bims-medica 2025-03-16 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–03–16
fifteen papers selected by
Brett Chrest, Wake Forest University

Succinate dehydrogenase activity supports de novo purine synthesis.
Pyruvate dehydrogenase kinase 1 controls triacylglycerol hydrolysis in cardiomyocytes.
Pathway Coessentiality Mapping Reveals Complex II is Required for de novo Purine Biosynthesis in Acute Myeloid Leukemia.
Arylamine N-acetyltransferase 1 expression predicts glucose dependence and mitochondrial bioenergetics in cancer cells.
Mitochondrial ACSS1-K635 acetylation knock-in mice exhibit altered liver lipid metabolism on a ketogenic diet.
Glucose Metabolism and Tumor Microenvironment: Mechanistic Insights and Therapeutic Implications.
Engineering mtDNA deletions by reconstituting end joining in human mitochondria.
Deciphering Colorectal Cancer-Hepatocyte Interactions: A Multiomics Platform for Interrogation of Metabolic Crosstalk in the Liver-Tumor Microenvironment.
Fatty Acid Trafficking Between Lipid Droplets and Mitochondria: An Emerging Perspective.
Branched-chain amino acid catabolism promotes ovarian cancer cell proliferation via phosphorylation of mTOR.
A dual-purification system to isolate mitochondrial subpopulations.
Targeting metabolic reprogramming in glioblastoma as a new strategy to overcome therapy resistance.
Mitochondrial priming and response to BH3 mimetics in "one-two punch" senogenic-senolytic strategies.
Fasting is not always good: perioperative fasting leads to pronounced ketone body production in patients treated with SGLT2 inhibitors: a case report.
Measurement of Mitochondrial Membrane Potential In Vivo using a Genetically Encoded Voltage Indicator.

bioRxiv. 2025 Mar 01. pii: 2025.02.26.640389. [Epub ahead of print]

Succinate dehydrogenase activity supports de novo purine synthesis.

Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.

The de novo purine synthesis pathway is fundamental for nucleic acid production and cellular energetics, yet the role of mitochondrial metabolism in modulating this process remains underexplored. In many cancers, metabolic reprogramming supports rapid proliferation and survival, but the specific contributions of the tricarboxylic acid (TCA) cycle enzymes to nucleotide biosynthesis are not fully understood. Here, we demonstrate that the TCA cycle enzyme succinate dehydrogenase (SDH) is essential for maintaining optimal de novo purine synthesis in normal and cancer cells. Genetic or pharmacological inhibition of SDH markedly attenuates purine synthesis, leading to a significant reduction in cell proliferation. Mechanistically, SDH inhibition causes an accumulation of succinate, which directly impairs the purine biosynthetic pathway. In response, cancer cells compensate by upregulating the purine salvage pathway, a metabolic adaptation that represents a potential therapeutic vulnerability. Notably, co-inhibition of SDH and the purine salvage pathway induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings not only reveal a signaling role for mitochondrial succinate in regulating nucleotide metabolism but also provide a promising therapeutic strategy for targeting metabolic dependencies in cancer.

DOI: https://doi.org/10.1101/2025.02.26.640389
J Biol Chem. 2025 Mar 10. pii: S0021-9258(25)00247-9. [Epub ahead of print] 108398

Pyruvate dehydrogenase kinase 1 controls triacylglycerol hydrolysis in cardiomyocytes.

Michael G Atser, Chelsea D Wenyonu, Elyn M Rowe, Connie L K Leung, Haoning Howard Cen, Eric D Queathem, Leo T Liu, Renata Moravcova, Jason Rogalski, David Perrin, Peter Crawford, Leonard J Foster, Armando Alcazar, James D Johnson.

