bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–10–19
fifteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia.
  2. Quiescent OXPHOS-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend on BCL-XL for Survival.
  3. Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis.
  4. SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.
  5. Metabolic Dependency on De Novo Pyrimidine Synthesis is a Targetable Vulnerability in Platinum Resistant Ovarian Cancer.
  6. Bioenergetics of cancer cells: insights into the Warburg effect and regulation of ATP synthase.
  7. Nutrient allocation fuels T cell-mediated immunity.
  8. Mitochondrial function regulates cell growth kinetics to maintain mitochondrial homeostasis.
  9. BNIP3L/BNIP3-Mediated Mitophagy Contributes to the Maintenance of Ovarian Cancer Stem Cells.
  10. Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.
  11. POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels.
  12. Aged mice exhibit widespread metabolic changes but preserved major fluxes.
  13. Efficient identification of new small molecules targeting succinate dehydrogenase in non-small cell lung cancer.
  14. Spatial metabolic gradients in the liver and small intestine.
  15. Detecting mitochondrial electron transport chain enzyme defects in low-heteroplasmy single large-scale mtDNA deletion syndromes (SLSMDSs).
  1. Sci Adv. 2025 Oct 17. 11(42): eadx8662
    Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia.
    Sofia La Vecchia, Saurav Doshi, Petros Antonoglou, Tanima Kundu, Wafa Al Santli, Kleopatra Avrampou, Matthew T Witkowski, Anna Pellattiero, Federico Magrin, Kristina Ames, Amit Verma, Kira Gritsman, Xiaoyang Su, Andrea Mattarei, Iannis Aifantis, Luca Scorrano, Christina Glytsou.
      Acute myeloid leukemia (AML) is the most prevalent and deadliest adult leukemia. Its frontline treatment uses the BH3 mimetic venetoclax to trigger mitochondria-dependent apoptosis. However, drug resistance nearly always develops, calling for therapies to circumvent it. Advanced microscopy and genome-wide CRISPRi screen analyses pinpointed mitochondrial adaptations primarily mediated by the master regulator of cristae shape optic atrophy 1 (OPA1) as critical for BH3 mimetics resistance. Resistant AML cells up-regulate OPA1 to modify their mitochondrial structure and evade apoptosis. MYLS22 and Opitor-0, two specific and nontoxic OPA1 inhibitors, promote apoptotic cristae remodeling and cytochrome c release, synergizing with venetoclax in AML cells and xenografts derived from AML patients ex vivo and in vivo. Mechanistically, OPA1 loss renders AML cells dependent on glutamine and sensitizes them to ferroptosis by activating ATF4-regulated integrated stress responses. Overall, our data clarify how OPA1 up-regulation allows AML cells' metabolic flexibility and survival and nominates specific OPA1 inhibitors as efficacious tools to overcome venetoclax resistance in leukemia.
    DOI:  https://doi.org/10.1126/sciadv.adx8662
  2. Cells. 2025 Oct 08. pii: 1557. [Epub ahead of print]14(19):
    Quiescent OXPHOS-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend on BCL-XL for Survival.
    Slawomir Andrzejewski, Marie Winter, Leandro Encarnacao Garcia, Olusiji Akinrinmade, Francisco Madeira Marques, Emmanouil Zacharioudakis, Anna Skwarska, Julio Aguirre-Ghiso, Marina Konopleva, Guangrong Zheng, Susan A Fineberg, Daohong Zhou, Evripidis Gavathiotis, Tao Wang, Eugen Dhimolea.
      The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function ("OXPHOS-high" cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, suggestive of increased mitochondrial fusion. A genome-wide CRISPR editing screen in doxorubicin-persistent OXPHOS-high TNBC cells revealed the BCL-XL gene as the top survival dependency in these quiescent tumor cells, but not in their untreated proliferating counterparts. Quiescent OXPHOS-high TNBC cells were highly sensitive to BCL-XL inhibitors, but not to inhibitors of BCL2 and MCL1. Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis-targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy.
