bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–02–02
29 papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
  2. Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
  3. BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer.
  4. An Addendum to the Chemiosmotic Theory of Mitochondrial Activity: The Role of RNA as a Proton Sink.
  5. Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival.
  6. FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.
  7. The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives.
  8. Mitochondrial cristae: lung cancer metabolism architects.
  9. SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.
  10. Autophagic flux-lipid droplet biogenesis cascade sustains mitochondrial fitness in colorectal cancer cells adapted to acidosis.
  11. Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth.
  12. Electrical homeostasis of the inner mitochondrial membrane potential.
  13. Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.
  14. Epstein-Barr virus-driven cardiolipin synthesis sustains metabolic remodeling during B cell transformation.
  15. Sub-organellar mitochondrial hydrogen peroxide observed using a SNAP tag targeted coumarin-based fluorescent reporter.
  16. Methylmalonic acid at the serum level in the elderly contributes to cell growth via mitochondrial dysfunction in colorectal cancer cell spheroids.
  17. Germline Single-Nucleotide Polymorphism GFI1-36N Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia.
  18. Spatial metabolomics to unravel cellular metabolism.
  19. The curious case of mitochondrial sirtuin in rewiring breast cancer metabolism: Mr Hyde or Dr Jekyll?
  20. Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability.
  21. SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation.
  22. Flux measurements of the tricarboxylic acid cycle in the tumors of mice.
  23. A novel FOXM1-BCL2A1 axis determines unfavourable response to venetoclax in AML.
  24. Cellular senescence induced by down-regulation of PTBP1 correlates with exon skipping of mitochondrial-related gene NDUFV3.
  25. Redirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy.
  26. OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth.
  27. Serine phosphorylation facilitates protein degradation by the human mitochondrial ClpXP protease.
  28. Atovaquone and selinexor as a novel combination treatment option in acute myeloid leukemia.
  29. Correcting a pathogenic mitochondrial DNA mutation by base editing in mice.
  1. Trends Endocrinol Metab. 2025 Jan 28. pii: S1043-2760(25)00003-7. [Epub ahead of print]
    Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
    Brandon Chen, Yatrik M Shah, Costas A Lyssiotis.
      Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell. They demonstrate that subcellular mitochondrial heterogeneity enables metabolic compartmentalization to permit concurrent oxidative ATP production and reductive proline biosynthesis.
    Keywords:  metabolic compartmentalization; mitochondria dynamics; mitochondrial ultrastructure; organelle communication; proline metabolism
    DOI:  https://doi.org/10.1016/j.tem.2025.01.003
  2. Nat Cell Biol. 2025 Jan 24.
    Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
      
    DOI:  https://doi.org/10.1038/s41556-024-01603-8
  3. Life Metab. 2024 Aug;3(4): loae016
    BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer.
    Wen Mi, Jianwei You, Liucheng Li, Lingzhi Zhu, Xinyi Xia, Li Yang, Fei Li, Yi Xu, Junfeng Bi, Pingyu Liu, Li Chen, Fuming Li.
      Bromodomain and extra-terminal domain (BET) proteins, which function partly through MYC proto-oncogene (MYC), are critical epigenetic readers and emerging therapeutic targets in cancer. Whether and how BET inhibition simultaneously induces metabolic remodeling in cancer cells remains unclear. Here we find that even transient BET inhibition by JQ-1 and other pan-BET inhibitors (pan-BETis) blunts liver cancer cell proliferation and tumor growth. BET inhibition decreases glycolytic gene expression but enhances mitochondrial glucose and glutamine oxidative metabolism revealed by metabolomics and isotope labeling analysis. Specifically, BET inhibition downregulates miR-30a to upregulate glutamate dehydrogenase 1 (GDH1) independent of MYC, which produces α-ketoglutarate for mitochondrial oxidative phosphorylation (OXPHOS). Targeting GDH1 or OXPHOS is synthetic lethal to BET inhibition, and combined BET and OXPHOS inhibition therapeutically prevents liver tumor growth in vitro and in vivo. Together, we uncover an important epigenetic-metabolic crosstalk whereby BET inhibition induces MYC-independent and GDH1-dependent glutamine metabolic remodeling that can be exploited for innovative combination therapy of liver cancer.
    Keywords:  BET; glutamate dehydrogenase 1; glutamine metabolism; oxidative phosphorylation; synthetic lethality
    DOI:  https://doi.org/10.1093/lifemeta/loae016
  4. Biomolecules. 2025 Jan 08. pii: 87. [Epub ahead of print]15(1):
    An Addendum to the Chemiosmotic Theory of Mitochondrial Activity: The Role of RNA as a Proton Sink.
    Ramin M Farahani.
      Mitochondrial ATP synthesis is driven by harnessing the electrochemical gradient of protons (proton motive force) across the mitochondrial inner membrane via the process of chemiosmosis. While there is consensus that the proton gradient is generated by components of the electron transport chain, the mechanism by which protons are supplied to ATP synthase remains controversial. As opposed to a global coupling model whereby protons diffuse into the intermembrane space, a localised coupling model predicts that protons remain closely associated with the lipid membrane prior to interaction with ATP synthase. Herein, a revised version of the chemiosmotic theory is proposed by introducing an RNA-based proton sink which aligns the release of sequestered protons to availability of ADP and Pi thereby maximising the efficiency of oxidative phosphorylation.
    Keywords:  RNA; chemiosmosis; proton motive force; proton sink
    DOI:  https://doi.org/10.3390/biom15010087
  5. Cell Commun Signal. 2025 Jan 25. 23(1): 47
    Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival.
