bims-medica 2026-08-23 papers

Issue of 2026–08–23
seven papers selected by
Brett Chrest, Wake Forest University

Biochim Biophys Acta Bioenerg. 2026 Aug 17. pii: S0005-2728(26)00022-8. [Epub ahead of print] 149602

Disease-mutations perturb proton transfer reactions in respiratory complex I.

Patricia Saura, Sofia Badolato, Andrea Gangdal, Adel Beghiah, Ville R I Kaila.

Respiratory Complex I powers oxidative phosphorylation by a long-range proton-coupled electron transfer (PCET) reaction, with mutations linked to more than half of all human mitochondrial disorders. Yet, the molecular principles underlying the functional impairment remain difficult to test, as most mutations impede both the proton pumping and oxidoreductase activities due to the tightly coupled PCET process. Here, we probe how key disease mutations in the terminal ND5 subunit (NuoL/Nqo12), linked to the development of Leigh's syndrome (LS) and LHON/MELAS (F124L, M252T, D393N), affect the proton transport activity within the dissected antiporter module Nqo12. All constructs result in fully folded antiporter modules, with the introduced substitutions showing enhanced proton conduction rates across the proteoliposome membranes relative to the wild type module. Our molecular dynamics simulations reveal that the mutations perturb the internal water network and ion-pair dynamics that are central for the long-range PCET activity in Complex I. Taken together, we suggest that the mitochondrial disease mutations alter the redox-driven proton pumping activity of Complex I by perturbing the function of local proton gates, and result in an uncontrolled proton translocation across the antiporter module. The molecular consequences of disease mutations are discussed in the context of the proposed pumping mechanism.

Keywords: Cellular respiration; LHON, MELAS; Leigh syndrome; Mitochondrial disease; Molecular mechanism

DOI: https://doi.org/10.1016/j.bbabio.2026.149602

Mol Nutr Food Res. 2026 Aug;70(16): e70578

Ketogenic Diet: A Metabolic Key to Overcoming Cancer Therapy Resistance.

Seerwan Hamadameen Sulaiman, Rebaz Anwar Omer, Khalamala Ibrahim Salih Barzani, Zanco Hassan Jawhar, Hemn A H Barzani.

The ketogenic diet (KD), characterized by very low carbohydrate intake, moderate protein consumption, and variable fat content depending on the specific dietary protocol, has emerged as a promising metabolic approach in oncology. Although significant progress has been achieved in chemotherapy and immunotherapy for cancer treatment, it still faces challenges in terms of resistance to drugs, systemic toxicity, and immunosuppressive microenvironments of tumor tissues. The KD has been reported to exploit the metabolic weaknesses of tumor cells, such as glycolytic addiction and mitochondrial rigidity, while sparing normal tissue metabolism. The anticancer effects of KD are linked to metabolic and signaling reprogramming that may increase tumor sensitivity to treatment. The ketone bodies, especially β-hydroxybutyrate, play a significant role in tumor metabolism and stress response through histone deacetylase inhibition, anti-inflammatory properties in normal tissues, and modulation of chemotherapy-induced toxicity. A large body of preclinical data supports the use of KD to enhance the efficacy of chemotherapeutic agents, such as cisplatin, doxorubicin, temozolomide, and gemcitabine, through mechanisms that include redox imbalance, inhibition of DNA repair, and induction of apoptosis in tumor cells. Emerging experimental data also indicate that KD may affect the tumor immune microenvironment by modulating effector and suppressive immune cells and by interacting with immune checkpoint therapy. However, the translation of these data into the clinic is heterogeneous. Early-phase clinical trials and feasibility studies in glioblastoma, breast, colorectal, and pancreatic cancers have shown that KD is feasible in the clinic and that some benefits in metabolic parameters and quality of life are observed, but evidence of anticancer activity remains limited. Importantly, the response to KD in the clinic seems to depend on the formulation and implementation of the dietary intervention, including the use of high-fat KDs versus very-low-calorie ketogenic diets (VLCKDs), as well as the metabolic context in which the intervention is performed, including obesity and insulin resistance. Overall, current data support KD as a biologically plausible and hypothesis-generating immunometabolic strategy that warrants further evaluation in well-designed, controlled clinical trials with careful attention to dietary composition, metabolic phenotype, safety, and patient adherence.

