bims-mibica 2025-04-13 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–04–13
34 papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.
Re-appraising assays on permeabilized blood cancer cells testing venetoclax or other BH3 mimetic agents selectively targeting pro-survival BCL2 proteins.
Sirtuin 3-mediated delactylation of malic enzyme 2 disrupts redox balance and inhibits colorectal cancer growth.
Structural basis of BAK sequestration by MCL-1 in apoptosis.
ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution.
Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming.
Mild Uncoupling of Mitochondria Synergistically Enhances Senolytic Specificity and Sensitivity of BH3 Mimetics.
TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia.
Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.
The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer.
Small molecules restore mutant mitochondrial DNA polymerase activity.
Metabolite tunes MDV pathway to maintain mitochondrial fitness.
Mitochondrial, metabolic and bioenergetic adaptations drive plasticity of colorectal cancer cells and shape their chemosensitivity.
Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.
Myeloma mesenchymal stem cells' bioenergetics afford a novel selective therapeutic target.
Mitochondria and cell death signalling.
PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma.
RNA G-quadruplexes control mitochondria-localized mRNA translation and energy metabolism.
Modeling Krebs cycle from liver, heart and hepatoma mitochondria, supported Complex I as target for specific inhibition of cancer cell proliferation.
The potential role of BCL-2 inhibition in amyloidosis and plasma cell leukemia.
Identification of CD84 as a potent survival factor in acute myeloid leukemia.
In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
Cells are swapping their mitochondria. What does this mean for our health?
Hijacking the powerhouse: Mitochondrial transfer and mitophagy as emerging mechanisms of immune evasion.
FAO-fueled OXPHOS and NRF2-mediated stress resilience in MICs drive lymph node metastasis.
Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates.
Metabolic reprogramming in T cell senescence: a novel strategy for cancer immunotherapy.
Filtering cells with high mitochondrial content depletes viable metabolically altered malignant cell populations in cancer single-cell studies.
Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy.
Dysregulated glutathione metabolism impairs natural killer cell function in patients with acute leukemia.
Pharmacological targeting of the mitochondrial phosphatase PTPMT1 sensitizes hepatocellular carcinoma to ferroptosis.
Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors.
The BCL-2 protein family: from discovery to drug development.
An unconventional autophagic pathway that inhibits ATP secretion during apoptotic cell death.

Sci Adv. 2025 Apr 11. 11(15): eadu5511

Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.

James T Hagen, McLane M Montgomery, Raphael T Aruleba, Brett R Chrest, Polina Krassovskaia, Thomas D Green, Emely A Pacheco, Miki Kassai, Tonya N Zeczycki, Cameron A Schmidt, Debajit Bhowmick, Su-Fern Tan, David J Feith, Charles E Chalfant, Thomas P Loughran, Darla Liles, Mark D Minden, Aaron D Schimmer, Md Salman Shakil, Matthew J McBride, Myles C Cabot, Joseph M McClung, Kelsey H Fisher-Wellman.

OxPhos inhibitors have struggled to show a clinical benefit because of their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to acute myeloid leukemia (AML) mitochondria. Unlike healthy cells that couple respiration to ATP synthesis, AML mitochondria support inner-membrane polarization by consuming ATP. Matrix ATP consumption allows cells to survive bioenergetic stress. Thus, we hypothesized AML cells may resist chemotherapy-induced cell death by reversing the ATP synthase reaction. In support, BCL-2 inhibition with venetoclax abolished OxPhos flux without affecting mitochondrial polarization. In surviving AML cells, sustained mitochondrial polarization depended on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to down-regulations in the endogenous F1-ATPase inhibitor ATP5IF1. Knockdown of ATP5IF1 conferred venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. These data identify matrix ATP consumption as a cancer cell-intrinsic bioenergetic vulnerability actionable in the context of BCL-2 targeted chemotherapy.

DOI: https://doi.org/10.1126/sciadv.adu5511
Cell Death Differ. 2025 Apr 09.

Re-appraising assays on permeabilized blood cancer cells testing venetoclax or other BH3 mimetic agents selectively targeting pro-survival BCL2 proteins.

Jia-Nan Gong, Tirta M Djajawi, Donia M Moujalled, Giovanna Pomilio, Tiffany Khong, Li-Ping Zhang, Pasquale L Fedele, Michael S Low, Mary Ann Anderson, Christopher D Riffkin, Christine A White, Ping Lan, Guillaume Lessene, Marco J Herold, Andreas Strasser, Andrew Spencer, George Grigoriadis, Andrew H Wei, Mark F van Delft, Andrew W Roberts, David C S Huang.

BH3 mimetic drugs that selectively target the pro-survival BCL2 proteins are highly promising for cancer treatment, most notably for treating blood cancers. Venetoclax, which inhibits BCL2, is now approved for treating chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). Preferably, robust and validated assays would identify patients most likely to benefit from therapy with venetoclax itself or with inhibitors of other pro-survival proteins. A sophisticated method that has been developed is the BH3 profiling assay. In this assay, permeabilized, instead of intact, cells are treated for a few hours with inhibitors of the pro-survival BCL2 proteins, and the resultant mitochondrial depolarization measured. Sensitivity to a specific inhibitor (e.g., venetoclax or other BH3 mimetics) is then used to infer the reliance of a tumor (e.g., CLL) on one or more pro-survival BCL2 proteins. However, we found that this methodology cannot reliably identify such dependencies. In part, this is because almost all cells express multiple pro-survival BCL2 proteins that restrain BAX and BAK which must be inhibited before mitochondrial depolarization and apoptosis can proceed. Using genetic and pharmacological tools across multiple cell line models of blood cancer, we demonstrated that selective BCL2 inhibitors have important flow-on effects that includes the redistribution of BH3-only proteins to ancillary pro-survival proteins not directly engaged by the inhibitor. These secondary effects, critical to the biological action of selective inhibitors, were not accurately recapitulated in permeabilized cells, probably due to the limited time frame possible in such assays or the altered biophysical conditions when cells are permeabilized. While we could consistently define the sensitivity of a tumor cell to a particular BH3 mimetic drugs using intact cells, this was not reliable with permeabilized cells. These studies emphasize the need to carefully evaluate assays on permeabilized cells undertaken with inhibitors of the pro-survival BCL2 proteins.

DOI: https://doi.org/10.1038/s41418-025-01487-7
Cell Oncol (Dordr). 2025 Apr 07.

Sirtuin 3-mediated delactylation of malic enzyme 2 disrupts redox balance and inhibits colorectal cancer growth.

Chaoqun Li, Cun Ge, Qingwen Wang, Peng Teng, Heyuan Jia, Surui Yao, Zhaohui Huang.