    Monika Komza, Jesminara Khatun, Jesse D Gelles, Andrew P Trotta, Ioana Abraham-Enachescu, Juan Henao, Ahmed Elsaadi, Andriana G Kotini, Cara Clementelli, JoAnn Arandela, Sebastian El Ghaity-Beckley, Agneesh Barua, Yiyang Chen, Mirela Berisa, Bridget K Marcellino, Eirini P Papapetrou, Masha V Poyurovsky, Jerry Edward Chipuk.
      One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.
    Keywords:  Adaptations; Bioenergetics; Cancer; Chemotherapy; Glucose; Leukemia; Metabolism; Mitochondria; Oncogenes; Stem cells
    DOI:  https://doi.org/10.1186/s12964-025-02044-y
  6. J Cell Biol. 2025 Mar 03. pii: e202311082. [Epub ahead of print]224(3):
    FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.
    Alva G Sainz, Gladys R Rojas, Alexandra G Moyzis, Matthew P Donnelly, Kailash C Mangalhara, Melissa A Johnson, Pau B Esparza-Moltó, Kym J Grae, Reuben J Shaw, Gerald S Shadel.
      Mitochondrial retrograde signaling (MRS) pathways relay the functional status of mitochondria to elicit homeostatic or adaptive changes in nuclear gene expression. Budding yeast have "intergenomic signaling" pathways that sense the amount of mitochondrial DNA (mtDNA) independently of oxidative phosphorylation (OXPHOS), the primary function of genes encoded by mtDNA. However, MRS pathways that sense the amount of mtDNA in mammalian cells remain poorly understood. We found that mtDNA-depleted IMR90 cells can sustain OXPHOS for a significant amount of time, providing a robust model system to interrogate human intergenomic signaling. We identified FAM43A, a largely uncharacterized protein, as a CHK2-dependent early responder to mtDNA depletion. Depletion of FAM43A activates a mitochondrial biogenesis program, resulting in an increase in mitochondrial mass and mtDNA copy number via CHK2-mediated upregulation of the p53R2 form of ribonucleotide reductase. We propose that FAM43A performs a checkpoint-like function to limit mitochondrial biogenesis and turnover under conditions of mtDNA depletion or replication stress.
    DOI:  https://doi.org/10.1083/jcb.202311082
  7. Int J Mol Sci. 2024 Dec 26. pii: 92. [Epub ahead of print]26(1):
    The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives.
    Amer Ahmed, Giorgia Natalia Iaconisi, Daria Di Molfetta, Vincenzo Coppola, Antonello Caponio, Ansu Singh, Aasia Bibi, Loredana Capobianco, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte.
      Cancer cells undergo remarkable metabolic changes to meet their high energetic and biosynthetic demands. The Warburg effect is the most well-characterized metabolic alteration, driving cancer cells to catabolize glucose through aerobic glycolysis to promote proliferation. Another prominent metabolic hallmark of cancer cells is their increased reliance on glutamine to replenish tricarboxylic acid (TCA) cycle intermediates essential for ATP production, aspartate and fatty acid synthesis, and maintaining redox homeostasis. In this context, mitochondria, which are primarily used to maintain energy homeostasis and support balanced biosynthesis in normal cells, become central organelles for fulfilling the heightened biosynthetic and energetic demands of proliferating cancer cells. Mitochondrial coordination and metabolite exchange with other cellular compartments are crucial. The human SLC25 mitochondrial carrier family, comprising 53 members, plays a pivotal role in transporting TCA intermediates, amino acids, vitamins, nucleotides, and cofactors across the inner mitochondrial membrane, thereby facilitating this cross-talk. Numerous studies have demonstrated that mitochondrial carriers are altered in cancer cells, actively contributing to tumorigenesis. This review comprehensively discusses the role of SLC25 carriers in cancer pathogenesis and metabolic reprogramming based on current experimental evidence. It also highlights the research gaps that need to be addressed in future studies. Understanding the involvement of these carriers in tumorigenesis may provide valuable novel targets for drug development.
    Keywords:  cancer; metabolic reprogramming; metabolism; mitochondria; mitochondrial carriers
    DOI:  https://doi.org/10.3390/ijms26010092
  8. Life Metab. 2023 Apr;2(2): load015
    Mitochondrial cristae: lung cancer metabolism architects.
    Masafumi Noguchi, Luca Scorrano.
      
    DOI:  https://doi.org/10.1093/lifemeta/load015
  9. Nat Commun. 2025 Jan 24. 16(1): 978
    SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.
    Izabella A Pena, Jeffrey S Shi, Sarah M Chang, Jason Yang, Samuel Block, Charles H Adelmann, Heather R Keys, Preston Ge, Shveta Bathla, Isabella H Witham, Grzegorz Sienski, Angus C Nairn, David M Sabatini, Caroline A Lewis, Nora Kory, Matthew G Vander Heiden, Myriam Heiman.