  Pyruvate dehydrogenase kinase (PDK) 1 is one of four isozymes that inhibit the oxidative decarboxylation of pyruvate to acetyl-CoA via pyruvate dehydrogenase. PDK activity is elevated in fasting or starvation conditions to conserve carbohydrate reserves. PDK has also been shown to increase mitochondrial fatty acid utilization. In cardiomyocytes, metabolic flexibility is crucial for the fulfillment of high energy requirements. The PDK1 isoform is abundant in cardiomyocytes, but its specific contribution to cardiomyocyte metabolism is unclear. Here we show that PDK1 regulates cardiomyocyte fuel preference by mediating triacylglycerol turnover in differentiated H9c2 myoblasts using lentiviral shRNA to knockdown Pdk1. Somewhat surprisingly, PDK1 loss did not affect overall PDH activity, basal glycolysis, or glucose oxidation revealed by oxygen consumption rate experiments and 13C6 glucose labelling. On the other hand, we observed decreased triacylglycerol turnover in H9c2 cells with PDK1 knockdown, which was accompanied by decreased mitochondrial fatty acid utilization following nutrient deprivation. 13C16 palmitate tracing of uniformly labelled acyl chains revealed minimal acyl chain shuffling within triacylglycerol, indicating that the triacylglycerol hydrolysis, and not re-esterification, was dysfunctional in PDK1 suppressed cells. Importantly, PDK1 loss did not significantly impact the cellular lipidome or triacylglycerol accumulation following palmitic acid treatment, suggesting that effects of PDK1 on lipid metabolism were specific to the nutrient-deprived state. We validated that PDK1 loss decreased triacylglycerol turnover in Pdk1 knockout mice. Together, these findings implicate a novel role for PDK1 in lipid metabolism in cardiomyocytes, independent of its canonical roles in glucose metabolism.

Keywords:  carbohydrate metabolism; cardiac metabolism; lipid metabolism; pyruvate dehydrogenase kinase; triacylglycerol

DOI:  https://doi.org/10.1016/j.jbc.2025.108398
bioRxiv. 2025 Mar 02. pii: 2025.02.26.640463. [Epub ahead of print]

Pathway Coessentiality Mapping Reveals Complex II is Required for de novo Purine Biosynthesis in Acute Myeloid Leukemia.

Amy E Stewart, Derek K Zachman, Pol Castellano-Escuder, Lois M Kelly, Ben Zolyomi, Michael D I Aiduk, Christopher D Delaney, Ian C Lock, Claudie Bosc, John Bradley, Shane T Killarney, Olga R Ilkayeva, Christopher B Newgard, Navdeep S Chandel, Alexandre Puissant, Kris C Wood, Matthew D Hirschey.

Understanding how cellular pathways interact is crucial for treating complex diseases like cancer, yet our ability to map these connections systematically remains limited. Individual gene-gene interaction studies have provided insights 1,2 , but they miss the emergent properties of pathways working together. To address this challenge, we developed a multi-gene approach to pathway mapping and applied it to CRISPR data from the Cancer Dependency Map 3 . Our analysis of the electron transport chain revealed certain blood cancers, including acute myeloid leukemia (AML), depend on an unexpected link between Complex II and purine metabolism. Through stable isotope metabolomic tracing, we found that Complex II directly supports de novo purine biosynthesis and exogenous purines rescue AML from Complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that Complex II must oxidize to sustain purine synthesis. This connection translated to a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML to Complex II inhibition. In mouse models, targeting Complex II triggered rapid disease regression and extended survival in aggressive AML. The clinical relevance of this pathway emerged in human studies, where higher Complex II gene expression correlates with both resistance to mitochondria-targeted therapies and worse survival outcomes specifically in AML patients. These findings establish Complex II as a central regulator of de novo purine biosynthesis and identify it as a promising therapeutic target in AML.

DOI: https://doi.org/10.1101/2025.02.26.640463
Biochim Biophys Acta Mol Cell Res. 2025 Mar 05. pii: S0167-4889(25)00034-5. [Epub ahead of print] 119929

Arylamine N-acetyltransferase 1 expression predicts glucose dependence and mitochondrial bioenergetics in cancer cells.

Chandra Choudhury, Neville J Butcher, Rodney F Minchin.