   PURPOSE: Post-translational modifications, such as lactylation, are emerging as critical regulators of metabolic enzymes in cancer progression. Mitochondrial malic enzyme 2 (ME2), a key enzyme in the TCA cycle, plays a pivotal role in maintaining redox homeostasis and supporting tumor metabolism. However, the functional significance of ME2 lactylation and its regulatory mechanisms remain unclear. This study investigates the role of ME2 K352 lactylation in modulating enzymatic activity, redox balance, and tumor progression.
METHODS: Immunoprecipitation and western blotting were used to assess ME2 lactylation and its interaction with Sirtuin 3 (SIRT3). Mass spectrometry identified the lactylation site on ME2. Enzymatic activity was measured using NADH production assays. The functional effects of ME2 K352 lactylation were analyzed by measuring ROS levels, NADP⁺/NADPH ratios, metabolic intermediates, and mitochondrial respiration parameters. Cell proliferation was evaluated via CCK-8 and colony formation assays. Xenograft tumor models and Ki-67 immunohistochemical staining were used to assess tumor growth and proliferation in vivo.
RESULTS: Mass spectrometry identified K352 as the primary lactylation site on ME2. Sodium lactate treatment enhanced ME2 lactylation and enzymatic activity, while SIRT3-mediated delactylation at K352 reduced ME2 activity, disrupting redox homeostasis. Cells expressing the K352R mutant exhibited elevated ROS levels, higher NADP⁺/NADPH ratios, and altered levels of metabolic intermediates, including increased malate and lactate with reduced pyruvate. Additionally, re-expression of ME2 K352R in HCT116 cells significantly impaired proliferation and colony formation. In vivo, xenograft models demonstrated that ME2 K352R expression suppressed tumor growth, as evidenced by reduced tumor volume, weight, and Ki-67 staining.
CONCLUSIONS: This study reveals that ME2 K352 lactylation is a critical regulatory mechanism that modulates enzymatic activity, mitochondrial function, and tumor progression. SIRT3-mediated delactylation of ME2 K352 disrupts redox homeostasis and inhibits tumor growth. These findings highlight the potential of targeting ME2 lactylation as a therapeutic strategy in cancer treatment.

Keywords:  Cancer metabolism; Lactylation; ME2; Mitochondrion; Posttranslational modification; SIRT3

DOI:  https://doi.org/10.1007/s13402-025-01058-5
Mol Cell. 2025 Mar 28. pii: S1097-2765(25)00251-5. [Epub ahead of print]

Structural basis of BAK sequestration by MCL-1 in apoptosis.

Shagun Srivastava, Giridhar Sekar, Adedolapo Ojoawo, Anup Aggarwal, Elisabeth Ferreira, Emiko Uchikawa, Meek Yang, Christy R Grace, Raja Dey, Yi-Lun Lin, Cristina D Guibao, Seetharaman Jayaraman, Somnath Mukherjee, Anthony A Kossiakoff, Bin Dong, Alexander Myasnikov, Tudor Moldoveanu.

  Apoptosis controls cell fate, ensuring tissue homeostasis and promoting disease when dysregulated. The rate-limiting step in apoptosis is mitochondrial poration by the effector B cell lymphoma 2 (BCL-2) family proteins BAK and BAX, which are activated by initiator BCL-2 homology 3 (BH3)-only proteins (e.g., BIM) and inhibited by guardian BCL-2 family proteins (e.g., MCL-1). We integrated structural, biochemical, and pharmacological approaches to characterize the human prosurvival MCL-1:BAK complex assembled from their BCL-2 globular core domains. We reveal a canonical interaction with BAK BH3 bound to the hydrophobic groove of MCL-1 and disordered and highly dynamic BAK regions outside the complex interface. We predict similar conformations of activated effectors in complex with other guardians or effectors. The MCL-1:BAK complex is a major cancer drug target. We show that MCL-1 inhibitors are inefficient in neutralizing the MCL-1:BAK complex, requiring high doses to initiate apoptosis. Our study underscores the need to design superior clinical candidate MCL-1 inhibitors.

Keywords:  BCL-2 antagonist killer BAK; BCL-2 family proteins; BCL-2-like protein 11 BIM; BH3 mimetics; BH3-interacting domain death agonist BID; BH3-only initiator; MCL-1 inhibitors; NMR spectroscopy; Phorbol-12-myristate-13-acetate-induced protein 1 NOXA; X-ray crystallography; apoptosis; apoptosis resistance; cryo-electron microscopy; direct BAK activation; induced myeloid leukemia cell differentiation protein MCL-1; mitochondrial outer membrane permeabilization MOMP; mode II MCL-1:BAK sequestration; mode II neutralization; prodeath effector; prosurvival guardian

DOI:  https://doi.org/10.1016/j.molcel.2025.03.013
Sci Adv. 2025 Apr 11. 11(15): eadu5091

ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution.

Michael J McKenna, Felix Kraus, João P L Coelho, Muskaan Vasandani, Jiuchun Zhang, Benjamin M Adams, Joao A Paulo, J Wade Harper, Sichen Shao.

Maintaining an optimal mitochondrial distribution is critical to ensure an adequate supply of energy and metabolites to support important cellular functions. How cells balance dynamic mitochondrial processes to achieve homeostasis is incompletely understood. Here, we show that ARMC1 partitioning between distinct mitochondrial protein complexes is a key determinant of mitochondrial distribution. In one complex, the mitochondrial trafficking adaptor MIRO recruits ARMC1, which mediates the assembly of a mitochondrial fission regulator (MTFR). MTFR stability depends on ARMC1, and MIRO-MTFR complexes specifically antagonize retrograde mitochondrial movement. In another complex, DNAJC11 facilitates ARMC1 release from mitochondria. Disrupting MIRO-MTFR assembly fails to rescue aberrant mitochondrial distributions clustered in the perinuclear area observed with ARMC1 deletion, while disrupting ARMC1 interaction with DNAJC11 leads to excessive mitochondrially localized ARMC1 and distinct mitochondrial defects. Thus, the abundance and trafficking impact of MIRO-MTFR complexes require ARMC1, whose mito-cytoplasmic shuttling balanced by DNAJC11 tunes steady-state mitochondrial distributions.

DOI: https://doi.org/10.1126/sciadv.adu5091
J Exp Clin Cancer Res. 2025 Apr 07. 44(1): 114

Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming.

Su Jung Park, Claudia Cerella, Jin Mo Kang, Jinyoung Byun, David Kum, Barbora Orlikova-Boyer, Anne Lorant, Michael Schnekenburger, Ali Al-Mourabit, Christo Christov, Juyong Lee, Byung Woo Han, Marc Diederich.

   BACKGROUND: Acute myeloid leukemia (AML) is a highly aggressive cancer with a 5-year survival rate of less than 35%. It is characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics and metabolism are crucial for AML cell survival. Mitochondrial fusion protein optic atrophy (OPA)1 is upregulated in AML patients with adverse mutations and correlates with poor prognosis.
METHOD: This study investigated targeting OPA1 with TMQ0153, a tetrahydrobenzimidazole derivative, to disrupt mitochondrial metabolism and dynamics as a novel therapeutic approach to overcome treatment resistance. Effects of TMQ0153 treatment on OPA1 and mitofusin (MFN)2 protein levels, mitochondrial morphology, and function in AML cells. In this study, we examined reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, mitochondrial membrane potential (MMP) depolarization, and apoptosis. Additionally, metabolic profiling was conducted to analyze changes in metabolic pathways.
RESULTS: TMQ0153 treatment significantly reduced OPA1 and mitofusin (MFN)2 protein levels and disrupted the mitochondrial morphology and function in AML cells. This increases ROS production and inhibits OXPHOS, MMP depolarization, and caspase-dependent apoptosis. Metabolic reprogramming was observed, shifting from mitochondrial respiration to glycolysis and impaired respiratory chain activity. Profiling revealed reduced overall metabolism along with changes in the glutathione (GSH)/oxidized glutathione (GSSG) and NAD⁺/NADH redox ratios. TMQ0153 treatment reduces tumor volume and weight in MV4-11 xenografts in vivo. Combination therapies with TMQ0153 and other AML drugs significantly reduced the leukemic burden and prolonged survival in NOD scid gamma (NSG) mice xenografted with U937-luc and MOLM-14-luc cells.
CONCLUSION: TMQ0153 targets mitochondrial dynamics by inhibiting OPA1, inducing metabolic reprogramming, and triggering apoptosis in AML cells. It enhances the efficacy of existing AML therapies and provides a promising combination treatment approach that exploits mitochondrial vulnerability and metabolic reprogramming to improve treatment outcomes in AML.