      Many essential proteins require pyridoxal 5'-phosphate, the active form of vitamin B6, as a cofactor for their activity. These include enzymes important for amino acid metabolism, one-carbon metabolism, polyamine synthesis, erythropoiesis, and neurotransmitter metabolism. A third of all mammalian pyridoxal 5'-phosphate-dependent enzymes are localized in the mitochondria; however, the molecular machinery involved in the regulation of mitochondrial pyridoxal 5'-phosphate levels in mammals remains unknown. In this study, we used a genome-wide CRISPR interference screen in erythroleukemia cells and organellar metabolomics to identify the mitochondrial inner membrane protein SLC25A38 as a regulator of mitochondrial pyridoxal 5'-phosphate. Loss of SLC25A38 causes depletion of mitochondrial, but not cellular, pyridoxal 5'-phosphate, and impairs cellular proliferation under both physiological and low vitamin B6 conditions. Metabolic changes associated with SLC25A38 loss suggest impaired mitochondrial pyridoxal 5'-phosphate-dependent enzymatic reactions, including serine to glycine conversion catalyzed by serine hydroxymethyltransferase-2 as well as ornithine aminotransferase. The proliferation defect of SLC25A38-null K562 cells in physiological and low vitamin B6 media can be explained by the loss of serine hydroxymethyltransferase-2-dependent production of one-carbon units and downstream de novo nucleotide synthesis. Our work points to a role for SLC25A38 in mitochondrial pyridoxal 5'-phosphate accumulation and provides insights into the pathology of congenital sideroblastic anemia.
    DOI:  https://doi.org/10.1038/s41467-025-56130-3
  10. Cell Death Discov. 2025 Jan 25. 11(1): 21
    Autophagic flux-lipid droplet biogenesis cascade sustains mitochondrial fitness in colorectal cancer cells adapted to acidosis.
    Xiaojie Liu, Xue Sun, Wenqing Mu, Yanan Li, Wenqing Bu, Tingting Yang, Jia Zhang, Rui Liu, Jiayu Ren, Jin Zhou, Peishan Li, Yufang Shi, Changshun Shao.
      Cancer development is associated with adaptation to various stressful conditions, such as extracellular acidosis. The adverse tumor microenvironment also selects for increased malignancy. Mitochondria are integral in stress sensing to allow for tumor cells to adapt to stressful conditions. Here, we show that colorectal cancer cells adapted to acidic microenvironment (CRC-AA) are more reliant on oxidative phosphorylation than their parental cells, and the acetyl-CoA in CRC-AA cells are generated from fatty acids and glutamine, but not from glucose. Consistently, CRC-AA cells exhibit increased mitochondrial mass and fitness that depends on an upregulated autophagic flux-lipid droplet axis. Lipid droplets (LDs) function as a buffering system to store the fatty acids derived from autophagy and to protect mitochondria from lipotoxicity in CRC-AA cells. Blockade of LD biogenesis causes mitochondrial dysfunction that can be rescued by inhibiting carnitine palmitoyltransferase 1 α (CPT1α). High level of mitochondrial superoxide is essential for the AMPK activation, resistance to apoptosis, high autophagic flux and mitochondrial function in CRC-AA cells. Thus, our results demonstrate that the cascade of autophagic flux and LD formation plays an essential role in sustaining mitochondrial fitness to promote cancer cell survival under chronic acidosis. Our findings provide insight into the pro-survival metabolic plasticity in cancer cells under microenvironmental or therapeutic stress and imply that this pro-survival cascade may potentially be targeted in cancer therapy.
    DOI:  https://doi.org/10.1038/s41420-025-02301-6
  11. Nat Commun. 2025 Jan 30. 16(1): 1191
    Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth.
    Yanhan Jia, Sheng Wang, Sylvia Urban, Judith M Müller, Manuela Sum, Qing Wang, Helena Bauer, Uwe Schulte, Heike Rampelt, Nikolaus Pfanner, Katrin M Schüle, Axel Imhof, Ignasi Forné, Christopher Berlin, August Sigle, Christian Gratzke, Holger Greschik, Eric Metzger, Roland Schüle.
      Prostate cancer (PCa) growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). In this study, we identify lysine methyltransferase (KMT)9 as a regulator of PDC activity. KMT9 is localized in mitochondria of PCa cells, but not in mitochondria of other tumor cell types. Mitochondrial KMT9 regulates PDC activity by monomethylation of its subunit dihydrolipoamide transacetylase (DLAT) at lysine 596. Depletion of KMT9 compromises PDC activity, de novo lipogenesis, and PCa cell proliferation, both in vitro and in a PCa mouse model. Finally, in human patients, levels of mitochondrial KMT9 and DLAT K596me1 correlate with Gleason grade. Together, we present a mechanism of PDC regulation and an example of a histone methyltransferase with nuclear and mitochondrial functions. The dependency of PCa cells on mitochondrial KMT9 allows to develop therapeutic strategies to selectively fight PCa.
    DOI:  https://doi.org/10.1038/s41467-025-56492-8
  12. Phys Biol. 2025 Jan 31. 22(2):
    Electrical homeostasis of the inner mitochondrial membrane potential.
    Peyman Fahimi, Lázaro A M Castanedo, P Thomas Vernier, Chérif F Matta.
      The electric potential across the inner mitochondrial membrane must be maintained within certain bounds for the proper functioning of the cell. A feedback control mechanism for the homeostasis of this membrane potential is proposed whereby an increase in the electric field decreases the rate-limiting steps of the electron transport chain (ETC). An increase in trans-membrane electric field limits the rate of proton pumping to the inter-membrane gap by slowing the ETC reactions and by intrinsically induced electroporation that depolarizes the inner membrane. The proposed feedback mechanism is akin to a Le Chatelier's-type principle of trans-membrane potential feedback control.
    Keywords:  chemiosmotic theory; electrical feedback control in biological systems; mitochondrial biophysics; mitochondrial electric potential; mitochondrial homeostasis
    DOI:  https://doi.org/10.1088/1478-3975/adaa47
  13. Cell Death Dis. 2025 Jan 25. 16(1): 40
    Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.
    Lohans Pedrera, Laura Prieto Clemente, Alina Dahlhaus, Sara Lotfipour Nasudivar, Sofya Tishina, Daniel Olmo González, Jenny Stroh, Fatma Isil Yapici, Randhwaj Pratap Singh, Nils Grotehans, Thomas Langer, Ana J García-Sáez, Silvia von Karstedt.