  To investigate the effects of varying NAT1 activity in different cell-lines, mitochondrial oxidative phosphorylation, aerobic glycolysis and mitochondrial fuel usage was quantified in a panel of human cell-lines. As NAT1 activity increased, mitochondrial reserve respiratory capacity increased while aerobic glycolysis decreased. In addition, phosphorylation of PDH-E1α in these cells limited their ability to use glucose as a primary fuel source. Those cells with high NAT1 activity exhibited a quiescent metabolic phenotype and proliferated more slowly. This might explain, in part, why some cancer patients with low NAT1 expression in their tumour tissue show poorer survival outcomes compared to those with high NAT1 expression. The current study demonstrated that NAT1 enzymatic activity is important for metabolism in cancer cell-lines and increasing NAT1 activity may better equip cells to survive under stressed conditions by increasing reserve respiratory capacity.

Keywords:  Acetyl-coenzyme A; Aerobic glycolysis; Arylamine N-acetyltransferase; Fuel usage; Mitochondrial respiration; Pyruvate dehydrogenase

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119929
Free Radic Biol Med. 2025 Mar 10. pii: S0891-5849(25)00159-5. [Epub ahead of print]

Mitochondrial ACSS1-K635 acetylation knock-in mice exhibit altered liver lipid metabolism on a ketogenic diet.

Guogang Xu, Joseph R Schell, Songhua Quan, Yucheng Gao, Sung-Jen Wei, Meixia Pan, Xianlin Han, Guiming Li, Daohong Zhou, Haiyan Jiang, Felix F Dong, Erin Munkácsy, Nobuo Horikoshi, David Gius.

  Acetyl-CoA Synthetase Short Chain Family Member-1 (ACSS1) catalyzes the ligation of acetate and coenzyme A to generate acetyl-CoA in the mitochondria to produce ATP through the tricarboxylic acid (TCA) cycle. We recently generated an ACSS1-acetylation (Ac) mimic knock-in mouse, where lysine 635 was mutated to glutamine (K635Q), which structurally and biochemically mimics an acetylated lysine. ACSS1 enzymatic activity is regulated, at least in part, through the acetylation of lysine 635 in mice (lysine 642 in humans), a Sirtuin 3 deacetylation target. We challenged our Acss1K635Q knock-in mice with a three-week ketogenic diet. While both wild-type and Acss1K635Q knock-in mice were in ketosis with similar blood glucose levels, the Acss1K635Q mice exhibited elevated blood acetate and liver acetyl-CoA. In addition, and importantly, compared to wild-type mice, the liver in the Acss1K635Q mice displayed a much more predominant liver steatosis morphology and accumulation of lipid drops, as measured by H&E and Oil Red O staining. RNAseq analysis identified that genes related to mitochondrial respiratory chain complexes and oxidative stress were significantly overexpressed in the Acss1K635Q mice on a KD. Finally, lipidomics analysis revealed very different lipid profiles for these groups, including a dramatic increase in triacylglycerides (TAGs), phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), and cardiolipins in the Acss1K635Q liver.

Keywords:  Acetate; Acetyl-CoA Synthetase; Ketogenic Diet; Lipid Metabolism; Steatosis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.03.009
Int J Mol Sci. 2025 Feb 22. pii: 1879. [Epub ahead of print]26(5):

Glucose Metabolism and Tumor Microenvironment: Mechanistic Insights and Therapeutic Implications.

Wiktoria Andryszkiewicz, Julia Gąsiorowska, Maja Kübler, Karolina Kublińska, Agata Pałkiewicz, Adam Wiatkowski, Urszula Szwedowicz, Anna Choromańska.

  Metabolic reprogramming in cancer cells involves changes in glucose metabolism, glutamine utilization, and lipid production, as well as promoting increased cell proliferation, survival, and immune resistance by altering the tumor microenvironment. Our study analyzes metabolic reprogramming in neoplastically transformed cells, focusing on changes in glucose metabolism, glutaminolysis, and lipid synthesis. Moreover, we discuss the therapeutic potential of targeting cancer metabolism, focusing on key enzymes involved in glycolysis, the pentose phosphate pathway, and amino acid metabolism, including lactate dehydrogenase A, hexokinase, phosphofructokinase and others. The review also highlights challenges such as metabolic heterogeneity, adaptability, and the need for personalized therapies to overcome resistance and minimize adverse effects in cancer treatment. This review underscores the significance of comprehending metabolic reprogramming in cancer cells to engineer targeted therapies, personalize treatment methodologies, and surmount challenges, including metabolic plasticity and therapeutic resistance.