Keywords:  Drug resistance; Glutathione; Glycolysis; Metabolic reprogramming; Monocytic myeloid leukemia; OXPHOS

DOI:  https://doi.org/10.1186/s13046-025-03372-0
Aging Biol. 2024 Feb 20. 1(1): 20240022

Mild Uncoupling of Mitochondria Synergistically Enhances Senolytic Specificity and Sensitivity of BH3 Mimetics.

Edward P Fielder, Abbas Ishaq, Evon Low, Joseph A Laws, Aisha Calista, Jemma Castle, Thomas von Zglinicki, Satomi Miwa.

Despite immense potential as anti-aging interventions, applications of current senolytics are limited due to low sensitivity and specificity. We demonstrate the specific loss of complex I-linked coupled respiration and the inability to maintain mitochondrial membrane potential upon respiratory stimulation as a specific vulnerability of senescent cells. Further decreasing the mitochondrial membrane potential of senescent cells with a mitochondrial uncoupler synergistically enhances the in vitro senolytic efficacy of BH3 mimetic drugs, including Navitoclax, by up to two orders of magnitude, whereas non-senescent cells remain unaffected. Moreover, a short-term intervention combining the mitochondrial uncoupler BAM15 with Navitoclax at a dose two orders of magnitude lower than typically used rescues radiation-induced premature aging in an in vivo mouse model, as demonstrated by reduced frailty and improved cognitive function for at least eight months. Our study shows compromised mitochondrial functional capacity is a senescence-specific vulnerability that can be targeted by mild uncoupling in vitro and in vivo.

DOI: https://doi.org/10.59368/agingbio.20240022
bioRxiv. 2025 Mar 27. pii: 2025.03.24.644993. [Epub ahead of print]

TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia.

Jeevitha D'Souza, Camille J Leung, Aishwarya C Ballapuram, Abigail S Lin, Alexa Rane Batingana, Adam J Lamble, Rhonda E Ries, Carolina E Morales, Charisa Cottonham, Pranav Gona, Li Fan, Xiaotu Ma, Kevin Shannon, Soheil Meshinchi, Benjamin S Braun, Benjamin J Huang.

Acute myeloid leukemia (AML) is a heterogeneous cancer that is associated with poor outcomes. Revumenib and other menin inhibitors have shown promising activity against AMLs with KMT2A -rearrangements or NPM1 mutations. However, mechanisms of de novo resistance have not yet been elucidated. We analyzed a panel of cell lines and generated an isogenic model to assess the impact of TP53 mutations on the response of AML cells to revumenib. TP53 mutations are associated with de novo resistance to revumenib, impaired induction of TP53 transcriptional targets, and deregulated expression of the BH3 proteins BCL-2 and MCL-1. The MCL-1 inhibitor MIK665, but not venetoclax, preferentially sensitized TP53 -mutant AML cells to revumenib. These data identify mutant TP53 as a potential biomarker for de novo resistance to revumenib, and provide a rationale to evaluate MCL-1 and menin inhibitor combinations in patients KMT2A -rearranged leukemias with TP53 mutations.

DOI: https://doi.org/10.1101/2025.03.24.644993
J Cell Sci. 2025 Apr 07. pii: jcs.263688. [Epub ahead of print]

Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.

Marc Severin, Rikke K Hansen, Michala G Rolver, Tove Hels, Kenji Maeda, Luis A Pardo, Stine F Pedersen.

  Tumor acidosis alters cancer cell metabolism and favors aggressive disease progression. Cancer cells in acidic environments increase lipid droplet (LD) accumulation and oxidative phosphorylation, characteristics of aggressive cancers. Here, we use live imaging, shotgun lipidomics, and immunofluorescence analyses of mammary and pancreatic cancer cells to demonstrate that both acute acidosis and adaptation to acidic growth drive rapid uptake of fatty acids (FA), which are converted to triacylglycerols (TAG) and stored in LDs. Consistent with its independence of de novo synthesis, TAG- and LD accumulation in acid-adapted cells is unaffected by FA-synthetase inhibitors. Macropinocytosis, which is upregulated in acid-adapted cells, partially contributes to FA uptake, which is independent of other protein-facilitated lipid uptake mechanisms, including CD36, FATP2, and caveolin- and clathrin-dependent endocytosis. We propose that a major mechanism by which tumor acidosis drives FA uptake is through neutralizing protonation of negatively charged FAs allowing their diffusive, transporter-independent uptake. We suggest that this could be a major factor triggering acidosis-driven metabolic rewiring.

Keywords:  CD36; FASN; Lipid diffusion; Macropinocytosis; Membrane contact sites; Protonation

DOI:  https://doi.org/10.1242/jcs.263688
J Bioenerg Biomembr. 2025 Apr 08.

The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer.

Thomas N Seyfried, Derek C Lee, Tomas Duraj, Nathan L Ta, Purna Mukherjee, Michael Kiebish, Gabriel Arismendi-Morillo, Christos Chinopoulos.

  Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second step involved a protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed that oxygen consumption was lower while lactate production was higher in cancerous tissues than in non-cancerous tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate markers for ATP production through OxPhos and glycolysis, respectively. Warburg's hypothesis was challenged from findings showing that oxygen consumption remained high in some cancer cells despite the elevated production of lactate suggesting that OxPhos was largely unimpaired. New information indicates that neither oxygen consumption nor lactate production are accurate surrogates for quantification of ATP production in cancer cells. Warburg also did not know that a significant amount of ATP could come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway with succinate produced as end product, thus confounding the linkage of oxygen consumption to the origin of ATP production within mitochondria. Moreover, new information shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation are both biomarkers for OxPhos insufficiency. Warburg's original hypothesis can now be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated cancer cell growth. These findings can also address several questionable assumptions regarding the origin of cancer thus allowing the field to advance with more effective therapeutic strategies for a less toxic metabolic management and prevention of cancer.

Keywords:  Cardiolipin; Lactate; Lipid droplets; Oxidative phosphorylation; Oxygen consumption; Somatic mutations; Substrate level phosphorylation; Succinate

DOI:  https://doi.org/10.1007/s10863-025-10059-w
Nature. 2025 Apr 09.

Small molecules restore mutant mitochondrial DNA polymerase activity.