      Constitutive mitochondrial dynamics ensure quality control and metabolic fitness of cells, and their dysregulation has been implicated in various human diseases. The large GTPase Dynamin-related protein 1 (Drp1) is intimately involved in mediating constitutive mitochondrial fission and has been implicated in mitochondrial cell death pathways. During ferroptosis, a recently identified type of regulated necrosis driven by excessive lipid peroxidation, mitochondrial fragmentation has been observed. Yet, how this is regulated and whether it is involved in ferroptotic cell death has remained unexplored. Here, we provide evidence that Drp1 is activated upon experimental induction of ferroptosis and promotes cell death execution and mitochondrial fragmentation. Using time-lapse microscopy, we found that ferroptosis induced mitochondrial fragmentation and loss of mitochondrial membrane potential, but not mitochondrial outer membrane permeabilization. Importantly, Drp1 accelerated ferroptotic cell death kinetics. Notably, this function was mediated by the regulation of mitochondrial dynamics, as overexpression of Mitofusin 2 phenocopied the effect of Drp1 deficiency in delaying ferroptosis cell death kinetics. Mechanistically, we found that Drp1 is phosphorylated and activated after induction of ferroptosis and that it translocates to mitochondria. Further activation at mitochondria through the phosphatase PGAM5 promoted ferroptotic cell death. Remarkably, Drp1 depletion delayed mitochondrial and plasma membrane lipid peroxidation. These data provide evidence for a functional role of Drp1 activation and mitochondrial fragmentation in the acceleration of ferroptotic cell death, with important implications for targeting mitochondrial dynamics in diseases associated with ferroptosis.
    DOI:  https://doi.org/10.1038/s41419-024-07312-2
  14. Sci Adv. 2025 Jan 31. 11(5): eadr8837
    Epstein-Barr virus-driven cardiolipin synthesis sustains metabolic remodeling during B cell transformation.
    Haixi You, Larissa Havey, Zhixuan Li, Yin Wang, John M Asara, Rui Guo.
      The Epstein-Barr virus (EBV) infects nearly 90% of adults globally and is linked to over 200,000 annual cancer cases. Immunocompromised individuals from conditions such as primary immune disorders, HIV, or posttransplant immunosuppressive therapies are particularly vulnerable because of EBV's transformative capability. EBV remodels B cell metabolism to support energy, biosynthetic precursors, and redox equivalents necessary for transformation. Most EBV-driven metabolic pathways center on mitochondria. However, how EBV regulates B cell mitochondrial function and metabolic fluxes remains unclear. Here, we show that EBV boosts cardiolipin (CL) biosynthesis, essential for mitochondrial cristae biogenesis, via EBV nuclear antigen 2/MYC-induced CL enzyme transactivation. Pharmacological and CRISPR genetic analyses underscore the essentiality of CL biosynthesis in EBV-transformed B cells. Metabolomic and isotopic tracing highlight CL's role in sustaining respiration, one-carbon metabolism, and aspartate synthesis. Disrupting CL biosynthesis destabilizes mitochondrial matrix enzymes pivotal to these pathways. We demonstrate EBV-induced CL metabolism as a therapeutic target, offering synthetic lethal strategies against EBV-associated B cell malignancies.
    DOI:  https://doi.org/10.1126/sciadv.adr8837
  15. Redox Biol. 2025 Jan 20. pii: S2213-2317(25)00015-1. [Epub ahead of print]80 103502
    Sub-organellar mitochondrial hydrogen peroxide observed using a SNAP tag targeted coumarin-based fluorescent reporter.
    Ross Eaglesfield, Erika Fernandez-Vizarra, Erik Lacko, Stuart T Caldwell, Nikki L Sloan, Daniel Siciarz, Richard C Hartley, Kostas Tokatlidis.
      Mitochondria are major sites of reactive oxygen species (ROS) production within cells. ROS are important signalling molecules, but excessive production can cause cellular damage and dysfunction. It is therefore crucial to accurately determine when, how and where ROS are produced within mitochondria. Previously, ROS detection involved various chemical probes and fluorescent proteins. These have limitations due to accumulation of the molecules only in the mitochondrial matrix, or the need for a new protein to be expressed for every different species. We report dynamic H2O2 flux changes within all mitochondrial sub-compartments with striking spatial resolution. We combined specific targeting of self-labeling proteins with novel H2O2-reactive probes. The approach is broad-ranging and flexible, with the same expressed proteins loadable with different dyes and sensors. It provides a framework for concomitant analysis of other chemical species, beyond ROS, whose dynamics within mitochondria are yet unknown, without needing to engineer new proteins.
    Keywords:  Mitochondria; Oxidative stress; ROS; Redox signalling; Self-labeling proteins; Sub-cellular compartments
    DOI:  https://doi.org/10.1016/j.redox.2025.103502
  16. Biochem Biophys Rep. 2025 Mar;41 101909
    Methylmalonic acid at the serum level in the elderly contributes to cell growth via mitochondrial dysfunction in colorectal cancer cell spheroids.
    Arowu R Tanaka, Chiho Murakami, Hideya Yamamoto.
