. pii: RP99438. [Epub ahead of print]13

Mitochondrial protein carboxyl-terminal alanine-threonine tailing promotes human glioblastoma growth by regulating mitochondrial function.

Bei Zhang, Ting Cai, Esha Reddy, Yuanna Wu, Isha Mondal, Yinglu Tang, Adaeze Scholastical Gbufor, Jerry Wang, Yawei Shen, Qing Liu, Raymond Sun, Winson S Ho, Rongze Olivia Lu, Zhihao Wu.

  The rapid and sustained proliferation of cancer cells necessitates increased protein production, which, along with their disrupted metabolism, elevates the likelihood of translation errors. Ribosome-associated quality control (RQC), a recently identified mechanism, mitigates ribosome collisions resulting from frequent translation stalls. However, the precise pathophysiological role of the RQC pathway in oncogenesis remains ambiguous. Our research centered on the pathogenic implications of mitochondrial stress-induced protein carboxyl-terminal alanine and threonine tailing (msiCAT-tailing), a specific RQC response to translational arrest on the outer mitochondrial membrane, in human glioblastoma multiforme (GBM). The presence of msiCAT-tailed mitochondrial proteins was observed commonly in glioblastoma stem cells (GSCs). The exogenous introduction of the mitochondrial ATP synthase F1 subunit alpha (ATP5α) protein, accompanied by artificial CAT-tail mimicking sequences, enhanced mitochondrial membrane potential (ΔΨm) and inhibited the formation of the mitochondrial permeability transition pore (MPTP). These alterations in mitochondrial characteristics provided resistance to staurosporine (STS)-induced apoptosis in GBM cells. Consequently, msiCAT-tailing can foster cell survival and migration, whereas blocking msiCAT-tailing via genetic or pharmacological intervention can impede GBM cell overgrowth.

Keywords:  cancer biology; carboxyl-terminal alanine and threonine tailing; cell biology; glioblastoma; human; mitochondria; ribosome-associated quality control

DOI:  https://doi.org/10.7554/eLife.99438
Haematologica. 2026 Jan 29.

Hematologic complications in patients exposed to poly-ADP ribose polymerase inhibitors.

Joseph M Cannova, Muriel R Battaglia, Gregory W Roloff, Sinan Cetin, Michael Tallarico, Wendy Stock, Anand A Patel, Olatoyosi Odenike, Richard A Larson, Michael J Thirman, Mariam T Nawas, Peng Wang, Melissa Y Tjota, Jeremy P Segal, Girish Venkataraman, Adam S DuVall, Michael W Drazer.

Not available.

DOI: https://doi.org/10.3324/haematol.2025.288518
Biosensors (Basel). 2026 Jan 01. pii: 28. [Epub ahead of print]16(1):

Label-Free Electrochemical Detection of K-562 Leukemia Cells Using TiO2-Modified Graphite Nanostructured Electrode.

Martha Esperanza Sevilla, Rubén Jesús Camargo Amado, Pablo Raúl Valle.

  This manuscript presents the development of an electrochemical biosensor designed to detect K-562 chronic myeloid leukemia (CML) cells. The biosensor was made of highly oriented pyrolytic graphite (HOPG), functionalized with -OH and -COOH groups by surface etching with strong acids, and subsequently coated with modified titanium dioxide (TiO2-m). TiO2-m is TiO2 modified during its synthesis process using carbon nanotubes functionalized with -OH and -COOH groups. These changes improve the electron transfer kinetics and physicochemical properties of the electrode surface. TiO2-m improves the sensitivity and selectivity towards leukemic cells. The detection process involved three stages: cell culture, cell adhesion onto the TiO2-m electrode, and measurement of the electrochemical signal. Fluorescence microscopy and SEM-EDS confirmed cell adhesion and pseudopod formation on the TiO2-m surface, which is an important finding because K-562 cells are typically nonadherent. Cyclic voltammetry (VC) and differential pulse voltammetry (VDP) demonstrated rapid and sensitive detection of leukemic cells within the concentration range of 6250 to 1,000,000 cells/mL, achieving high reproducibility and strong linearity (R2 = 98%) with a detection time of 25 s. The VC and VDP demonstrated rapid and sensitive detection of leukemic cells over a concentration range of 6250 to 1,000,000 cells/mL, achieving adequate reproducibility and stable linearity (R2 = 98%), with a detection time of 25 s. These results indicate that the TiO2-m biosensor is a promising platform for the rapid and efficient electrochemical detection of leukemia cells.