Sebastian Valenzuela, Xuefeng Zhu, Bertil Macao, Mattias Stamgren, Carol Geukens, Paul S Charifson, Gunther Kern, Emily Hoberg, Louise Jenninger, Anja V Gruszczyk, Seoeun Lee, Katarina A S Johansson, Javier Miralles Fusté, Yonghong Shi, S Jordan Kerns, Laleh Arabanian, Gabriel Martinez Botella, Sofie Ekström, Jeremy Green, Andrew M Griffin, Carlos Pardo-Hernández, Thomas A Keating, Barbara Küppers-Munther, Nils-Göran Larsson, Cindy Phan, Viktor Posse, Juli E Jones, Xie Xie, Simon Giroux, Claes M Gustafsson, Maria Falkenberg.

Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits1. More than 300 mutations in POLG, the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists2. Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating POLG disorders and other severe conditions linked to depletion of mtDNA.

DOI: https://doi.org/10.1038/s41586-025-08856-9
Mol Cell. 2025 Apr 03. pii: S1097-2765(25)00189-3. [Epub ahead of print]85(7): 1253-1255

Metabolite tunes MDV pathway to maintain mitochondrial fitness.

Shiori Sekine, Yusuke Sekine.

In this issue of Molecular Cell, Tang et al.1 demonstrate that the ketone body β-hydroxybutyrate (BHB) promotes the biogenesis of mitochondrial-derived vesicles (MDVs) via lysine β-hydroxybutyrylation (Kbhb) on SNX9, revealing a way to fine-tune the mitochondrial quality control pathway with metabolites.

DOI: https://doi.org/10.1016/j.molcel.2025.02.027
Cell Death Dis. 2025 Apr 05. 16(1): 253

Mitochondrial, metabolic and bioenergetic adaptations drive plasticity of colorectal cancer cells and shape their chemosensitivity.

Nikita Markov, Sirina Sabirova, Gulnaz Sharapova, Marina Gomzikova, Anna Brichkina, Nick A Barlev, Marcel Egger, Albert Rizvanov, Hans-Uwe Simon.

The extent of mitochondrial heterogeneity and the presence of mitochondrial archetypes in cancer remain unknown. Mitochondria play a central role in the metabolic reprogramming that occurs in cancer cells. This process adjusts the activity of metabolic pathways to support growth, proliferation, and survival of cancer cells. Using a panel of colorectal cancer (CRC) cell lines, we revealed extensive differences in their mitochondrial composition, suggesting functional specialisation of these organelles. We differentiated bioenergetic and mitochondrial phenotypes, which point to different strategies used by CRC cells to maintain their sustainability. Moreover, the efficacy of various treatments targeting metabolic pathways was dependent on the respiration and glycolysis levels of cancer cells. Furthermore, we identified metabolites associated with both bioenergetic profiles and cell responses to treatments. The levels of these molecules can be used to predict the therapeutic efficacy of anti-cancer drugs and identify metabolic vulnerabilities of CRC. Our study indicates that the efficacy of CRC therapies is closely linked to mitochondrial status and cellular bioenergetics.

DOI: https://doi.org/10.1038/s41419-025-07596-y
Cell Death Dis. 2025 Apr 05. 16(1): 254

Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.

Ru Deng, Lingyi Fu, Haoyu Liang, Xixiong Ai, Fangyi Liu, Nai Li, Liyan Wu, Shuo Li, Xia Yang, Yansong Lin, Yuhua Huang, Jingping Yun.

Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment.

DOI: https://doi.org/10.1038/s41419-025-07510-6
Oncogenesis. 2025 Apr 11. 14(1): 9

Myeloma mesenchymal stem cells' bioenergetics afford a novel selective therapeutic target.

Oded Komemi, Elina Orbuch, Osnat Jarchowsky-Dolberg, Yaron Shraga Brin, Shelly Tartakover-Matalon, Metsada Pasmanik-Chor, Michael Lishner, Liat Drucker.

Bone-marrow mesenchymal stem cells (BM-MSCs) rely on glycolysis, yet their trafficked mitochondria benefit recipient cells' bioenergetics in regenerative and cancerous settings, most relevant to BM-resident multiple myeloma (MM) cells. Fission/fusion dynamics regulate mitochondria function. Proteomics demonstrates excessive mitochondrial processes in BM-MSCs from MM patients compared to normal donors (ND). Thus, we aimed to characterize BM-MSCs (ND, MM) mitochondrial fitness, bioenergetics and dynamics with a focus on therapeutics. MM-MSCs displayed compromised mitochondria evidenced by decreased mitochondrial membrane potential (ΔΨm) and elevated proton leak. This was accompanied by stimulation of stress-coping mechanisms: spare respiratory capacity (SRC), mitochondrial fusion and UPRmt. Interfering with BM-MSCs mitochondrial dynamics equilibrium demonstrated their significance to bioenergetics and fitness according to the source. While ND-MSCs depended on fission, reducing MM-MSCs fusion attenuated glycolysis, OXPHOS and mtROS. Interestingly, optimization of mtROS levels is central to ΔΨm preservation in MM-MSCs only. MM-MSCs also demonstrated STAT3 activation, which regulates their OXPHOS and SRC. Targeting MM-MSC' SRC with Venetoclax diminished their pro-MM support and sensitized co-cultured MM cells to Bortezomib. Overall, MM-MSCs distinct mitochondrial bioenergetics are integral to their robustness. Repurposing Venetoclax as anti-SRC treatment in combination with conventional anti-MM drugs presents a potential selective way to target MM-MSCs conferred drug resistance.

DOI: https://doi.org/10.1038/s41389-025-00554-5
Curr Opin Cell Biol. 2025 Apr 10. pii: S0955-0674(25)00048-1. [Epub ahead of print]94 102510

Mitochondria and cell death signalling.

Ella Hall-Younger, Stephen Wg Tait.

Mitochondria are essential organelles in the life and death of a cell. During apoptosis, mitochondrial outer membrane permeabilisation (MOMP) engages caspase activation and cell death. Under nonlethal apoptotic stress, some mitochondria undergo permeabilisation, termed minority MOMP. Nonlethal apoptotic signalling impacts processes including genome stability, senescence and innate immunity. Recent studies have shown that upon MOMP, mitochondria and consequent signalling can trigger inflammation. We discuss how this occurs, and how mitochondrial inflammation might be targeted to increase tumour immunogenicity. Finally, we highlight how mitochondria contribute to other types of cell death including pyroptosis and ferroptosis. Collectively, these studies reveal critical new insights into how mitochondria regulate cell death, highlighting that mitochondrial signals engaged under nonlethal apoptotic stress have wide-ranging biological functions.

DOI: https://doi.org/10.1016/j.ceb.2025.102510
Cell. 2025 Apr 01. pii: S0092-8674(25)00281-8. [Epub ahead of print]

PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma.

Bhargab Kalita, Gerard Martinez-Cebrian, Justina McEvoy, Melody Allensworth, Michelle Knight, Alessandro Magli, Rita C R Perlingeiro, Michael A Dyer, Elizabeth Stewart, Brian David Dynlacht.