Keywords:  cancer stem cells; glycolysis; hexokinase; lactate dehydrogenase A; phosphofructokinase; pyruvate kinase; the Warburg effect; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/ijms26051879
Cell. 2025 Mar 05. pii: S0092-8674(25)00194-1. [Epub ahead of print]

Engineering mtDNA deletions by reconstituting end joining in human mitochondria.

Yi Fu, Max Land, Tamar Kavlashvili, Ruobing Cui, Minsoo Kim, Emily DeBitetto, Toby Lieber, Keun Woo Ryu, Elim Choi, Ignas Masilionis, Rahul Saha, Meril Takizawa, Daphne Baker, Marco Tigano, Caleb A Lareau, Ed Reznik, Roshan Sharma, Ronan Chaligne, Craig B Thompson, Dana Pe'er, Agnel Sfeir.

  Recent breakthroughs in the genetic manipulation of mitochondrial DNA (mtDNA) have enabled precise base substitutions and the efficient elimination of genomes carrying pathogenic mutations. However, reconstituting mtDNA deletions linked to mitochondrial myopathies remains challenging. Here, we engineered mtDNA deletions in human cells by co-expressing end-joining (EJ) machinery and targeted endonucleases. Using mitochondrial EJ (mito-EJ) and mito-ScaI, we generated a panel of clonal cell lines harboring a ∼3.5 kb mtDNA deletion across the full spectrum of heteroplasmy. Investigating these cells revealed a critical threshold of ∼75% deleted genomes, beyond which oxidative phosphorylation (OXPHOS) protein depletion, metabolic disruption, and impaired growth in galactose-containing media were observed. Single-cell multiomic profiling identified two distinct nuclear gene deregulation responses: one triggered at the deletion threshold and another progressively responding to heteroplasmy. Ultimately, we show that our method enables the modeling of disease-associated mtDNA deletions across cell types and could inform the development of targeted therapies.

Keywords:  DOGMA-seq; end joining; mitochondrial pathologies; mtDNA; mtDNA deletion

DOI:  https://doi.org/10.1016/j.cell.2025.02.009
Int J Mol Sci. 2025 Feb 25. pii: 1976. [Epub ahead of print]26(5):

Deciphering Colorectal Cancer-Hepatocyte Interactions: A Multiomics Platform for Interrogation of Metabolic Crosstalk in the Liver-Tumor Microenvironment.

Alisa B Nelson, Lyndsay E Reese, Elizabeth Rono, Eric D Queathem, Yinjie Qiu, Braedan M McCluskey, Alexandra Crampton, Eric Conniff, Katherine Cummins, Ella Boytim, Senali Dansou, Justin Hwang, Sandra E Safo, Patrycja Puchalska, David K Wood, Kathryn L Schwertfeger, Peter A Crawford.

  Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt to and exploit their microenvironment for sustained growth. The liver is a common site of metastasis, but the interactions between tumor cells and hepatocytes remain poorly understood. In the context of liver metastasis, these interactions play a crucial role in promoting tumor survival and progression. This study leverages multiomics coverage of the microenvironment via liquid chromatography and high-resolution, high-mass-accuracy mass spectrometry-based untargeted metabolomics, 13C-stable isotope tracing, and RNA sequencing to uncover the metabolic impact of co-localized primary hepatocytes and a colon adenocarcinoma cell line, SW480, using a 2D co-culture model. Metabolic profiling revealed disrupted Warburg metabolism with an 80% decrease in glucose consumption and 94% decrease in lactate production by hepatocyte-SW480 co-cultures relative to SW480 control cultures. Decreased glucose consumption was coupled with alterations in glutamine and ketone body metabolism, suggesting a possible fuel switch upon co-culturing. Further, integrated multiomics analysis indicates that disruptions in metabolic pathways, including nucleoside biosynthesis, amino acids, and TCA cycle, correlate with altered SW480 transcriptional profiles and highlight the importance of redox homeostasis in tumor adaptation. Finally, these findings were replicated in three-dimensional microtissue organoids. Taken together, these studies support a bioinformatic approach to study metabolic crosstalk and discovery of potential therapeutic targets in preclinical models of the tumor microenvironment.