Keywords:  TiO2-m electrodes; cancer; chronic myeloid leukemia; pyrolytic graphite

DOI:  https://doi.org/10.3390/bios16010028
Biomedicines. 2026 Jan 20. pii: 222. [Epub ahead of print]14(1):

Restoration of Interaction Between Fatty Acid Oxidation and Electron Transport Chain Proteins In Vitro by Addition of Recombinant VLCAD.

Yudong Wang, Gregory Varga, Meicheng Wang, Johan Palmfeldt, Shakuntala Basu, Erik Koppes, Andrew Jeffrey, Robert James Hannan, Grant Sykuta, Jerry Vockley.

  Background/Objectives: We have previously demonstrated that fatty acid oxidation (FAO) enzymes physically and functionally interact with electron transfer chain supercomplexes (ETC-SC) at two contact points. The FAO trifunctional protein (TFP) and electron transfer flavoprotein dehydrogenase (ETFDH) interact with the NADH+-binding domain of ETC complex I (com I) and the core 2 subunit of complex III (com III), respectively. In addition, the FAO enzyme very-long-chain acyl-CoA dehydrogenase (VLCAD) interacts with TFP. These interactions define a functional FAO-ETC macromolecular complex (FAO-ETC MEC) in which FAO-generated NADH+ and FADH2 can safely transfer electron equivalents to ETC in order to generate ATP. Methods: In this study, we use multiple mitochondrial functional studies to demonstrate the effect of added VLCAD protein on mutant mitochondria. Results: We demonstrate that heart mitochondria from a VLCAD knockout (KO) mouse exhibit disrupted supercomplexes, with significantly reduced levels of TFPα and TFPβ subunits, electron transfer flavoprotein a-subunit (ETFα), and NDUFV2 subunit of com I in the FAO-ETC MEC. In addition, the activities of individual oxidative phosphorylation (OXPHOS) enzymes are decreased, as is the transfer of reducing equivalents from palmitoyl-CoA to ETC (FAO-ETC flux). However, the total amount of these proteins did not decrease in VLCAD KO animals. These results suggest that loss of VLCAD affects the interactions of FAO and ETC proteins in the FAO-ETC MEC. Reconstitution of VLCAD-deficient heart mitochondria with recombinant VLCAD improved the levels of FAO-ETC MEC proteins and enzyme activities, as well as restoring FAO-ETC flux. It also reduced mitochondrial ROS levels, previously demonstrated to be elevated in VLCAD-deficient mitochondria. In contrast, incubation of VLCAD KO mitochondria with two VLCADs with mutations in the C-terminal domain of the enzyme (A450P and L462P) did not restore FAO-ETC MECs. Conclusions: These results suggest that VLCAD is a necessary component of the FAO-ETC MEC and plays a major role in assembly of the macro-supercomplex. These studies provide evidence that both the level of enzyme and its structural confirmation are necessary to stabilize the FAO-ETC MEC.

Keywords:  VLCAD deficiency; fatty acid oxidation; mitochondrial electron transfer chain supercomplex (ETC-SC); very-long-chain acyl-CoA dehydrogenase (VLCAD)

DOI:  https://doi.org/10.3390/biomedicines14010222
Geroscience. 2026 Jan 28.

Coenzyme Q10 supplementation raises plasma levels without improving mitochondrial function in older adults.