  Alveolar rhabdomyosarcoma (ARMS) patients harboring paired-box fusion proteins (PAX3/7-FOXO1) exhibit a greater incidence of tumor relapse, metastasis, and poor survival outcome, thereby underscoring the urgent need to develop effective therapies to treat this subtype of childhood cancer. To uncover mechanisms that contribute to tumor initiation, we develop a muscle progenitor model and use epigenomic approaches to unravel genome rewiring events mediated by PAX3/7 fusion proteins. Among the key targets of PAX3/7 fusion proteins, we identify a cohort of oncogenes, fibroblast growth factor (FGF) receptors, tRNA-modifying enzymes, and genes essential for mitochondrial metabolism and protein translation, which we successfully targeted in preclinical trials. We identify leucine usage as a key factor driving the growth of aggressive PAX-fusion tumors, as limiting its bioavailability impaired oxidative phosphorylation and mitochondrial metabolism, delaying tumor progression and improving survival in vivo. Our data provide a compelling list of actionable targets and suggest promising new strategies to treat this tumor.

Keywords:  3D/2D-adapted PDX models; Leucine; MYCN; TRMT5; alveolar rhabdomyosarcoma; mitochondrial metabolism; myogenic progenitors; roblitinib; tRNA modifications; tigecycline

DOI:  https://doi.org/10.1016/j.cell.2025.03.008
Nat Commun. 2025 Apr 07. 16(1): 3292

RNA G-quadruplexes control mitochondria-localized mRNA translation and energy metabolism.

Leïla Dumas, Sauyeun Shin, Quentin Rigaud, Marie Cargnello, Beatriz Hernández-Suárez, Pauline Herviou, Nathalie Saint-Laurent, Marjorie Leduc, Morgane Le Gall, David Monchaud, Erik Dassi, Anne Cammas, Stefania Millevoi.

Cancer cells rely on mitochondria for their bioenergetic supply and macromolecule synthesis. Central to mitochondrial function is the regulation of mitochondrial protein synthesis, which primarily depends on the cytoplasmic translation of nuclear-encoded mitochondrial mRNAs whose protein products are imported into mitochondria. Despite the growing evidence that mitochondrial protein synthesis contributes to the onset and progression of cancer, and can thus offer new opportunities for cancer therapy, knowledge of the underlying molecular mechanisms remains limited. Here, we show that RNA G-quadruplexes (RG4s) regulate mitochondrial function by modulating cytoplasmic mRNA translation of nuclear-encoded mitochondrial proteins. Our data support a model whereby the RG4 folding dynamics, under the control of oncogenic signaling and modulated by small molecule ligands or RG4-binding proteins, modifies mitochondria-localized cytoplasmic protein synthesis. Ultimately, this impairs mitochondrial functions, affecting energy metabolism and consequently cancer cell proliferation.

DOI: https://doi.org/10.1038/s41467-025-58118-5
Front Oncol. 2025 ;15 1557638

Modeling Krebs cycle from liver, heart and hepatoma mitochondria, supported Complex I as target for specific inhibition of cancer cell proliferation.

Luz Hernández-Esquivel, Isis Del Mazo-Monsalvo, Silvia Cecilia Pacheco-Velázquez, Rocío Daniela Feregrino-Mondragón, Diana Xochiquetzal Robledo-Cadena, Rosina Sánchez-Thomas, Ricardo Jasso-Chávez, Emma Saavedra, Álvaro Marín-Hernández.

   Introduction: The Krebs cycle (KC) is an important pathway for cancer cells because it produces reduced coenzymes for ATP synthesis and precursors for cellular proliferation. Described changes in cancer KC enzyme activities suggested modifications in the reactions that control the KC flux compared to normal cells.
Methods: In this work, kinetic metabolic models of KC of mitochondria from cancer (HepM), liver (RLM) and heart (RHM) to identify targets to decrease the KC flux were constructed from kinetic parameters (Vmax and Km) of enzymes here determined.
Results: The enzymes Vmax values were higher in the following order: RHM > HepM > RLM; meanwhile, Km values were similar. Kinetic modeling indicated that the NADH consumption reaction (complex I) exerted higher control on the Krebs cycle flux in HepM versus RLM and to a lesser extent in RHM. These results suggested that cancer cells may be more sensitive to complex I inhibition than heart and other non-cancer cells. Indeed, cancer cell proliferation was more sensitive to rotenone (a complex I inhibitor) than heart and non-cancer cells. In contrast, cell proliferation had similar sensitivities to malonate, an inhibitor of succinate dehydrogenase, an enzyme that does not exert control.
Discussion: Our results showed that kinetic modeling and metabolic control analysis allow the identification of high flux-controlling targets in cancer cells that help to design strategies to specifically inhibit their proliferation. This can minimize the toxic effects in normal cells, such as the cardiac ones that are highly sensitive to conventional chemotherapy.

Keywords:  Complex I; Krebs cycle; cancer; heart; kinetic modeling; liver; metabolic control analysis; mitochondria

DOI:  https://doi.org/10.3389/fonc.2025.1557638
Front Oncol. 2025 ;15 1549891

The potential role of BCL-2 inhibition in amyloidosis and plasma cell leukemia.

Grigorios Alvanidis, Dimitrios Kotsos, Christina Frouzaki, Amalia Fola, Evdoxia Hatjiharissi.

  Plasma cell neoplasms include a spectrum of disorders, such as plasma cell leukemia (PCL) and light chain (AL) amyloidosis, all associated with poor prognosis and limited therapeutic options. Venetoclax is the first-in-class B-cell lymphoma 2 (BCL-2) inhibitor and triggers apoptosis selectively in cells reliant on the BCL-2 pathway for survival. Randomized clinical trials have established the anti-tumor activity and efficacy of venetoclax in selected patients with hematologic malignancies such as acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM). At the same time, recent studies suggest its potential application in rare plasma cell dyscrasias. Preliminary results from case reports and a small cohort of patients indicate that venetoclax may benefit patients with PCL. Regimens incorporating venetoclax have also demonstrated promising outcomes in patients with AL amyloidosis, particularly those with translocation (11;14). This review analyzes new data on venetoclax in AL amyloidosis and PCL and highlights the increasing significance of BCL-2 inhibition in plasma cell neoplasms beyond MM.

Keywords:  AL amyloidosis; BCL-2 inhibition; hematologic malignancies; plasma cell leukemia; plasma cell neoplasms; venetoclax

DOI:  https://doi.org/10.3389/fonc.2025.1549891
J Clin Invest. 2025 Apr 08. pii: e176818. [Epub ahead of print]

Identification of CD84 as a potent survival factor in acute myeloid leukemia.

Yinghui Zhu, Mariam Murtadha, Miaomiao Liu, Enrico Caserta, Ottavio Napolitano, Le Xuan Truong Nguyen, Huafeng Wang, Milad Moloudizargari, Lokesh Nigam, Theophilus Tandoh, Xuemei Wang, Alex Pozhitkov, Rui Su, Xiangjie Lin, Marc Denisse Estepa, Raju Pillai, Joo Song, James F Sanchez, Yu-Hsuan Fu, Lianjun Zhang, Man Li, Bin Zhang, Ling Li, Ya-Huei Kuo, Steven Rosen, Guido Marcucci, John C Williams, Flavia Pichiorri.