      Methylmalonic acid (MMA) is a small molecule produced during the metabolism of propionate and branched-chain amino acids. Recently, it has been reported that the blood concentration of MMA increases with age and promotes lung cancer metastasis. However, little is known regarding its effects on cancers other than lung cancer. In the present study, we examined the effects of MMA on colorectal cancer cell spheroids. We found that MMA promoted the proliferation of colorectal cancer spheroids at physiological concentrations that can be exhibited by the elderly and induced mitochondrial reactive oxygen species generation, which in turn affected the promotion of cell growth. MMA treatment also induces a metabolic shift in the glycolytic system. These results suggest that MMA may promote cancer cell proliferation by decreasing mitochondrial function, inducing a metabolic shift, and provide new insights into the effects of aging on cancer.
    Keywords:  Aging; Cancer; Glutamine; Glycolytic system; Methylmalonic acid; Mitochondria; OXPHOS; ROS; Spheroid; Warburg effect
    DOI:  https://doi.org/10.1016/j.bbrep.2024.101909
  17. Biomedicines. 2025 Jan 05. pii: 107. [Epub ahead of print]13(1):
    Germline Single-Nucleotide Polymorphism GFI1-36N Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia.
    Jan Vorwerk, Longlong Liu, Theresa Helene Stadler, Daria Frank, Helal Mohammed Mohammed Ahmed, Pradeep Kumar Patnana, Maxim Kebenko, Eva Dazert, Bertram Opalka, Nikolas von Bubnoff, Cyrus Khandanpour.
      Background/Objectives: GFI1-36N represents a single-nucleotide polymorphism (SNP) of the zinc finger protein Growth Factor Independence 1 (GFI1), in which the amino acid serine (S) is replaced by asparagine (N). The presence of the GFI1-36N gene variant is associated with a reduced DNA repair capacity favoring myeloid leukemogenesis and leads to an inferior prognosis of acute myeloid leukemia (AML) patients. However, the underlying reasons for the reduced DNA repair capacity in GFI1-36N leukemic cells are largely unknown. Since we have demonstrated that GFI1 plays an active role in metabolism, in this study, we investigated whether increased levels of reactive oxygen species (ROS) could contribute to the accumulation of genetic damage in GFI1-36N leukemic cells. Methods: We pursued this question in a murine model of human AML by knocking in human GFI1-36S or GFI1-36N variant constructs into the murine Gfi1 gene locus and retrovirally expressing MLL-AF9 to induce AML. Results: Following the isolation of leukemic bone marrow cells, we were able to show that the GFI1-36N SNP in our model is associated with enhanced oxidative phosphorylation (OXPHOS), increased ROS levels, and results in elevated γ-H2AX levels as a marker of DNA double-strand breaks (DSBs). The use of free radical scavengers such as N-acetylcysteine (NAC) and α-tocopherol (αT) reduced ROS-induced DNA damage, particularly in GFI1-36N leukemic cells. Conclusions: We demonstrated that the GFI1-36N variant is associated with extensive metabolic changes that contribute to the accumulation of genetic damage.
    Keywords:  GFI1; ROS; acute myeloid leukemia; metabolism; single-nucleotide polymorphism
    DOI:  https://doi.org/10.3390/biomedicines13010107
  18. Nat Rev Genet. 2025 Jan 28.
    Spatial metabolomics to unravel cellular metabolism.
    Arafath K Najumudeen, Johan Vande Voorde.
      
    DOI:  https://doi.org/10.1038/s41576-025-00817-2
  19. Biochim Biophys Acta Mol Basis Dis. 2025 Jan 27. pii: S0925-4439(25)00036-5. [Epub ahead of print]1871(3): 167691
    The curious case of mitochondrial sirtuin in rewiring breast cancer metabolism: Mr Hyde or Dr Jekyll?
    Jesline Shaji Tharayil, Amoolya Kandettu, Sanjiban Chakrabarty.
      Mammalian sirtuins are class III histone deacetylases involved in the regulation of multiple biological processes including senescence, DNA repair, apoptosis, proliferation, caloric restriction, and metabolism. Among the mammalian sirtuins, SIRT3, SIRT4, and SIRT5 are localized in the mitochondria and collectively termed the mitochondrial sirtuins. Mitochondrial sirtuins are NAD+-dependent deacetylases that play a central role in cellular metabolism and function as epigenetic regulators by performing post-translational modification of cellular proteins. Several studies have identified the role of mitochondrial sirtuins in age-related pathologies and the rewiring of cancer metabolism. Mitochondrial sirtuins regulate cellular functions by contributing to post-translational modifications, including deacetylation, ADP-ribosylation, demalonylation, and desuccinylation of diverse cellular proteins to maintain cellular homeostasis. Here, we review and discuss the structure and function of the mitochondrial sirtuins and their role as metabolic regulators in breast cancer. Altered breast cancer metabolism may promote tumor progression and has been an essential target for therapy. Further, we discuss the potential role of targeting mitochondrial sirtuin and its impact on breast cancer progression using sirtuin inhibitors and activators as anticancer agents.
    Keywords:  Breast cancer; Glutamine; Glycolysis; Mitochondrial sirtuins; Oxidative phosphorylation; ROS
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167691
  20. Life Metab. 2025 Feb;4(1): loae040
    Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability.
    Yik-Lam Cho, Hayden Weng Siong Tan, Jicheng Yang, Basil Zheng Mian Kuah, Nicole Si Ying Lim, Naiyang Fu, Boon-Huat Bay, Shuo-Chien Ling, Han-Ming Shen.
      Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the pentose phosphate pathway (PPP) in glycolysis. Glucose metabolism is closely implicated in the regulation of mitophagy, a selective form of autophagy for the degradation of damaged mitochondria. The PPP and its key enzymes such as G6PD possess important metabolic functions, including biosynthesis and maintenance of intracellular redox balance, while their implication in mitophagy is largely unknown. Here, via a whole-genome CRISPR-Cas9 screening, we identified that G6PD regulates PINK1 (phosphatase and tensin homolog [PTEN]-induced kinase 1)-Parkin-mediated mitophagy. The function of G6PD in mitophagy was verified via multiple approaches. G6PD deletion significantly inhibited mitophagy, which can be rescued by G6PD reconstitution. Intriguingly, while the catalytic activity of G6PD is required, the known PPP functions per se are not involved in mitophagy regulation. Importantly, we found a portion of G6PD localized at mitochondria where it interacts with PINK1. G6PD deletion resulted in an impairment in PINK1 stabilization and subsequent inhibition of ubiquitin phosphorylation, a key starting point of mitophagy. Finally, we found that G6PD deletion resulted in lower cell viability upon mitochondrial depolarization, indicating the physiological function of G6PD-mediated mitophagy in response to mitochondrial stress. In summary, our study reveals a novel role of G6PD as a key positive regulator in mitophagy, which bridges several important cellular processes, namely glucose metabolism, redox homeostasis, and mitochondrial quality control.
    Keywords:  G6PD; NADPH; PINK1; PPP; ROS; mitophagy
    DOI:  https://doi.org/10.1093/lifemeta/loae040
  21. EMBO J. 2025 Jan 29.
    SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation.
    Wei Li, Jing Han, Bin Huang, Tengteng Xu, Yihong Wan, Dan Luo, Weiyao Kong, Ying Yu, Lei Zhang, Yong Nian, Bo Chu, Chengqian Yin.
      Ferroptosis, an iron-dependent form of programmed cell death characterized by excessive lipid hydroperoxides accumulation, emerges as a promising target in cancer therapy. Among the solute carrier (SLC) superfamily, the cystine/glutamate transporter system antiporter components SLC3A2 and SLC7A11 are known to regulate ferroptosis by facilitating cystine import for ferroptosis inhibition. However, the contribution of additional SLC superfamily members to ferroptosis remains poorly understood. Here, we use a targeted CRISPR-Cas9 screen of the SLC superfamily to identify SLC25A1 as a critical ferroptosis regulator in human cancer cells. SLC25A1 drives citrate export from the mitochondria to the cytosol, where it fuels acetyl-CoA synthesis by ATP citrate lyase (ACLY). This acetyl-CoA supply sustains FSP1 acetylation and prevents its degradation by the proteasome via K29-linked ubiquitin chains. K168 is the primary site of FSP1 acetylation and deacetylation by KAT2B and HDAC3, respectively. Pharmacological inhibition of SLC25A1 and ACLY significantly enhances cancer cell susceptibility to ferroptosis both in vitro and in vivo. Targeting the SLC25A1-ACLY axis is therefore a potential therapeutic strategy for ferroptosis-targeted cancer intervention.
    Keywords:  ACLY; Acetylation; FSP1; Ferroptosis; SLC25A1
    DOI:  https://doi.org/10.1038/s44318-025-00369-5
  22. Life Metab. 2023 Jun;2(3): load020
    Flux measurements of the tricarboxylic acid cycle in the tumors of mice.
    Shiyu Liu, Jason W Locasale.
      
    DOI:  https://doi.org/10.1093/lifemeta/load020
  23. J Biol Chem. 2025 Jan 27. pii: S0021-9258(25)00087-0. [Epub ahead of print] 108240
    A novel FOXM1-BCL2A1 axis determines unfavourable response to venetoclax in AML.
    Sanjeev Raghuwanshi, Ahmed Magdy, Nissim Hay, Andrei Gartel.
      Forkhead box M1 (FOXM1), a Forkhead family transcription factor, is often overexpressed in a variety of human cancers, including AML and strongly associated with therapy resistance and unfavourable outcomes. In AML with NPM1 mutations NPM1/FOXM1 complex sequesters FOXM1 in the cytoplasm and confers favourable treatment outcomes for AML patients, because of FOXM1 inactivation. Inhibition of FOXM1 in AML cell lines and animal models of AML sensitizes AML cells to the Bcl2-inhibitor, venetoclax. In a recent study the upregulation of the BCL2-family protein, BCL2A1 conferred resistance to venetoclax and multiple venetoclax combinations.In this study, we investigated FOXM1/BCL2A1 axis and determined that FOXM1 specifically inhibits venetoclax-induced apoptosis in AML via upregulation of BCL2A1.The knockdown of BCL2A1 in AML in the presence of high levels of FOXM1 led to sensitization of AML cells to venetoclax, suggesting that BCL2A1 is a major target of FOXM1 responsible for resistance to venetoclax. Venetoclax in combination with FOXM1 inhibitor STL001 inhibited BCL2A1 and circumvented venetoclax resistance. Pharmacological inhibition of FOXM1/BCL2A1 axis represents a therapeutic strategy to sensitize AML cells to venetoclax-induced apoptosis.
    DOI:  https://doi.org/10.1016/j.jbc.2025.108240
  24. Life Med. 2024 Apr;3(2): lnae021
    Cellular senescence induced by down-regulation of PTBP1 correlates with exon skipping of mitochondrial-related gene NDUFV3.
    Yu Yang, Haimei Wen, Yuxin Li, Xin Zeng, Gang Wei, Zhenglong Gu, Ting Ni.