Keywords:  cancer metabolism; metabolomics; multiomics; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms26051976
Int J Biol Sci. 2025 ;21(5): 1863-1873

Fatty Acid Trafficking Between Lipid Droplets and Mitochondria: An Emerging Perspective.

Katarína Smolková, Klára Gotvaldová.

  The current understanding of lipid droplets (LDs) in cell biology has evolved from being viewed merely as storage compartments. LDs are now recognized as metabolic hubs that act as cytosolic buffers against the detrimental effects of free fatty acids (FAs). Upon activation, FAs traverse various cellular pathways, including oxidation in mitochondria, integration into complex lipids, or storage in triacylglycerols (TGs). Maintaining a balance among these processes is crucial in cellular FA trafficking, and under metabolically challenging circumstances the routes of FA metabolism adapt to meet the current cellular needs. This typically involves an increased demand for anabolic intermediates or energy and the prevention of redox stress. Surprisingly, LDs accumulate under certain conditions such as amino acid starvation. This review explores the biochemical aspects of FA utilization in both physiological contexts and within cancer cells, focusing on the metabolism of TGs, cholesteryl esters (CEs), and mitochondrial FA oxidation. Emphasis is placed on the potential toxicity associated with non-esterified FAs in cytosolic and mitochondrial compartments. Additionally, we discuss mechanisms that lead to increased LD biogenesis due to an inhibited mitochondrial import of FAs.

Keywords:  CPT1; ferroptosis; lipid droplets; lipotoxicity; mitochondria; triglycerides

DOI:  https://doi.org/10.7150/ijbs.105361
Cancer Res Commun. 2025 Mar 11.

Branched-chain amino acid catabolism promotes ovarian cancer cell proliferation via phosphorylation of mTOR.

Hannah J Lusk, Monica A Haughan, Tova M Bergsten, Joanna E Burdette, Laura M Sanchez.

Ovarian cancer is the sixth leading cause of cancer-related mortality among individuals with ovaries, and high-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype. Characterized by a distinct and aggressive metastatic pattern, HGSOC can originate in the fallopian tube with the transformation of fallopian tube epithelial (FTE) cells, which metastasize to the ovary and subsequently to the omentum and peritoneal cavity. The omentum is a privileged metastatic site, and the metabolic exchange underlying omental metastasis could provide enzyme or receptor targets to block spread. In this study, we adapted a mass spectrometry imaging (MSI) protocol to investigate spatial location of 3D cocultures of tumorigenic FTE cells when grown in proximity to murine omental explants as a model of early metastatic colonization. Our analysis revealed several altered metabolites in tumorigenic FTE/omentum cocultures, namely changes in branched-chain amino acids (BCAA), including valine. We quantified the heightened consumption of valine, other BCAAs, and other amino acid-derived metabolites in omental cocultures using LC-MS assays. Our analysis revealed that metabolite concentrations when monitored with MSI from cell culture media in living culture systems have notable considerations for how MSI data may produce signatures that induce ionization suppression. Supplementation with valine enhanced proliferation and mTOR signaling in tumorigenic FTE cells, suggesting the potential of BCAA's as a nutrient utilized by tumor cells during omental colonization and a possible target for metastasis.

DOI: https://doi.org/10.1158/2767-9764.CRC-24-0532
J Cell Sci. 2025 Mar 13. pii: jcs.263693. [Epub ahead of print]

A dual-purification system to isolate mitochondrial subpopulations.

Corey N Cunningham, Jonathan G Van Vranken, Jakeline Larios, Katarina Heyden, Steven P Gygi, Jared Rutter.