    Keywords:  BCL-XL; chemotherapy; oxidative phosphorylation; quiescence; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/cells14191557
  3. Cell Metab. 2025 Oct 10. pii: S1550-4131(25)00434-6. [Epub ahead of print]
    Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis.
    Artem Khan, Frederick S Yen, Gokhan Unlu, Nicole L DelGaudio, Ranya Erdal, Michael Xiao, Khando Wangdu, Kevin Cho, Eric R Gamazon, Gary J Patti, Kıvanç Birsoy.
      Solute carriers (SLCs) regulate cellular and organismal metabolism by transporting small molecules and ions across membranes, yet the physiological substrates of ∼20% remain elusive. To address this, we developed a machine-learning platform to predict gene-metabolite associations. This approach identifies UNC93A and SLC45A4 as candidate plasma membrane transporters for acetylglucosamine and polyamines, respectively. Additionally, we uncover SLC25A45 as a mitochondrial transporter linked to serum levels of methylated basic amino acids, products of protein catabolism. Mechanistically, SLC25A45 is necessary for the mitochondrial import of methylated basic amino acids, including ADMA and TML, the latter serving as a precursor for carnitine synthesis. In line with this observation, SLC25A45 loss impairs carnitine synthesis and blunts upregulation of carnitine-containing metabolites under fasted conditions. By facilitating mitochondrial TML import, SLC25A45 connects protein catabolism to carnitine production, sustaining β-oxidation during fasting. Altogether, our study identifies putative substrates for three SLCs and provides a resource for transporter deorphanization.
    Keywords:  SLC25A45; SLC45A4; UNC93A; acetylglucosamine; carnitine synthesis; fasting; metabolomic GWAS; mitochondrial metabolism; polyamines; solute carrier transporters
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.015
  4. Mol Cell. 2025 Oct 10. pii: S1097-2765(25)00703-8. [Epub ahead of print]
    SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.
    Marilia M Dias, Martin S King, Engy Shokry, Sergio Lilla, Nikki Paul, Peter Thomason, Sara Zanivan, David Sumpton, Edmund R S Kunji, Thomas MacVicar.
      Methylated amino acids accumulate upon the degradation of methylated proteins and are implicated in diverse metabolic and signaling pathways. Disturbed methylated amino acid homeostasis is associated with cardiovascular disease and renal failure. Mitochondria are core processing hubs in conventional amino acid metabolism, but how they interact with methylated amino acids is unclear. Here, we reveal that the orphan mitochondrial solute carrier 25A45 (SLC25A45) is required for the mitochondrial uptake of methylated amino acids. SLC25A45 binds with dimethylarginine and trimethyllysine but has no affinity for unmethylated arginine and lysine. A non-synonymous mutation of human SLC25A45 (R285C) stabilizes the carrier by limiting its proteolytic degradation and associates with altered methylated amino acids in human plasma. Metabolic tracing of trimethyllysine in cancer cells demonstrates that SLC25A45 drives the biosynthesis of the key amino acid derivative, carnitine. SLC25A45 is therefore an essential mediator of compartmentalized methylated amino acid metabolism.
    Keywords:  SLC25; carnitine; metabolism; metabolite transport; methylated amino acids; mitochondria; solute carriers
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.018
  5. Cancer Res. 2025 Oct 15.
    Metabolic Dependency on De Novo Pyrimidine Synthesis is a Targetable Vulnerability in Platinum Resistant Ovarian Cancer.
    Horacio Cardenas, Yinu Wang, Guangyuan Zhao, Delan Xingyue Hao, Ana Maria Isac, Vanessa Hernandez, Ujin Kim, Wenan Qiang, Hao F Zhang, Daniela Matei.