  Acute myeloid leukemia (AML) is an aggressive and often deadly malignancy associated with proliferative immature myeloid blasts. Here, we identified CD84 as a critical survival regulator in AML. High levels of CD84 expression provided a survival advantage to leukemia cells, whereas CD84 downregulation disrupted their proliferation, clonogenicity and engraftment capabilities in both human cell lines and patient derived xenograft cells. Critically, loss of CD84 also markedly blocked leukemia engraftment and clonogenicity in MLL-AF9 and inv(16) AML mouse models, highlighting its pivotal role as survival factor across species. Mechanistically, CD84 regulated leukemia cells' energy metabolism and mitochondrial dynamics. Depletion of CD84 altered mitochondrial ultra-structure and function of leukemia cells, and it caused down-modulation of both oxidative phosphorylation and fatty acid oxidation pathways. CD84 knockdown induced a block of Akt phosphorylation and down-modulation of nuclear factor erythroid 2-related factor 2 (NRF2), impairing AML antioxidant defense. Conversely, CD84 over-expression stabilized NRF2 and promoted its transcriptional activation, thereby supporting redox homeostasis and mitochondrial function in AML. Collectively, our findings indicated that AML cells depend on CD84 to support antioxidant pro-survival pathways, highlighting a therapeutic vulnerability of leukemia cells.

Keywords:  Antigen; Bone marrow; Cancer immunotherapy; Cell biology; Hematology; Oncology

DOI:  https://doi.org/10.1172/JCI176818
bioRxiv. 2025 Mar 25. pii: 2025.03.24.645001. [Epub ahead of print]

In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.

Kevin Rose, Eric Herrmann, Eve Kakudji, Javier Lizarrondo, A Yasemin Celebi, Florian Wilfling, Samantha C Lewis, James H Hurley.

Defective mitochondrial quality control in response to loss of mitochondrial membrane polarization is implicated in Parkinson's disease by mutations in PINK1 and PRKN . Application of in situ cryo-electron tomography (cryo-ET) made it possible to visualize the consequences of mitochondrial depolarization at higher resolution than heretofore attainable. Parkin-expressing U2OS cells were treated with the depolarizing agents oligomycin and antimycin A (OA), subjected to cryo-FIB milling, and mitochondrial structure was characterized by in situ cryo-ET. Phagophores were visualized in association with mitochondrial fragments. Bridge-like lipid transporter (BLTP) densities potentially corresponding to ATG2A were seen connected to mitophagic phagophores. Mitochondria in OA-treated cells were fragmented and devoid of matrix calcium phosphate crystals. The intermembrane gap of cristae was narrowed and the intermembrane volume reduced, and some fragments were devoid of cristae. A subpopulation of ATP synthases re-localized from cristae to the inner boundary membrane (IBM) apposed to the outer membrane (OMM). The structure of the dome-shaped prohibitin complex, a dodecamer of PHB1-PHB2 dimers, was determined in situ by sub-tomogram averaging in untreated and treated cells and found to exist in open and closed conformations, with the closed conformation is enriched by OA treatment. These findings provide a set of native snapshots of the manifold nano-structural consequences of mitochondrial depolarization and provide a baseline for future in situ dissection of Parkin-dependent mitophagy.

DOI: https://doi.org/10.1101/2025.03.24.645001
Nature. 2025 Apr;640(8058): 302-304

Cells are swapping their mitochondria. What does this mean for our health?

Gemma Conroy.



Keywords:  Cancer; Cell biology; Diseases

DOI:  https://doi.org/10.1038/d41586-025-01064-5
Mol Cell. 2025 Apr 03. pii: S1097-2765(25)00188-1. [Epub ahead of print]85(7): 1258-1259

Hijacking the powerhouse: Mitochondrial transfer and mitophagy as emerging mechanisms of immune evasion.

Maria T Diaz-Meco, Juan F Linares, Jorge Moscat.

Cancer cells subvert the immune system by reprogramming their metabolism. In a recent study in Nature, Ikeda et al.1 show how cancer cells can directly transfer mitophagy-resistant mitochondria to tumor-infiltrating lymphocytes, promoting their homoplasmic replacement and undermining cancer immunity.

DOI: https://doi.org/10.1016/j.molcel.2025.02.026
Proc Natl Acad Sci U S A. 2025 Apr 15. 122(15): e2411241122

FAO-fueled OXPHOS and NRF2-mediated stress resilience in MICs drive lymph node metastasis.

Shan-Shan Li, Baifeng Zhang, Cuicui Huang, Yuying Fu, Yuying Zhao, Lanqi Gong, Yanan Tan, Huali Wang, Wenqi Chen, Jie Luo, Yu Zhang, Stephanie Ma, Li Fu, Chenli Liu, Jiandong Huang, Huai-Qiang Ju, Anne Wing-Mui Lee, Xin-Yuan Guan.

  Metastasis is an inefficient process requiring cancer cells to adapt metabolically for survival and colonization in new environments. The contributions of tumor metabolic reprogramming to lymph node (LN) metastasis and its underlying mechanisms remain elusive. Through single-cell RNA sequencing, we identified rare metastasis-initiating cells (MICs) with stem-like properties that drive early LN metastasis. Integrated transcriptome, lipidomic, metabolomic, and functional analyses demonstrated that MICs depend on oxidative phosphorylation (OXPHOS) fueled by fatty acid oxidation (FAO) in the lipid-rich LN microenvironment. Mechanistically, the NRF2-SLC7A11 axis promotes glutathione synthesis to mitigate oxidative stress, thereby enhancing stress resistance and metastatic potential of MICs. Inhibition of NRF2-SLC7A11 reduced LN metastasis and sensitized tumors to cisplatin. Clinically, elevated NRF2-SLC7A11 expression was observed in tumors, with high expression correlating with LN metastasis, chemoresistance, and poor prognosis in esophageal squamous cell carcinoma (ESCC). These findings highlight the pivotal roles of FAO-fueled OXPHOS and NRF2 in LN metastasis and suggest targeting these pathways as a promising therapeutic strategy for metastatic ESCC.

Keywords:  NRF2; esophageal cancer; lymph node metastasis; metabolic reprogramming; oxidative phosphorylation

DOI:  https://doi.org/10.1073/pnas.2411241122
Biophys J. 2025 Apr 03. pii: S0006-3495(25)00211-5. [Epub ahead of print]

Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates.

Mangyu Choe, Tal Einav, Rob Phillips, Denis V Titov.

  Glycolysis is a conserved metabolic pathway that produces ATP and biosynthetic precursors. It is not well understood how the control of mammalian glycolytic enzymes through allosteric feedback and mass action accomplishes various tasks of ATP homeostasis, such as controlling the rate of ATP production, maintaining high and stable ATP levels, ensuring that ATP hydrolysis generates a net excess of energy, and maintaining glycolytic intermediate concentrations within physiological levels. To investigate these questions, we developed a biophysical model of glycolysis based on enzyme rate equations derived from in vitro kinetic data. This is the first biophysical model of human glycolysis that successfully recapitulates the above tasks of ATP homeostasis and predicts absolute concentrations of glycolytic intermediates and isotope tracing kinetics that align with experimental measurements in human cells. We use the model to show that mass action alone is sufficient to control the ATP production rate and maintain the high energy of ATP hydrolysis. Meanwhile, allosteric regulation of hexokinase (HK) and phosphofructokinase (PFK) by ATP, ADP, inorganic phosphate, and glucose-6-phosphate is required to maintain high ATP levels and to prevent uncontrolled accumulation of phosphorylated intermediates of glycolysis. Allosteric feedback achieves the latter by maintaining HK and PFK enzyme activity at one-half of ATP demand and, thus, inhibiting the reaction of Harden and Young, which otherwise converts glucose to supraphysiological levels of phosphorylated glycolytic intermediates at the expense of ATP. Our methodology provides a roadmap for a quantitative understanding of how metabolic homeostasis emerges from the activities of individual enzymes.