  Mitochondria perform diverse functions, such as producing ATP through oxidative phosphorylation, synthesizing macromolecule precursors, maintaining redox balance, and many others. Given this diversity of functions, we and others have hypothesized that cells maintain specialized subpopulations of mitochondria. To begin addressing this hypothesis, we developed a new dual-purification system to isolate subpopulations of mitochondria for chemical and biochemical analyses. We used APEX2 proximity labeling such that mitochondria were biotinylated based on proximity to another organelle. All mitochondria were isolated by an elutable MitoTag-based affinity precipitation system. Biotinylated mitochondria were then purified using immobilized avidin. We used this system to compare the proteomes of endosome- and lipid droplet-associated mitochondria in U-2 OS cells, which demonstrated that these subpopulations were indistinguishable from one another but were distinct from the global mitochondria proteome. Our results suggest that this purification system could aid in describing subpopulations that contribute to intracellular mitochondrial heterogeneity, and that this heterogeneity might be more substantial than previously imagined.

Keywords:  Biochemistry; Mitochondria; Proximity Labeling; Purification

DOI:  https://doi.org/10.1242/jcs.263693
Front Cell Dev Biol. 2025 ;13 1535073

Targeting metabolic reprogramming in glioblastoma as a new strategy to overcome therapy resistance.

Simona D'Aprile, Simona Denaro, Anna Gervasi, Nunzio Vicario, Rosalba Parenti.

  Glioblastoma (GBM) is one of the deadliest tumors due to its high aggressiveness and resistance to standard therapies, resulting in a dismal prognosis. This lethal tumor carries out metabolic reprogramming in order to modulate specific pathways, providing metabolites that promote GBM cells proliferation and limit the efficacy of standard treatments. Indeed, GBM remodels glucose metabolism and undergoes Warburg effect, fuelling glycolysis even when oxygen is available. Moreover, recent evidence revealed a rewiring in nucleotide, lipid and iron metabolism, resulting not only in an increased tumor growth, but also in radio- and chemo-resistance. Thus, while on the one hand metabolic reprogramming is an advantage for GBM, on the other hand it may represent an exploitable target to hamper GBM progression. Lately, a number of studies focused on drugs targeting metabolism to uncover their effects on tumor proliferation and therapy resistance, demonstrating that some of these are effective, in combination with conventional treatments, sensitizing GBM to radiotherapy and chemotherapy. However, GBM heterogeneity could lead to a plethora of metabolic alterations among subtypes, hence a metabolic treatment might be effective for proneural tumors but not for mesenchymal ones, which are more aggressive and resistant to conventional approaches. This review explores key mechanisms of GBM metabolic reprogramming and their involvement in therapy resistance, highlighting how metabolism acts as a double-edged sword for GBM, taking into account metabolic pathways that seem to offer promising treatment options for GBM.

Keywords:  Warburg effect; chemotherapy; iron; lipids; metabolism; nucleotides; radiotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2025.1535073
Cell Death Discov. 2025 Mar 07. 11(1): 91

Mitochondrial priming and response to BH3 mimetics in "one-two punch" senogenic-senolytic strategies.

Júlia López, Àngela Llop-Hernández, Sara Verdura, Eila Serrano-Hervás, Eva Martinez-Balibrea, Joaquim Bosch-Barrera, Eduard Teixidor, Eugeni López-Bonet, Begoña Martin-Castillo, Josep Sardanyés, Tomás Alarcón, Ruth Lupu, Elisabet Cuyàs, Javier A Menendez.