Keywords: cancer metabolism; chemotherapy sensitization; immunometabolic therapy; ketogenic diet; tumor immune microenvironment

DOI: https://doi.org/10.1002/mnfr.70578

Mol Cell. 2026 Aug 21. pii: S1097-2765(26)00517-4. [Epub ahead of print]

Nicotinamide nucleotide transhydrogenase directly couples redox homeostasis to proline biosynthesis in human glioma.

Lisa A Vettore, Adam Boufersaoui, Yingying Lyu, Anaïs Oudin, Keene L Abbott, Sonu Subudhi, Yetiş Gültekin, Katherine L Eales, Ishana Rajgopal, Cristina Escribano-Gonzalez, Rahatil A Chowdhury, Himani Rana, Victoria Wykes, Rakesh K Jain, Anna Golebiewska, Matthew G Vander Heiden, Daniel A Tennant.

Cancer cell proliferation requires a precise balance between biomass production and nutrient catabolism. The pyridine nucleotide cofactors nicotinamide adenine dinucleotide NAD(H) and NAD phosphate NADP(H) are central to this process, but their compartment-specific regulation is incompletely understood. Using in vivo isotope-labeled metabolite tracing in an orthotopic xenograft model, we find that human gliomas extensively synthesize proline, an amino acid previously associated with hypoxia tolerance. In glioma cells, we identify a hypoxia-enhanced proliferative sensitivity to environmental proline dependent on NADH to NADPH transhydrogenation from a spatially compartmentalized mitochondrial pool by the enzyme nicotinamide nucleotide transhydrogenase (NNT). We demonstrate NNT-dependent generation of mitochondrial NADPH is important for proline accumulation, maintenance of antioxidant systems, and reductive metabolism in hypoxic glioma cells in vitro and tumor progression in vivo. Collectively, these results highlight proline accumulation as a marker of mitochondrial NAD(P)(H) homeostasis and NNT as a specific metabolic dependency in human glioma.

Keywords: NNT; glioma; hypoxia; proline; redox

DOI: https://doi.org/10.1016/j.molcel.2026.07.031

Arch Biochem Biophys. 2026 Aug 19. pii: S0003-9861(26)00250-X. [Epub ahead of print] 110978

The Impact of Medium Chain Triglyceride Ketogenic Diet on Liver Mitochondria and Cytochrome P450 2E1.

Abigail S Ryan, Reagan M Roberts, Kristina M Stayer, Alexandra A Tomasevich, Kelly R Misare, Fiona Hollis, Joseph A McQuail, Jessica H Hartman.

The ketogenic diet is increasingly used for metabolic and neurologic indications, yet its impact on hepatic mitochondrial function and xenobiotic metabolism remains incompletely defined. Cytochrome P450 2E1 (CYP2E1) is induced by the ketone body acetone and contributes to oxidative and carbonyl stress, but prior studies examining CYP2E1 regulation during ketosis have yielded conflicting results. Here, we investigated the effects of an 8-week medium chain triglyceride ketogenic diet (MCT-KD) on liver mitochondrial respiratory chain activity and CYP2E1 expression in young and aged Fisher 344 × Brown Norway F1 rats. In young animals, MCT-KD significantly reduced mitochondrial complex I activity without significant changes in complexes II, III, or IV. These changes occurred without altered citrate synthase activity, suggesting comparable mitochondrial content. In parallel, MCT-KD robustly increased hepatic CYP2E1 protein levels and activity in young and aged animals and upregulated its electron donor, P450 oxidoreductase (POR), particularly in young rats. Despite robust induction of the acetone-CYP2E1 pathway, methylglyoxal-derived protein adducts did not accumulate, even though hepatic GLO1 expression was reduced. Together, these findings demonstrate that long-term MCT-KD induces coordinated adaptations in hepatic mitochondrial function and the CYP2E1-POR pathway without increasing methylglyoxal-derived protein damage.

Keywords: CYP2E1; Ketogenic diet; P450 oxidoreductase; electron transport chain; liver; medium chain triglycerides; methylglyoxal; mitochondria

DOI: https://doi.org/10.1016/j.abb.2026.110978

Nat Metab. 2026 Aug;8(8): 1772-1790

Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism.

Zhongchi Li, Shuchen Liu, Wenbing Jin, Leyi Xiao, Olivia Kester, Nayah Bullen, Xuanrong Chen, Un In Chan, Jude Owiredu, Zhucui Li, Rabia Khan, Jennifer Endress, Moniquetta Shafer, Vivien Low, Nikolaos Koundouros, Sungyun Cho, Christopher Barbieri, Chun-Jun Guo, John Blenis.