Malte Schmücker, Cathrine Tranberg, Jacob Borch, Mette Killerup Kaae, Michelle Damgaard, Mathias Flensted-Jensen, Ida Blom, Marco Morosetti, Sara Barbarossa, Patrick Orlando, Luca Tiano, Flemming Dela, Jørn Wulff Helge, Steen Larsen.

  Mitochondrial function is important to healthy aging, as it influences energy metabolism, oxidative stress, and physical performance. With age, mitochondrial function and biosynthesis of coenzyme Q10 (CoQ10) may change. CoQ10 serves as a key antioxidant and component of the electron transport system. Supplementation with CoQ10 may help preserve mitochondrial function and support healthy aging. Forty older community-dwelling adults (74 ± 4 years) received either daily oral CoQ10 supplementation (400 mg daily) or a placebo in a 12-week double-blinded, randomized, placebo-controlled design. Before and after the supplementation period, muscle biopsies were obtained. Subsequently, oral glucose tolerance tests (OGTT) and VO2max tests were conducted. Mitochondrial respiratory capacity (MRC), mitochondrial H2O2 emission, and mitochondrial content were assessed in both isolated mitochondria and permeabilized muscle fibers. Levels and redox status of CoQ10 were measured in plasma, muscle tissue, and isolated skeletal muscle mitochondria. Additionally, resting metabolic rate, cognitive function, and body composition were investigated. Plasma levels of CoQ10 increased significantly without changes in redox status after the intervention. No changes between groups or time were observed in muscle and isolated mitochondria regarding MRC, H2O2 emission, mitochondrial content, and levels of CoQ10. Glucose homeostasis, VO2max, and body composition were also unchanged. Twelve weeks of supplementation led to increased plasma levels of CoQ10, with unchanged levels in muscle tissue and isolated mitochondria. No differences in mitochondrial function, glucose homeostasis, and physical performance were found in a cohort of robust older adults.

Keywords:  Antioxidant; Healthy aging; Mitochondrial function; Reactive oxygen species

DOI:  https://doi.org/10.1007/s11357-025-02068-9
Biotechnol Appl Biochem. 2026 Jan 29.

N-3 PUFAs Enhancing Chemotherapy Efficacy in Acute Myeloid Leukemia While Safeguarding Healthy Cells.

Pradnya Gurav, Aruna Sivaram, R N Kedar.

  Acute myeloid leukemia (AML) is a rapidly progressing blood cancer with poor survival rates, necessitating aggressive treatment strategies like chemotherapy. Doxorubicin (DOXO) is commonly used but is limited by severe side effects, including myeloablation, which involves the depletion of bone marrow cells leading to immunosuppression and heightened infection risk. This study explores the potential of omega-3 polyunsaturated fatty acids (n-3 PUFAs), specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), to enhance the efficacy of DOXO against AML cells while mitigating some of its toxicities. The results show that DHA and EPA increase the DOXO-induced apoptosis in KG1a cells and greater accumulation in the sub-G1 phase, suggesting enhanced cell death. TUNEL assays confirmed increased DNA fragmentation, whereas mRNA analysis revealed upregulation of apoptosis and cell cycle regulation genes. Importantly, DHA and EPA also reduced the hemolytic activity of DOXO, suggesting a protective effect against chemotherapy-associated side effects. These findings suggest that DHA and EPA could enhance the anti-leukemic impact of DOXO, potentially reducing the need for high-dose chemotherapy and alleviating risks like myeloablation, offering a promising adjunct strategy for AML treatment.

Keywords:  acute myeloid leukemia; cytotoxicity; doxorubicin; myeloablation; n‐3 PUFAs

DOI:  https://doi.org/10.1002/bab.70137
Haematologica. 2026 Jan 29.

Hypomethylating agents plus venetoclax versus intensive chemotherapy in acute myeloid leukemia with chromosome 5 and 7 abnormalities.