A one-two punch sequential regimen of senescence-inducing agents followed by senolytic drugs has emerged as a novel therapeutic strategy in cancer. Unfortunately, cancer cells undergoing therapy-induced senescence (TIS) vary widely in their sensitivity to senotherapeutics, and companion diagnostics to predict the response of TIS cancer cells to a specific senolytic drug are lacking. Here, we hypothesized that the ability of the BH3 profiling assay to functionally measure the mitochondrial priming state-the proximity to the apoptotic threshold-and the dependencies on pro-survival BCL-2 family proteins can be exploited to inform the sensitivity of TIS cancer cells to BH3-mimetics. Replicative, mitotic, oxidative, and genotoxic forms of TIS were induced in p16-null/p53-proficient, BAX-deficient, and BRCA1-mutant cancer cells using mechanistically distinct TIS-inducing cancer therapeutics, including palbociclib, alisertib, doxorubicin, bleomycin, and olaparib. When the overall state of mitochondrial priming and competence was determined using activator peptides, the expected increase in overall mitochondrial priming was an exception rather than a generalizable feature across TIS phenotypes. A higher level of overall priming paralleled a higher sensitivity of competent TIS cancer cells to BCL-2/BCL-xL- and BCL-xL-targeted inhibitors when comparing TIS phenotypes among themselves. Unexpectedly, however, TIS cancer cells remained equally or even less overally primed than their proliferative counterparts. When sensitizing peptides were used to map dependencies on anti-apoptotic BCL-2 family proteins, competent TIS cancer cells appeared to share a dependency on BCL-xL. Furthermore, regardless of senescence-inducing therapeutic, stable/transient senescence acquisition, or genetic context, all TIS phenotypes shared a variable but significant senolytic response to the BCL-xL-selective BH3 mimetic A1331852. These findings may help to rethink the traditional assumption of the primed apoptotic landscape of TIS cancer cells. BCL-xL is a conserved anti-apoptotic effector of the TIS BCL2/BH3 interactome that can be exploited to maximize the efficacy of "one-two punch" senogenic-senolytic strategies.

DOI: https://doi.org/10.1038/s41420-025-02379-y
Korean J Fam Med. 2025 Mar 07.

Fasting is not always good: perioperative fasting leads to pronounced ketone body production in patients treated with SGLT2 inhibitors: a case report.

Jae Chan Choi, Yo Nam Jang, Jong Hoon Lee, Sang Wook Park, Jeong A Park, Hye Sook Kim, Jae Won Choi, Joo Hyung Lee, Yong Jae Lee.

  Ketone bodies produced by sodium-glucose cotransporter 2 (SGLT2) inhibitors can be advantageous, providing an efficient and stable energy source for the brain and muscles. However, in patients with diabetes, ketogenesis induced by SGLT2 inhibitors may be harmful, potentially resulting in severe diabetic ketoacidosis (DKA). During fasting, ketone body production serves as an alternative and efficient energy source for the brain by utilizing stored fat, promoting mental clarity, and reducing dependence on glucose. The concurrent use of SGLT2 inhibitors during perioperative fasting may further elevate the risk of euglycemic DKA. We describe a case of DKA that occurred during perioperative fasting in a patient receiving empagliflozin, an SGLT2 inhibitor. This case underscores the importance of recognizing the potential risk of DKA in patients with diabetes using SGLT2 inhibitors during perioperative fasting.

Keywords:  Case Reports; Diabetic Ketoacidosis; Fasting; Preoperative Care; Sodium-Glucose Transporter 2 Inhibitors

DOI:  https://doi.org/10.4082/kjfm.24.0210
J Vis Exp. 2025 Feb 21.

Measurement of Mitochondrial Membrane Potential In Vivo using a Genetically Encoded Voltage Indicator.

Run-Zhou Yang, Dian-Dian Wang, Sen-Miao Li, Pei-Pei Liu, Jian-Sheng Kang.

Mitochondrial membrane potential (MMP, ΔΨm) is critical for mitochondrial functions, including ATP synthesis, ion transport, reactive oxygen species (ROS) generation, and the import of proteins encoded by the nucleus. Existing methods for measuring ΔΨm typically use lipophilic cation dyes, such as Rhodamine 800 and tetramethylrhodamine methyl ester (TMRM), but these are limited by low specificity and are not well-suited for in vivo applications. To address these limitations, we have developed a novel protocol utilizing genetically encoded voltage indicators (GEVIs). Genetically encoded voltage indicators (GEVIs), which generate fluorescent signals in response to membrane potential changes, have demonstrated significant potential for monitoring plasma membrane and neuronal potentials. However, their application to mitochondrial membranes remains unexplored. Here, we developed protein-based mitochondrial-targeted GEVIs capable of detecting ΔΨm fluctuations in cells and the motor cortex of living animals. The mitochondrial potential indicator (MPI)offers a non-invasive approach to study ΔΨm dynamics in real-time, providing a method to investigate mitochondrial function under both normal and pathological conditions.

DOI: https://doi.org/10.3791/67911