Keywords:  allosteric feedback; glycolysis; metabolism; modeling

DOI:  https://doi.org/10.1016/j.bpj.2025.03.037
Cell Death Discov. 2025 Apr 09. 11(1): 161

Metabolic reprogramming in T cell senescence: a novel strategy for cancer immunotherapy.

Li Liu, Zhanying Hao, Xi Yang, Yan Li, Siyang Wang, Linze Li.

The complex interplay between cancer progression and immune senescence is critically influenced by metabolic reprogramming in T cells. As T cells age, especially within the tumor microenvironment, they undergo significant metabolic shifts that may hinder their proliferation and functionality. This manuscript reviews how metabolic alterations contribute to T cell senescence in cancer and discusses potential therapeutic strategies aimed at reversing these metabolic changes. We explore interventions such as mitochondrial enhancement, glycolytic inhibition, and lipid metabolism adjustments that could rejuvenate senescent T cells, potentially restoring their efficacy in tumor suppression. This review also focuses on the significance of metabolic interventions in T cells with aging and further explores the future direction of the metabolism-based cancer immunotherapy in senescent T cells.

DOI: https://doi.org/10.1038/s41420-025-02468-y
Genome Biol. 2025 Apr 09. 26(1): 91

Filtering cells with high mitochondrial content depletes viable metabolically altered malignant cell populations in cancer single-cell studies.

Josephine Yates, Agnieszka Kraft, Valentina Boeva.

   BACKGROUND: Single-cell transcriptomics has transformed our understanding of cellular diversity, yet noise from technical artifacts and low-quality cells can obscure key biological signals. A common practice is filtering out cells with a high percentage of mitochondrial RNA counts (pctMT), typically indicative of cell death. However, commonly used filtering thresholds, primarily derived from studies on healthy tissues, may be overly stringent for malignant cells, which often naturally exhibit higher baseline mitochondrial gene expression.
RESULTS: We examine nine public single-cell RNA-seq datasets from various cancers, including 441,445 cells from 134 patients, and public spatial transcriptomics data, assessing the viability of malignant cells with high pctMT. Our analysis reveals that malignant cells exhibit significantly higher pctMT than nonmalignant cells, without a notable increase in dissociation-induced stress scores. Malignant cells with high pctMT show metabolic dysregulation, including increased xenobiotic metabolism, relevant to therapeutic response. Analysis of pctMT in cancer cell lines further reveals links to drug resistance. We also observe associations between pctMT and malignant cell transcriptional heterogeneity, as well as patient clinical features.
CONCLUSIONS: This study provides insights into the functional characteristics of malignant cells with elevated pctMT, challenging current quality control practices in tumor single-cell RNA-seq analyses and offering potential improvements in data interpretation for future cancer studies.

Keywords:  Cancer; Data quality; Drug resistance; MT-RNA; Metabolism; Single-cell RNA-seq

DOI:  https://doi.org/10.1186/s13059-025-03559-w
Cell Metab. 2025 Apr 02. pii: S1550-4131(25)00106-8. [Epub ahead of print]

Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy.

Seyedeh Sahar Mortazavi Farsani, Jignesh Soni, Lu Jin, Anil Kumar Yadav, Shivani Bansal, Tian Mi, Leena Hilakivi-Clarke, Robert Clarke, Benjamin Youngblood, Amrita Cheema, Vivek Verma.

  Mitochondria regulate T cell functions and response to immunotherapy. We show that pyruvate kinase M2 (PKM2) activation enhances mitochondria-dependent effector functions in CD8 and chimeric antigen receptor (CAR)-T cells. Multi-omics and 13C-glucose tracer studies showed that PKM2 agonism alters one-carbon metabolism, decreasing methionine levels, resulting in hypomethylated nuclear and mitochondrial DNA and enhancing mitochondrial biogenesis and functions. PKM2 activation increased the recall responses and anti-tumor functions of CD8 T cells, enhancing adoptive cell therapy. In preclinical models, the PKM2 agonist induced CD8 T cell-dependent anti-tumor responses that synergized with anti-programmed death 1 (PD1) therapy. Immunologically, PKM2 agonists boosted the activation of effector T cells while reducing FoxP3+ T regulatory (Treg) cells in the tumors. The anti-PD1 combination enhanced the frequency of tumor-specific activated CD8 T cells. Together, PKM2 agonism increased mitochondrial functions supporting cell cytotoxicity. Hence, pharmacological targeting of PKM2 can be a clinically viable strategy for enhancement of adoptive cell therapy, in situ anti-tumor immune responses, and immune checkpoint blockade therapy. VIDEO ABSTRACT.

Keywords:  CD8 T cells; PD1 blockade; PKM2; adoptive cell therapy; immunotherapy; melanoma; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2025.03.003
Int Immunopharmacol. 2025 Apr 03. pii: S1567-5769(25)00556-9. [Epub ahead of print]154 114566

Dysregulated glutathione metabolism impairs natural killer cell function in patients with acute leukemia.

Yue Zhao, Yan Wang, Tingting Liang, Xian Song, Yingqiao Zhu, Xinru Liu, Mengya Lv, Changcheng Zheng, Fang Ni.

  Natural killer (NK) cell function is markedly impaired in patients with acute leukemia, weakening their anti-tumor immune response. However, the mechanisms underlying NK cell dysfunction are not fully understood. Here, we reveal that NK cells from patients with acute leukemia (AL-NK) exhibit significantly reduced intracellular glutathione (GSH) levels, accompanied by disrupted redox homeostasis and increased levels of mitochondrial reactive oxygen species. Flow cytometry and transcriptomic analyses indicate that dysregulated GSH metabolism leads to mitochondrial dysfunction in NK cells, thereby impairing their antileukemic cytotoxicity and proliferative capacity. Notably, supplementation with glutathione reduced ethyl ester (GSHEE)-a GSH precursor-effectively restores GSH levels in AL-NK cells, enhancing mitochondrial activity, oxidative phosphorylation, ATP production, and NK cell-mediated cytotoxicity. Moreover, GSHEE treatment activates the mTOR signaling pathway in NK cells, further promoting their function and proliferation. Overall, our study identifies dysregulated GSH metabolism as a key driver of NK cell dysfunction in acute leukemia and suggests that GSH-based interventions may provide a promising strategy to enhance NK cell-mediated immunotherapies.

Keywords:  Acute leukemia; Cytotoxicity; Glutathione; Mitochondria; Natural killer cells; RNA-sequencing

DOI:  https://doi.org/10.1016/j.intimp.2025.114566
Cell Death Dis. 2025 Apr 06. 16(1): 257

Pharmacological targeting of the mitochondrial phosphatase PTPMT1 sensitizes hepatocellular carcinoma to ferroptosis.