      Ovarian cancer (OC) is lethal due to near universal development of resistance to platinum-based chemotherapy. Metabolic adaptations can play a pivotal role in therapy resistance. Here, we aimed to identify key metabolic pathways that regulate platinum response and represent potential therapeutic targets. Transcriptomic and metabolomic analyses in cisplatin sensitive and resistant ovarian cancer cells identified enrichment of pyrimidine metabolism related to upregulated de novo pyrimidine synthesis. 15N-glutamine flux analysis confirmed increased de novo pyrimidine synthesis in cisplatin resistant cells. Targeting this pathway using brequinar (BRQ), an inhibitor of the key enzyme dihydroorotate dehydrogenase (DHODH), decreased cell viability, delayed G2/M cell cycle progression, and altered expression of genes related to mitochondrial electron transport in resistant cells. Under basal conditions, cisplatin resistant cells had a lower oxygen consumption rate (OCR) and spare respiratory capacity (SRC) than sensitive cells. BRQ suppressed OCR in both sensitive and resistant but only inhibited SRC in resistant cells. In cell line-derived and patient-derived xenograft models, BRQ attenuated the growth of cisplatin resistant ovarian tumors and enhanced the inhibitory effects of carboplatin. Together, these results identify metabolic reprogramming in cisplatin resistant ovarian cancer that induces an acquired dependency on de novo pyrimidine synthesis, which can be targeted to sensitize tumors to chemotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0043
  6. Mol Med. 2025 Oct 13. 31(1): 311
    Bioenergetics of cancer cells: insights into the Warburg effect and regulation of ATP synthase.
    Valentina Del Dotto, Silvia Grillini, Riccardo Righetti, Martina Grandi, Valentina Giorgio, Giancarlo Solaini, Alessandra Baracca.
      The study reported here offers new insights into the metabolic changes associated with the Warburg effect (i.e. aerobic glycolysis) in cancer cells and into the possible role of IF1, the endogenous inhibitor of ATP synthase that preserves cellular energy when it works in reverse, hydrolyzing ATP. We investigated biochemical and main bioenergetic parameters in cell lines derived from three human tumors: osteosarcoma (143B), colon carcinoma (HCT116), and cervix carcinoma (HeLa). The combination analysis of cellular glucose consumption, lactate production, ATP-linked respiration rate, ATP level, cell culture medium acidification rate, and ROS level demonstrates that aerobic glycolysis is differently expressed by the three different types of tumor cells, although all cell types exhibited a Warburg phenotype. The superoxide anion level was found to be lower in HCT116 cells, which showed the highest ratio between oxidative phosphorylation and glycolysis rates, while ROS level was similar in all cells examined, suggesting that mitochondria in HCT116 are very efficient in both energy production and limiting their oxidative stress. Additionally, IF1 KD cells of all kinds of tumor showed higher level of ROS compared to their related IF1-expressing cells. Most of the results reported here clearly demonstrate that aerobic glycolysis is completely independent on both the level of IF1 and the IF1/ATP synthase ratio, excluding the contribution of an IF1-dependent mechanism in the metabolic shift of cancer cells towards glycolysis. Indeed, the study provides a detailed analysis of the bioenergetics of tumor cells exhibiting very different IF1/ATP synthase ratios and shows that IF1 KD cells of all tumor types had a higher level of ROS than their related IF1-expressing cells. Overall, the comprehensive picture of tumor cell bioenergetics would facilitate the identification of appropriate drugs for targeted tumor treatments, such as ATP synthase-IF1 immunotherapy that would strongly limit cellular resistance to severe hypoxia or anoxia, where IF1 plays an effective critical role.
    Keywords:  ATP synthase; Aerobic glycolysis; Bioenergetics; Cancer; IF1 ; Mitochondria; ROS
    DOI:  https://doi.org/10.1186/s10020-025-01378-0
  7. Cell Metab. 2025 Oct 15. pii: S1550-4131(25)00393-6. [Epub ahead of print]
    Nutrient allocation fuels T cell-mediated immunity.
    Joseph Longo, McLane J Watson, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.
      T cell activation and function are intricately linked to metabolic reprogramming. The classic view of T cell metabolic reprogramming centers on glucose as the dominant bioenergetic fuel, where T cell receptor (TCR) stimulation promotes a metabolic switch from relying primarily on oxidative phosphorylation (OXPHOS) for energy production to aerobic glycolysis (i.e., the Warburg effect). More recently, studies have revealed this classic model to be overly simplistic. Activated T cells run both glycolysis and OXPHOS programs concurrently, allocating diverse nutrient sources toward distinct biosynthetic and bioenergetic fates. Moreover, studies of T cell metabolism in vivo and ex vivo highlight that physiologic nutrient availability influences how glucose is allocated by T cells to fuel both optimal proliferation and effector function. Here, we summarize recent advancements that support a revised model of effector T cell metabolism, where strategic nutrient allocation fuels optimal T cell-mediated immunity.