      As the most prevalent type of alternative splicing in animal cells, exon skipping plays an important role in expanding the diversity of transcriptome and proteome, thereby participating in the regulation of diverse physiological and pathological processes such as development, aging, and cancer. Cellular senescence serving as an anti-cancer mechanism could also contribute to individual aging. Although the dynamic changes of exon skipping during cellular senescence were revealed, its biological consequence and upstream regulator remain poorly understood. Here, by using human foreskin fibroblasts (HFF) replicative senescence as a model, we discovered that splicing factor PTBP1 was an important contributor for global exon skipping events during senescence. Down-regulated expression of PTBP1 induced senescence-associated phenotypes and related mitochondrial functional changes. Mechanistically, PTBP1 binds to the third exon of mitochondrial complex I subunit coding gene NDUFV3 and protects the exon from skipping. We further confirmed that exon skipping of NDUFV3 correlates with and partially contributes to cellular senescence and related mitochondrial functional changes upon PTBP1 knockdown. Together, we revealed for the first time that mitochondrial-related gene NDUFV3 is a new downstream target for PTBP1-regulated exon skipping to mediate cellular senescence and mitochondrial functional changes.
    Keywords:  NDUFV3; PTBP1; cellular senescence; exon skipping; mitochondria
    DOI:  https://doi.org/10.1093/lifemedi/lnae021
  25. Cell Metab. 2025 Jan 24. pii: S1550-4131(24)00489-3. [Epub ahead of print]
    Redirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy.
    Andrew T Frisch, Yiyang Wang, Bingxian Xie, Aaron Yang, B Rhodes Ford, Supriya Joshi, Katarzyna M Kedziora, Ronal Peralta, Drew Wilfahrt, Steven J Mullett, Kellie Spahr, Konstantinos Lontos, Jessica A Jana, Victoria G Dean, William G Gunn, Stacy Gelhaus, Amanda C Poholek, Dayana B Rivadeneira, Greg M Delgoffe.
      Cellular therapies are living drugs whose efficacy depends on persistence and survival. Expansion of therapeutic T cells employs hypermetabolic culture conditions to promote T cell expansion. We show that typical in vitro expansion conditions generate metabolically and functionally impaired T cells more reliant on aerobic glycolysis than those expanding in vivo. We used dichloroacetate (DCA) to modulate glycolytic metabolism during expansion, resulting in elevated mitochondrial capacity, stemness, and improved antitumor efficacy in murine T cell receptor (TCR)-Tg and human CAR-T cells. DCA-conditioned T cells surprisingly show no elevated intratumoral effector function but rather have improved engraftment. DCA conditioning decreases reliance on glucose, promoting usage of serum-prevalent physiologic carbon sources. Further, DCA conditioning promotes metabolic flux from mitochondria to chromatin, resulting in increased histone acetylation at key longevity genes. Thus, hyperglycemic culture conditions promote expansion at the expense of metabolic flexibility and suggest pharmacologic metabolic rewiring as a beneficial strategy for improvement of cellular immunotherapies.
    Keywords:  CAR-T; Immunometabolism; T cell; cell therapy; epigenetics; glucose; immunotherapy; longevity; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.007
  26. Mol Cell. 2025 Jan 21. pii: S1097-2765(24)01066-9. [Epub ahead of print]
    OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth.
    Dong Guo, Qiujing Yu, Yingying Tong, Xu Qian, Ying Meng, Fei Ye, Xiaoming Jiang, Lihui Wu, Qingqing Yang, Suyao Li, Min Li, Qingang Wu, Liwei Xiao, Xuxiao He, Rongxuan Zhu, Guijun Liu, Dou Nie, Shudi Luo, Leina Ma, Ren-An Jin, Zhihua Liu, Xiao Liang, Dong Yan, Zhimin Lu.
      Ketone bodies generated in hepatocytes in the adult liver are used for nonhepatic tissues as an energy source. However, ketolysis is reactivated in hepatocellular carcinoma (HCC) cells with largely unelucidated mechanisms. Here, we demonstrate that 3-oxoacid CoA-transferase 1 (OXCT1), a rate-limiting enzyme in ketolysis, interacts with SUCLA2 upon IGF1 stimulation in HCC cells. This interaction results from ERK2-mediated SUCLA2 S124 phosphorylation and subsequent PIN1-mediated cis-trans isomerization of SUCLA2. OXCT1-associated SUCLA2 generates succinyl-CoA, which not only serves as a substrate for OXCT1 but also directly succinylates OXCT1 at K421 and activates OXCT1. SUCLA2-regulated OXCT1 activation substantially enhances ketolysis, HCC cell proliferation, and tumor growth in mice. Notably, treatment with acetohydroxamic acid, an OXCT1 inhibitor used clinically for urinary infection, inhibits liver tumor growth in mice and significantly enhances lenvatinib therapy. Our findings highlight the role of SUCLA2-coupled regulation of OXCT1 succinylation in ketolysis and unveil an unprecedented strategy for treating HCC by interrupting ketolysis.
    Keywords:  OXCT1; SUCLA2; ketolysis; ketone body; succinyl-CoA; succinylation; tumorigenesis
    DOI:  https://doi.org/10.1016/j.molcel.2024.12.025
  27. Proc Natl Acad Sci U S A. 2025 Feb 04. 122(5): e2422447122
    Serine phosphorylation facilitates protein degradation by the human mitochondrial ClpXP protease.
    Yue Feng, Monica M Goncalves, Yulia Jitkova, Alexander F A Keszei, Yongran Yan, Chaitra Sarathy, Jonathan St-Germain, Tristan M G Kenney, Matthew Tcheng, Vincent Trudel, Ross S Mancini, Rahul Upadhyay, Rose Hurren, Marcela Gronda, Matthew Schultz, Kaylen Soriano, Kaitlin Lees, Neil C Pomroy, S Quinn W Currie, Gilbert G Privé, Mark A Reed, Andrei K Yudin, Linda Z Penn, Cheryl H Arrowsmith, Brian Raught, Mohammad T Mazhab-Jafari, Siavash Vahidi, Aaron D Schimmer.