Miaomiao Li, Yi Wang, Xinyan Li, Jiayi Xu, Liangwen Yan, Shenkang Tang, Chenyue Liu, Mengjiao Shi, Rongrong Liu, Yaping Zhao, Yi Zhang, Lan Yang, Yinggang Zhang, Gang Wang, Zongfang Li, Ying Guo, Yetong Feng, Pengfei Liu.

Protein tyrosine phosphatase mitochondrial 1 (PTPMT1), is a member of the protein tyrosine phosphatase superfamily localized on the mitochondrial inner membrane, and regulates the biosynthesis of cardiolipin. Given the important position of PTPMT1 in mitochondrial function and metabolism, pharmacological targeting of PTPMT1 is considered a promising manner in disease treatments. In this study, we mainly investigated the role of PTPMT1 in hepatocellular carcinoma (HCC) ferroptosis, a new type of cell death accompanied by significant iron accumulation and lipid peroxidation. Herein, the pharmacological inhibition of PTPMT1 was induced by alexidine dihydrochloride (AD, a dibiguanide compound). Human HCC cell lines with PTPMT1 knockout and PTPMT1 overexpression were established using CRISPR/Cas9 and lentiviral transduction methods, respectively. The position of PTPMT1 in regulating HCC ferroptosis was evaluated in vitro and in vivo. Our results indicated that pharmacological inhibition of PTPMT1, facilitated by AD treatment, heightens the susceptibility of HCC to cystine deprivation-ferroptosis, and AD treatment promoted the conversion from ferritin-bound Fe3+ to free Fe2+, which contributed to the labile iron pool in cytoplasm. Meanwhile, pharmacological inhibition of PTPMT1 also induced the formation of both swollen mitochondria and donut mitochondria, and enhanced the metabolism process form succinate to fumarate in mitochondrial tricarboxylic acid (TCA) cycle, which increased the sensitivity of HCC cells to cystine deprivation-induced ferroptosis. In total, our work reveals the close association of PTPMT1 with cysteine deprivation-induced ferroptosis, providing a novel insight into chemotherapy strategies against human HCC.

DOI: https://doi.org/10.1038/s41419-025-07581-5
Cell Death Discov. 2025 Apr 06. 11(1): 147

Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors.

Jorge Antonio Elias Godoy Carlos, Mauricio Temotheo Tavares, Keli Lima, Larissa Costa de Almeida, Karoline de Barros Waitman, Leticia Veras Costa-Lotufo, Roberto Parise-Filho, João Agostinho Machado-Neto.

Epigenetic modifications significantly influence gene expression and play crucial roles in various biological processes, including carcinogenesis. This study investigates the effects of novel purine-benzohydroxamate compounds, particularly 4 f, as hybrid kinase/histone deacetylase (HDAC) inhibitors in hematological malignancies, focusing on acute myeloid leukemia (AML). Our results demonstrate that these compounds selectively reduce cell viability in blood cancer cells, with inhibitory concentration values indicating higher potency against neoplastic cells compared to normal leukocytes. Mechanistically, 4 f induces apoptosis and cell cycle arrest, promoting differentiation in leukemia cells, while effectively inhibiting HDAC activity. Furthermore, 4 f enhances the therapeutic efficacy of venetoclax, a BCL2 inhibitor, in AML models sensitive and resistant to this drug. The combination treatment significantly increases apoptosis and reduces cell viability, suggesting a synergistic effect that may overcome drug resistance. This study provides valuable insights into the potential of HDAC inhibitors, particularly 4 f, as a promising therapeutic strategy for treating resistant hematological malignancies. Our findings underscore the importance of further exploring hybrid kinase/HDAC inhibitors in combination therapies to improve outcomes in patients with acute leukemias and other hematological malignancies.

DOI: https://doi.org/10.1038/s41420-025-02446-4
Cell Death Differ. 2025 Apr 09.

The BCL-2 protein family: from discovery to drug development.

Carlo M Croce, David Vaux, Andreas Strasser, Joseph T Opferman, Peter E Czabotar, Stephen W Fesik.

The landmark discovery of the BCL-2 gene and then its function marked the identification of inhibition of apoptotic cell death as a crucial novel mechanism driving cancer development and launched the quest to discover the molecular control of apoptosis. This work culminated in the generation of specific inhibitors that are now in clinical use, saving and improving tens of thousands of lives annually. Here, some of the original players of this story, describe the sequence of critical discoveries. The t(14;18) chromosomal translocation, frequently observed in follicular lymphoma, allowed the identification and the cloning of a novel oncogene (BCL-2) juxtaposed to the immunoglobulin heavy chain gene locus (IgH). Of note, BCL-2 acted in a distinct manner as compared to then already known oncogenic proteins like ABL and c-MYC. BCL-2 did not promote cell proliferation but inhibited cell death, as originally shown in growth factor dependent haematopoietic progenitor cell lines (e.g., FDC-P1) and in Eμ-Myc/Eμ-Bcl-2 double transgenic mice. Following a rapid expansion of the BCL-2 protein family, the Abbott Laboratories solved the first structure of BCL-XL and subsequently the BCL-XL/BAK peptide complex, opening the way to understanding the structures of other BCL-2 family members and, finally, to the generation of inhibitors of the different pro-survival BCL-2 proteins, thanks to the efforts of Servier/Norvartis, Genentech/WEHI, AbbVie, Amgen, Prelude and Gilead. Although the BCL-2 inhibitor Venetoclax is in clinical use and inhibitors of BCL-XL and MCL-1 are undergoing clinical trials, several questions remain on whether therapeutic windows can be achieved and what other agents should be used in combination with BH3 mimetics to achieve optimal therapeutic impact for cancer therapy. Finally, the control of the expression of BH3-only proteins and pro-survival BCL-2 family members needs to be better understood as this may identify novel targets for cancer therapy. This story is still not concluded!

DOI: https://doi.org/10.1038/s41418-025-01481-z
Nat Commun. 2025 Apr 10. 16(1): 3409

An unconventional autophagic pathway that inhibits ATP secretion during apoptotic cell death.

Elena Terraza-Silvestre, Raquel Villamuera, Julia Bandera-Linero, Michal Letek, Daniel Oña-Sánchez, Cristina Ramón-Barros, Clara Moyano-Jimeno, Felipe X Pimentel-Muiños.

Mobilisation of Damage-Associated Molecular Patterns (DAMPs) determines the immunogenic properties of apoptosis, but the mechanisms that control DAMP exposure are still unclear. Here we describe an unconventional autophagic pathway that inhibits the release of ATP, a critical DAMP in immunogenic apoptosis, from dying cells. Mitochondrial BAK activated by BH3-only molecules interacts with prohibitins and stomatin-1 through its latch domain, indicating the existence of an interactome specifically assembled by unfolded BAK. This complex engages the WD40 domain of the autophagic effector ATG16L1 to induce unconventional autophagy, and the resulting LC3-positive vesicles contain ATP. Functional interference with the pathway increases ATP release during cell death, reduces ATP levels remaining in the apoptotic bodies, and improves phagocyte activation. These results reveal that an unconventional component of the autophagic burst that often accompanies apoptosis sequesters intracellular ATP to prevent its release, thus favouring the immunosilent nature of apoptotic cell death.

DOI: https://doi.org/10.1038/s41467-025-58619-3