    Keywords:  T cells; adaptive immunity; effector function; glucose; immunometabolism; nutrient allocation
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.008
  8. Curr Biol. 2025 Oct 15. pii: S0960-9822(25)01246-1. [Epub ahead of print]
    Mitochondrial function regulates cell growth kinetics to maintain mitochondrial homeostasis.
    Leeba A Chacko, Hidenori Nakaoka, Richard G Morris, Wallace F Marshall, Vaishnavi Ananthanarayanan.
      Mitochondria are not produced de novo in newly divided daughter cells but are inherited from the mother cell during mitosis. While mitochondrial homeostasis is crucial for living cells, the feedback responses that maintain mitochondrial volume across generations of dividing cells remain elusive. Here, using a microfluidic yeast "mother machine," we tracked several generations of fission yeast cells and observed that cell size and mitochondrial volume grew exponentially during the cell cycle. We discovered that while mitochondrial homeostasis relied on the "sizer" mechanism of cell size maintenance, mitochondrial function was a critical determinant of the timing of cell division; cells born with lower-than-average amounts of mitochondria grew slower and thus added more mitochondria before they divided. Thus, mitochondrial addition during the cell cycle was tailored to the volume of mitochondria at birth, such that all cells ultimately contained the same mitochondrial volume at cell division. Quantitative modeling and experiments with mitochondrial DNA-deficient rho0 cells additionally revealed that mitochondrial function was essential for driving the exponential growth of cells. Altogether, we demonstrate a central role for mitochondrial activity in dictating cellular growth rates and ensuring mitochondrial volume homeostasis.
    Keywords:  S. pombe; fission yeast; growth kinetics; homeostasis; microfluidics; mitochondria; yeast mother machine
    DOI:  https://doi.org/10.1016/j.cub.2025.09.046
  9. J Cell Mol Med. 2025 Oct;29(19): e70704
    BNIP3L/BNIP3-Mediated Mitophagy Contributes to the Maintenance of Ovarian Cancer Stem Cells.
    Na Li, Tejinder Pal Khaket, Yajing Yang, Linzhou Wang, Shurui Cai, Aidan Li, Elsa Wani, Jessica Miao, Nan Zhang, Qingfei Zheng, Junran Zhang, Xuefeng Liu, Selvendiran Karuppaiyah, Dehua Pei, Qi-En Wang.
      Ovarian cancer remains the most lethal gynaecological malignancy, with tumour recurrence and chemoresistance posing significant therapeutic challenges. Emerging evidence suggests that cancer stem cells (CSCs), a rare subpopulation within tumours with self-renewal and differentiation capacities, contribute to these hurdles. Therefore, elucidating the mechanisms that sustain CSCs is critical for improving treatment strategies. Mitophagy, a selective process for eliminating damaged mitochondria, plays a key role in maintaining cellular homeostasis, including CSC survival. Our study demonstrates that ovarian CSCs exhibit enhanced mitophagy, accompanied by elevated expression of the mitochondrial outer membrane receptors BNIP3 and BNIP3L. Knockdown of BNIP3 or BNIP3L significantly reduces mitophagy and impairs CSC self-renewal, indicating that receptor-mediated mitophagy is essential for CSC maintenance. Mechanistically, we identify that hyperactivated NF-κB signalling drives the upregulation of BNIP3 and BNIP3L in ovarian CSCs. Inhibition of NF-κB signalling, either via p65 knockdown or pharmacological inhibitors, effectively suppresses mitophagy. Furthermore, we demonstrate that elevated DNA-PK expression contributes to the constitutive activation of NF-κB signalling, thereby promoting mitophagy in ovarian CSCs. In summary, our findings establish that BNIP3/BNIP3L-mediated mitophagy, driven by DNA-PK-dependent NF-κB hyperactivation, is essential for CSC maintenance. Targeting the DNA-PK/NF-κB/BNIP3L-BNIP3 axis to disrupt mitochondrial quality control in CSCs represents a promising therapeutic strategy to prevent ovarian cancer recurrence and metastasis.