      ClpXP is a two-component mitochondrial matrix protease. The caseinolytic mitochondrial matrix peptidase chaperone subunit X (ClpX) recognizes and translocates protein substrates into the degradation chamber of the caseinolytic protease P (ClpP) for proteolysis. ClpXP degrades damaged respiratory chain proteins and is necessary for cancer cell survival. Despite the critical role of ClpXP in mitochondrial protein quality control, the specific degrons, or modifications that tag substrate proteins for degradation by human ClpXP, are still unknown. We demonstrated that phosphorylated serine (pSer) targets substrates to ClpX and facilitates their degradation by ClpXP in biochemical assays. In contrast, ClpP hyperactivated by the small-molecule drug ONC201 lost the preference for phosphorylated substrates. Hydrogen deuterium exchange mass spectrometry combined with biochemical assays showed that pSer binds the RKL loop of ClpX. ClpX variants with substitutions in the RKL loop failed to recognize phosphorylated substrates. In intact cells, ClpXP also preferentially degraded substrates with pSer. Moreover, ClpX substrates with the pSer were selectively found in aggregated mitochondrial proteins. Our work uncovers a mechanism for substrate recognition by ClpXP, with implications for targeting acute myeloid leukemia and other disorders involving ClpXP dysfunction.
    Keywords:  AAA+ proteases; degron; mitochondrial proteostasis; phosphorylation; protein degradation
    DOI:  https://doi.org/10.1073/pnas.2422447122
  28. Cancer Lett. 2025 Jan 24. pii: S0304-3835(25)00065-5. [Epub ahead of print]613 217501
    Atovaquone and selinexor as a novel combination treatment option in acute myeloid leukemia.
    Stefanie Weiss, Bernhard Zdársky, Agnieszka Witalisz-Siepracka, Sophie Edtmayer, Anja Holzer, Kerstin Heindl, Emilio Casanova, Klaus Podar, Dagmar Stoiber.
      Acute myeloid leukemia (AML) is the most common acute leukemia and is predominantly affecting the elderly. It is a heterogenous disease, showing a broad spectrum of genomic alterations and mutations that influence the clinical outcome and treatment options. The expression of the signal transducer and activator of transcription 3 (STAT3) is often dysregulated in AML and its constitutive activation is associated with poor outcome. Thus, STAT3 became an attractive therapeutic target but until now drugs targeting STAT3 only had moderate efficacy. This phenomenon might be related to the expression ratio of the two alternatively spliced isoforms: the full-length isoform STAT3α and the truncated version STAT3β, which play opposite roles in AML. In this study, we investigated the potential of selected, well-established drugs to impact the STAT3β/α ratio, as a higher STAT3β/α ratio is associated with better disease outcome. Atovaquone and selinexor independently elevated the STAT3β/α ratio and led to an upregulation of the STAT3β target gene SELL (CD62L). The combined treatment with atovaquone and selinexor entailed synergistic killing of AML cells in vitro and impaired the leukemic cell infiltration in vivo. Moreover, CD62L overexpression in a human AML cell line resulted in significantly prolonged survival in a xenograft mouse model. We propose that targeting the STAT3β/α ratio could be a promising new strategy for treating patients with AML and that the combination of selinexor and atovaquone could offer enhanced treatment outcomes.
    Keywords:  Acute myeloid leukemia; Atovaquone; CD62L/SELL; STAT3 isoforms; Selinexor
    DOI:  https://doi.org/10.1016/j.canlet.2025.217501
  29. Sci Transl Med. 2025 Jan 29. 17(783): eadr0792
    Correcting a pathogenic mitochondrial DNA mutation by base editing in mice.
    Jose D Barrera-Paez, Sandra R Bacman, Till Balla, Derek Van Booven, Durga P Gannamedi, James B Stewart, Beverly Mok, David R Liu, David B Lombard, Anthony J Griswold, Danny D Nedialkova, Carlos T Moraes.
      Primary mitochondrial disorders are most often caused by deleterious mutations in the mitochondrial DNA (mtDNA). Here, we used a mitochondrial DddA-derived cytosine base editor (DdCBE) to introduce a compensatory edit in a mouse model that carries the pathological mutation in the mitochondrial transfer RNA (tRNA) alanine (mt-tRNAAla) gene. Because the original m.5024C→T mutation (G→A in the mt-tRNAAla) destabilizes the mt-tRNAAla aminoacyl stem, we designed a compensatory m.5081G→A edit (C→T in the mt-tRNAAla) that could restore the secondary structure of the tRNAAla aminoacyl stem. For this, the DdCBE gene construct was initially tested in an m.5024C→T mutant cell line. The reduced mt-tRNAAla amounts in these cells were increased after editing up to 78% of the mtDNA. Then, DdCBE was packaged in recombinant adeno-associated virus 9 (AAV9) and intravenously administered by retro-orbital injections into mice. Expression of the transduced DdCBE was observed in the heart and skeletal muscle. Total mt-tRNAAla amounts were restored in heart and muscle by the m.5081G→A edit in a dose-dependent manner. Lactate amounts, which were increased in the heart, were also decreased in treated mice. However, the highest dose tested of AAV9-DdCBE also induced severe adverse effects in vivo because of the extensive mtDNA off-target editing that it generated. These results show that although DdCBE is a promising gene therapy tool for mitochondrial disorders, the doses of the therapeutic constructs must be carefully monitored to avoid deleterious off-target editing.
    DOI:  https://doi.org/10.1126/scitranslmed.adr0792
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