Leora Boussi, Jan Philipp Bewersdorf, Yiwen Liu, Rory M Shallis, Luis E Aguirre, Rebecca P Bystrom, Andrius Zucenka, Sylvain Garciaz, Daniel J DeAngelo, Richard M Stone, Marlise R Luskin, Jacqueline S Garcia, Eric S Winer, Evan C Chen, Martha Wadleigh, Guillaume Berton, Kelly Ling, Amer M Zeidan, Eytan M Stein, Shai Shimony, Aaron D Goldberg, Maximilian Stahl.

Abnormalities in chromosomes 5 and 7 are frequently identified in acute myeloid leukemia (AML), particularly enriched in therapy-and myelodysplasia-related disease, and confer an adverse prognosis. Given the high risk of relapse, allogeneic stem cell transplant (allo-SCT) is typically recommended for patients achieving complete remission (CR) following induction chemotherapy. We currently lack prospective data to decide whether intensive chemotherapy (IC) versus hypomethylating agent+venetoclax (HMA+ven) is the superior frontline treatment approach for these patients. Hence, we performed a retrospective study in a large cohort of patients with AML and deletion 7 (-7) and/or deletion 5 or 5q (-5/del5q) comparing outcomes between IC-versus HMA+ven-treated patients. Remission rates after IC and HMA+ven were found to be comparable (43% vs 52%, p=0.2). When adjusting for patient and disease characteristics in multivariable analysis (MVA), treatment with IC vs HMA+ven did not significantly impact overall survival (OS) (HR 1.02, p=0.9202), while age at diagnosis (HR 1.02, p=0.0324), prior myeloid disease (HR 1.42, p=0.0266), monosomal karyotype (HR 1.48, p=0.029), complex karyotype (HR 1.61, p=0.0156), and KRAS mutations (HR 2.21, p=0.0063) were associated with inferior survival. There was also no difference in OS in patients age 60-75 years by treatment strategy (7.8 vs 6.4 months, p=0.56), motivating future randomized trials of IC versus HMA+ven in this older population to inform optimal therapy. Importantly, OS was significantly improved in patients undergoing allo-SCT irrespective of frontline therapy, and allo-SCT consolidation was the most important predictor of long-term survival in MVA (HR 0.36, p.

DOI: https://doi.org/10.3324/haematol.2025.288891
Curr Protein Pept Sci. 2026 Jan 22.

The Role of Mitochondrial Ion Channels in the Evolution of Anticancer Drug Resistance.

Swaroop Kumar Pandey, Ayush Kulshreshtha, Anuja Mishra.

  Apoptosis, drug resistance, and cellular metabolism are all crucially regulated by mitochondria, especially through ion channels and translocases embedded in their membranes. The outer mitochondrial membrane (OMM) contains the voltage dependent anion channel (VDAC), which acts with proteins such as hexokinase II and BAX to regulate apoptosis and metabolic reprogramming in cancer while facilitating the flow of important metabolites and ions. Anti apoptotic proteins like Bcl2 and Mcl1 closely regulate the mitochondrial apoptosis induced channel (MAC), which is created by pro-apoptotic Bcl2 family members BAX and BAK and controls cytochrome c release when overexpressed, leading to drug resistance. Furthermore, the translocase of the outer membrane (TOM) complex, which regulates mitochondrial protein import, is frequently dysregulated in cancers. Numerous ion channels, such as potassium channels, the mitochondrial calcium uniporter (MCU), and the mitochondrial permeability transition pore (m-PTP), are found within the inner mitochondrial membrane (IMM) and regulate important functions like ATP synthesis, the control of reactive oxygen species (ROS), and apoptotic signaling. Cancer cells can avoid apoptosis, adapt to environmental stress, and become resistant to treatments like doxorubicin and cisplatin when these channels are dysregulated. Metabolic flexibility and antioxidant defense are improved by overexpressing or functionally modifying IMM potassium channels and calcium transporters. Additionally, drug resistance is facilitated by increased mitophagy and anti-apoptotic proteins that inhibit m-PTP opening. This review discusses the functions of mitochondrial ion channels.