    Keywords:  BNIP3; BNIP3L; DNA‐PK; NF‐κB; cancer stem cells; mitophagy; ovarian cancer
    DOI:  https://doi.org/10.1111/jcmm.70704
  10. Biochim Biophys Acta Mol Basis Dis. 2025 Oct 10. pii: S0925-4439(25)00418-1. [Epub ahead of print]1872(2): 168070
    Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.
    Zeinab Alsadat Ahmadi, Alfredo Cabrera-Orefice, Marta Zaninello, Esther Barth, Matteo Veronese, Richard Rodenburg, Elena I Rugarli, Susanne Brodesser, Susanne Arnold, Ulrich Brandt.
      Inherited mitochondrial disorders are of multiple genetic origins and may lead to a broad range of frequently severe disease phenotypes. Yet, how molecular causes ultimately present as a clinical phenotype is poorly understood. To address this conundrum starting from the molecular defect, we thoroughly investigated the consequences of the well-known pathogenic mitochondrial DNA mutation m.10191T>C. The mutation changes serine-45 in subunit ND3 of respiratory chain complex I to proline and causes Leigh syndrome, which is one of the most devastating mitochondrial diseases. Human mitochondria carrying the mutation ND3S45P retained 30-40 % of complex I activity and oxidative phosphorylation capacity. In stark contrast, intact mutant cells exhibited only minimal oxygen consumption and a massively increased NADH/NAD+ ratio. Since the energy barrier for the Active/Deactive transition of complex I was reduced by ∼20 kJ∙mol-1 in mutant cells, we concluded that complex I was shut-off by malfunctioning of an as yet unknown regulatory pathway. Comprehensive analysis of the mitochondrial complexome of cybrids, patient fibroblasts and muscle biopsies rendered other causes for the accumulation of NADH unlikely. The complexome datasets provide a rich resource for further studies to discover possible additional factors involved in regulating complex I. We propose that the derailed regulation of complex I is the main culprit leading to NADH accumulation and eventually the severity of the disease phenotype caused by mutation ND3S45P.
    Keywords:  Active/deactive transition; Complex I; Complexome profiling; Mitochondria; Mitochondrial disease; mtDNA
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168070
  11. Life Sci Alliance. 2025 Dec;pii: e202302563. [Epub ahead of print]8(12):
    POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels.
    Maria Miranda, Andrea Mesaros, Nathalie Scrima, Louise Pérard, Irina Kuznetsova, Martin Purrio, Ilian Atanassov, Aleksandra Filipovska, Arnaud Mourier, Nils-Göran Larsson, Inge Kühl.
      POLRMT is the sole RNA polymerase in human mitochondria, where it generates primers for mitochondrial DNA (mtDNA) replication and transcribes the mtDNA to express genes encoding essential components of the oxidative phosphorylation (OXPHOS) system. Elevated POLRMT levels are found in several cancers and in mouse models with severe mitochondrial dysfunction. Here, we generated and characterized mice overexpressing Polrmt to investigate the physiological and molecular consequences of elevated POLRMT levels. Increasing POLRMT levels did not result in any pathological phenotype but led to increased exercise performance in male mice under stress conditions. Polrmt overexpression increased mtDNA transcription initiation, resulting in higher steady-state levels of the promoter-proximal L-strand transcript 7S RNA. Surprisingly, the abundance of mature mitochondrial RNAs was not affected by the elevated POLRMT levels. Furthermore, ubiquitous simultaneous overexpression of Polrmt and Lrpprc, which stabilizes mitochondrial messenger RNAs, did not increase steady-state levels of mitochondrial transcripts in the mouse. Our data show that POLRMT levels regulate transcription initiation, but additional regulatory steps downstream of transcription initiation and transcript stability limit OXPHOS biogenesis.