Enhanced cholesterol synthesis and lipid droplet accumulation are hallmarks of aggressive prostate cancer, yet how tumour cells sense metabolic inputs to dynamically regulate cholesterol homeostasis remains poorly defined. Here we uncover a metabolic signalling mechanism in which prostate cancer cells remodel propionyl-CoA metabolism to support stress adaptation during disease progression. We show that the catabolism of branched-chain amino acid, specifically isoleucine and valine, is the primary source of intracellular propionyl-CoA in prostate cancer cells. Beyond its metabolic role, propionyl-CoA functions as a signalling molecule that stabilizes nuclear sterol regulatory element-binding protein 2 (SREBP2) through site-specific lysine propionylation, thereby enhancing its transcriptional activity. This activation promotes cholesterol biosynthesis, fuels de novo androgen production, and sustains androgen receptor signalling under metabolic and therapeutic stress, including androgen deprivation. Together, our findings establish propionyl-CoA as a key metabolic signal linking amino acid catabolism to cholesterol-driven oncogenic programmes and highlight targeting isoleucine and valine metabolism as a potential strategy to disrupt lipid reprogramming in prostate cancer.

DOI: https://doi.org/10.1038/s42255-026-01583-z

Am J Physiol Endocrinol Metab. 2026 Aug 21.

Impact of Intestinal Propionate Metabolism on Systemic Metabolic Homeostasis.

Jasmine Encarnacion, Michael J Wolfgang.

Propionate is an abundant short-chain fatty acid largely derived from gut microbiota in mammals. Propionate metabolism is essential to maintain systemic homeostasis and inborn errors of essential metabolic enzymes in this pathway cause severe illness. The juxtaposition of high concentrations of propionate with the intestinal epithelium suggests a need for propionate catabolism. To understand the requirement of propionate metabolism in intestinal epithelium, we generated mice with a conditional knockout of Propionyl-CoA Carboxylase A (Pcca) specifically in the intestine (PccaVil-Cre). Male and female PccaVil-Cre mice were born and weaned at the expected Mendelian ratio and gained weight normally on chow and high fat diets. Liver metabolomics of PccaVil-Cre mice suggest that propionate metabolism affects the gut liver axis. However, the loss of Pcca in the intestine did not affect the colonic transcriptome. These data suggest that intestinal propionate metabolism is largely dispensable, and hepatic capture and metabolism of propionate dominates systemic physiology.

Keywords: Propionate; Propionyl-CoA Carboxylase; gut knockout; propionic acidemia

DOI: https://doi.org/10.1152/ajpendo.00168.2026

Cancer Metab. 2026 Jul 24. pii: 26. [Epub ahead of print]14(1):

PKM2 modulation regulates leukemia cell survival.

Nikolina Vrdoljak, Ekaterina N Parfenova, Alessia Roma, Drake A Mosca, Mark D Minden, Paul A Spagnuolo.

Acute myeloid leukemia (AML) cells exhibit aberrant metabolism defined by a shift away from oxidative phosphorylation and towards anaerobic glycolysis, favouring cell growth. Glycolytic enzymes are altered for this change to occur, including pyruvate kinase (PK), where the tetrameric and high activity M1 isoform (PKM1) is replaced with the predominantly dimeric and low activity M2 isoform (PKM2). Dimeric PKM2 produces less pyruvate and acts as a protein kinase in the nucleus, demonstrating divergent roles in both cell metabolism and as a transcriptional co-activator. In this study, the role of PKM2 in AML was defined, as PKM2 levels were elevated but PK enzymatic activity was reduced in AML cells compared to normal hematopoietic cells. Genetic and pharmacological studies show that decreasing and increasing PKM2 activity resulted in anti-AML effects both in vitro and in vivo. Indeed, these models show that inhibition and activation of PKM2 disrupt the native oligomeric state of the protein, resulting in reduced nuclear PKM2 accumulation and c-Myc expression, ultimately leading to cell death. Together, these results highlight the importance of PKM2 in AML, uncover the mechanisms by which both inhibition and activation cause AML cell death, and identify a novel modulator of PKM2 activity.

DOI: https://doi.org/10.1186/s40170-026-00440-7