Keywords:  Apoptosis; cancer; cellular metabolism.; drug resistance; ion channels; mitochondria

DOI:  https://doi.org/10.2174/0113892037410334251021155546
J Clin Med. 2026 Jan 21. pii: 854. [Epub ahead of print]15(2):

Real-World Utilization of Midostaurin in Combination with Intensive Chemotherapy for Patients with FLT3 Mutated Acute Myeloid Leukemia: A Multicenter Study.

Sema Seçilmiş, Sibel Kabukçu Hacıoğlu, Fehmi Hindilerden, Burhan Turgut, Düzgün Özatlı, Gülsüm Akgün Çağlıyan, Abdulkadir Baştürk, Aslı Yüksel Öztürkmen, Yavuz Katırcılar, Sinem Namdaroğlu, Başak Ünver Koluman, Cenk Sunu, Serdal Korkmaz, Ayşe Uysal, Yusuf Bilen, Mehmet Ali Erkurt, Mehmet Sinan Dal, Turgay Ulaş, Fevzi Altuntaş.

  Background/Objectives: Real-world data on the therapeutic use of FLT3 inhibitors in Turkey remain limited. Therefore, we retrospectively evaluated outcomes from 13 academic centers nationwide, focusing on the multikinase inhibitor midostaurin in patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML). Methods: We collected comprehensive information regarding treatment efficacy, safety, and tolerability. Results: The overall response rate to intensive chemotherapy (3 + 7) plus midostaurin was 87.7%, with a complete remission rate of 84.2%, consistent with previously reported clinical trial results. Treatment discontinuation due to intolerance or toxicity was low (3.5%). One patient discontinued therapy because of septic shock during induction, and another due to a drug-drug interaction during consolidation. Median overall survival was 21.4 months. Allogeneic stem cell transplantation was performed in first remission in 52.6% of patients. Five patients (8.8%) were refractory to induction therapy, and relapse occurred in 21.1% (12 patients). Conclusions: These findings support the effectiveness and acceptable tolerability of midostaurin in routine clinical practice for FLT3-mutated AML.

Keywords:  AML; FLT3 inhibitors; acute myeloid leukemia; midostaurin

DOI:  https://doi.org/10.3390/jcm15020854
Molecules. 2026 Jan 11. pii: 242. [Epub ahead of print]31(2):

Energy-Rich Molecules and Group Transfer Potentials in Energetic Coupling Reactions.

Lucien Bettendorff, Pierre Wins.

  The concept of energy-rich molecules is central to metabolic activity and the coupling of catabolic and anabolic processes. Here, we use the term "energy-rich" only in the (bio)chemical sense, i.e., for molecules containing particularly weak bonds that when exchanged for stronger bonds results in a release of energy (generally ≥ 20 kJ mol-1). The typical energy-rich molecules are nucleoside triphosphates (NTPs), thioesters, and dioxygen. It must be emphasized that the number of bonds is conserved in biochemical reactions, so that the difference in free energy between substrates and products only depends on the difference in bond energies. It is evident that using the term "energy-rich" for molecules with weak bonds is subject to misinterpretation. Therefore, some authors suggested to replace this term by molecule of high group transfer potential. This is justified for NTPs and thioesters, which have a high transfer potential for, respectively, phosphoryl or acyl groups, but not for dioxygen. Therefore, the concepts of energy-richness and group transfer potential should be treated as different and only be used within specific contexts. We discuss how these two notions can be used to understand the coupling mechanisms in biochemical processes as well as the interplay between thioesters, redox coupling, and phosphate transfer reactions.

Keywords:  ATP; bond energies; energy coupling; energy metabolism; energy rich molecules; phosphoryl transfer; transfer potential

DOI:  https://doi.org/10.3390/molecules31020242