    DOI:  https://doi.org/10.26508/lsa.202302563
  12. Cell Metab. 2025 Oct 16. pii: S1550-4131(25)00394-8. [Epub ahead of print]
    Aged mice exhibit widespread metabolic changes but preserved major fluxes.
    Connor S R Jankowski, Laith Z Samarah, Michael R MacArthur, Sarah J Mitchell, Daniel R Weilandt, Craig J Hunter, Xianfeng Zeng, Melanie R McReynolds, Joshua D Rabinowitz.
      Metabolic dysregulation is a hallmark of aging. Here, we investigate in mice age-induced metabolic alterations using metabolomics and stable isotope tracing. Circulating metabolite fluxes and serum and tissue concentrations were measured in young and old (20-30 months) C57BL/6J mice, with young obese (ob/ob) mice as a comparator. For major circulating metabolites, concentrations changed more with age than fluxes, and fluxes changed more with obesity than with aging. Specifically, glucose, lactate, 3-hydroxybutryate, and many amino acids (but notably not taurine) change significantly in concentration with age. Only glutamine circulatory flux does so. The fluxes of major circulating metabolites remain stable despite underlying metabolic changes. For example, lysine catabolism shifts from the saccharopine toward the pipecolic acid pathway, and both pipecolic acid concentration and flux increase with aging. Other less-abundant metabolites also show coherent, age-induced concentration and flux changes. Thus, while aging leads to widespread metabolic changes, major metabolic fluxes are largely preserved.
    Keywords:  aging; fluxomics; glutamine; metabolic flux; metabolism; metabolomics; obesity; stable isotope tracing; systemic metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.009
  13. Cancer Cell Int. 2025 Oct 17. 25(1): 362
    Efficient identification of new small molecules targeting succinate dehydrogenase in non-small cell lung cancer.
    Luis Silva, Nicholas Skiados, Nikitha Murugavel, Karen Cover, Nastassja Luna, Manish K Gupta, Stephanie C Contreras, Terrence E O'Brien, Wen Cai Zhang.
       BACKGROUND: Lung cancer treatment efficacy remains a challenge due to limited therapeutic targets. Succinate dehydrogenase (SDH) enzyme, a crucial enzyme linking the citric acid cycle and the electron transport chain, is implicated in cancer metabolism. While existing compounds target metabolic diseases in vitro, SDH-targeted therapy for lung cancer remains elusive.
    METHODS: We assessed SDH expression levels in non-small cell lung (NSCLC) tissues and cell lines. Leveraging AtomNet® technology for compound identification, coupled with mitochondria- and cell-based enzyme activity assays, we discovered new SDH inhibitors. Using 2D monolayer, 3D organoid culture, and assays for cell viability, migration, mitochondrial reactive oxygen species, oxygen consumption rate, succinate accumulation, and apoptosis, we elucidated their mechanism targeting lung malignancy.
    RESULTS: SDH subunits were found to be overexpressed in NSCLC tissues compared to tumor-adjacent normal tissues. Two new SDH inhibitors were identified from 96 predicted candidates. Cellular thermal shift assay confirmed direct binding of these small molecules to SDH subunits in lung cancer cells. Mechanistically, treatment increased cellular and mitochondrial reactive oxygen species, succinate accumulation, and induced apoptosis by damaging mitochondria and DNA, while modulating SDH protein expression. Functionally, these molecules reduced growth, migration, and 3D organoid formation in lung cancer cell lines in vitro, both short and long term.
    CONCLUSIONS: Our SDH inhibitors halt tumor growth and migration by targeting key substrate binding sites, showing superior efficacy over existing small molecule antagonists. They also modulate SDH protein expression, suggesting a promising dual-targeting strategy for cancer therapy. This study sheds light on SDH function in cancer-related metabolic dysfunction and underscores the potential of SDH modulation as a therapeutic strategy for lung cancer and beyond.
    Keywords:  Cell apoptosis; Non-small cell lung cancer; Oxygen consumption rate; Reactive oxygen species; SDH; Small molecule inhibitor
    DOI:  https://doi.org/10.1186/s12935-025-04002-7
  14. Nature. 2025 Oct 15.
    Spatial metabolic gradients in the liver and small intestine.
    Laith Z Samarah, Clover Zheng, Xi Xing, Won Dong Lee, Amichay Afriat, Uthsav Chitra, Michael R MacArthur, Wenyun Lu, Connor S R Jankowski, Cong Ma, Craig J Hunter, Michael Neinast, Daniel R Weilandt, Benjamin J Raphael, Joshua D Rabinowitz.
      The properties of mammalian cells depend on their location within organs. Gene expression in the liver varies between periportal and pericentral hepatocytes1-3, and in the intestine from crypts to villus tips4,5. A key element of tissue spatial organization is probably metabolic, but direct assessments of spatial metabolism remain limited. Here we map spatial metabolic gradients in the mouse liver and intestine. We develop an integrated experimental-computational workflow using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS), isotope tracing and deep-learning artificial intelligence. Most measured metabolites (>90%) showed significant spatial concentration gradients in the liver lobules and intestinal villi. In the liver, tricarboxylic acid (TCA)-cycle metabolites and their isotope labelling from both glutamine and lactate localized periportally. Energy-stress metabolites, including adenosine monophosphate (AMP), also localized periportally, consistent with a high periportal energy demand. In the intestine, the TCA intermediates malate (tip) and citrate (crypt) showed opposite spatial patterns, aligning with higher glutamine catabolism in tips and lactate oxidation in crypts based on isotope tracing. Finally, we mapped the fate of the obesogenic dietary sugar fructose. In the intestine, oral fructose was catabolized faster in the villus bottom than in the tips. In the liver, fructose-derived carbon accumulated pericentrally as fructose-1-phosphate and triggered pericentral adenosine triphosphate (ATP) depletion. Thus, we both provide foundational knowledge regarding intestine and liver metabolic organization and identify fructose-induced focal derangements in liver metabolism.
    DOI:  https://doi.org/10.1038/s41586-025-09616-5
  15. Mol Genet Metab. 2025 Oct 08. pii: S1096-7192(25)00252-5. [Epub ahead of print]146(3): 109260
    Detecting mitochondrial electron transport chain enzyme defects in low-heteroplasmy single large-scale mtDNA deletion syndromes (SLSMDSs).
    Xueyang Pan, Yue Wang, Ning Liu, Xi Luo, V Reid Sutton, William J Craigen, Qin Sun.
      Large deletions in multi-copy mitochondrial DNA (mtDNA) are associated with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), and Pearson syndrome (PS), collectively referred to as single large-scale mtDNA deletion syndromes (SLSMDSs). These deletions are typically sporadic and heteroplasmic, yet the relationship between heteroplasmy levels and disease severity remains uncertain, particularly for low level deletions, making pathogenicity assessment challenging. To evaluate the functional impact of mtDNA deletions in muscle, we retrospectively analyzed 1104 consecutive clinical cases with both mtDNA sequencing and mitochondrial electron transport chain (ETC) enzyme assays performed on the same muscle specimen. Fifteen cases (1.4 %) carried a single large mtDNA deletion and exhibited clinical features consistent with the CPEO/KSS spectrum. Of these, seven showed ETC deficiencies despite low deletion heteroplasmy levels (<10 % in all cases). Four had enzyme deficiencies defined to a single complex, while three had deficiencies in multiple complexes. Complex IV was most frequently impaired, whereas nuclear-encoded complex II activity remained normal in all samples. Notably, the pattern of ETC impairment did not fully correlate with the specific mitochondrial genes disrupted by the deletions. These findings demonstrate that mitochondrial dysfunction can occur at mtDNA deletion heteroplasmy levels far below conventional pathogenic thresholds. This highlights the diagnostic relevance of low-level mtDNA deletions and supports the integration of molecular and functional testing in accurate SLSMDS diagnosis.
    Keywords:  Chronic progressive external ophthalmoplegia (CPEO); ETC complex enzymatic assay; Heteroplasmy; Kearns-Sayre syndrome (KSS); Mitochondrial electron transport chain (ETC); Single large-scale mtDNA deletion syndrome (SLSMDS); mtDNA deletion; mtDNA next-generation sequencing (NGS)
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109260
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