bims-mibica 2025-04-20 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–04–20
38 papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.
MitoSNO inhibits mitochondrial hydrogen peroxide (mtH2O2) generation by α-ketoglutarate dehydrogenase (KGDH).
Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.
Active control of mitochondrial network morphology by metabolism-driven redox state.
Genetically encoded tool for manipulation of ΔΨm identifies its role as the driver of ISR induced by ATP synthase dysfunction.
Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis.
UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples.
In vivo composition of the mitochondrial nucleoid in mice.
The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability.
STAR/STARD1: a mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
Spatial regulation of mitochondrial membrane potential by 𝛂5ꞵ1 integrin engagement in collective cell migration.
Inhibition of mitochondrial genome-encoded mitomiR-3 contributes to ZEB1 mediated GPX4 downregulation and pro-ferroptotic lipid metabolism to induce ferroptosis in breast cancer cells.
Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.
Mitochondrial function regulates cell growth kinetics to actively maintain mitochondrial homeostasis.
A red-shifted donor-acceptor hemicyanine-based probe for mitochondrial pH in live cells.
Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering.
SLC25A42 promotes gastric cancer growth by conferring ferroptosis resistance through enhancing CPT2-mediated fatty acid oxidation.
Mechanism of allosteric activation in human mitochondrial ClpP protease.
Approaches to reduce succinate accumulation by restoration of succinate dehydrogenase activity in cultured adrenal cells.
Metabolic remodelling produces fumarate via the aspartate-argininosuccinate shunt in macrophages as an antiviral defence.
Cytosolic cytochrome c represses ferroptosis.
Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs.
Coupling of ribosome biogenesis and translation initiation in human mitochondria.
RRM2B deficiency causes dATP and dGTP depletion through enhanced degradation and slower synthesis.
Interleukin-13-mediated alterations in esophageal epithelial mitochondria contribute to tissue remodeling in eosinophilic esophagitis.
Supinoxin blocks small cell lung cancer progression by inhibiting mitochondrial respiration through DDX5.
Age-related blood condition counteracted with a common diabetes drug.
A common ground: an in silico assessment of the sources of intrinsic ex vivo resistance to venetoclax in acute myeloid leukemia.
The mitochondrial unfolded protein response: acting near and far.
Mitochondrial quality control in hematopoietic stem cells: mechanisms, implications, and therapeutic opportunities.
Real-world (RW) study of outcomes for acute myeloid leukemia (AML) patients treated with glasdegib or venetoclax in US community oncology practices.
Mitochondrial classic metabolism and its often-underappreciated facets.
Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.
3-Bromopyruvate boosts the effect of chemotherapy in acute myeloid leukemia by a pro-oxidant mechanism.
Discovery of XZ338, a highly potent BCL-XL degrader.
CD37 regulates the self-renewal of leukemic stem cells via integrin-mediated signaling in acute myeloid leukemia.
Dysregulation of sphingolipid metabolism contributes to the pathogenesis of chronic myeloid leukemia.
Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis.

Cell Rep Methods. 2025 Apr 08. pii: S2667-2375(25)00063-3. [Epub ahead of print] 101027

Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.

Liam P Kelley, Song-Hua Hu, Sarah A Boswell, Peter K Sorger, Alison E Ringel, Marcia C Haigis.

  Mitochondrial stress arises from a variety of sources, including mutations to mitochondrial DNA, the generation of reactive oxygen species, and an insufficient supply of oxygen or fuel. Mitochondrial stress induces a range of dedicated responses that repair damage and restore mitochondrial health. However, a systematic characterization of transcriptional and metabolic signatures induced by distinct types of mitochondrial stress is lacking. Here, we defined how primary human fibroblasts respond to a panel of mitochondrial inhibitors to trigger adaptive stress responses. Using metabolomic and transcriptomic analyses, we established integrated signatures of mitochondrial stress. We developed a tool, stress quantification using integrated datasets (SQUID), to deconvolute mitochondrial stress signatures from existing datasets. Using SQUID, we profiled mitochondrial stress in The Cancer Genome Atlas (TCGA) PanCancer Atlas, identifying a signature of pyruvate import deficiency in IDH1-mutant glioma. Thus, this study defines a tool to identify specific mitochondrial stress signatures, which may be applied to a range of systems.

Keywords:  CP: Metabolism; CP: Systems biology; cancer metabolism; integrated multi-omics; integrated stress response; metabolomics; mitochondria; mitochondrial stress response; mitochondrial unfolded protein response; stress signatures

DOI:  https://doi.org/10.1016/j.crmeth.2025.101027
J Biol Chem. 2025 Apr 16. pii: S0021-9258(25)00359-X. [Epub ahead of print] 108510

MitoSNO inhibits mitochondrial hydrogen peroxide (mtH2O2) generation by α-ketoglutarate dehydrogenase (KGDH).

Olivia Chalifoux, Samantha Sterman, Ben Faerman, Meijing Li, Stephanie Trezza, Marek Michalak, Luis B Agellon, Ryan J Mailloux.

Here, we demonstrate mitochondrial hydrogen peroxide (mtH2O2) production by α-ketoglutarate dehydrogenase (KGDH) can be inhibited by MitoSNO, alleviating lipotoxicity. MitoSNO in the nanomolar range inhibits mtH2O2 by ∼50% in isolated liver mitochondria without disrupting respiration, whereas the mitochondria-selective derivative used to synthesize MitoSNO, mitochondria-selective N-acetyl-penicillamine (MitoNAP), had no effect on either mtH2O2 generation or oxidative phosphorylation (OxPhos). Additionally, mtH2O2 generation in isolated liver mitochondria was almost abolished when MitoSNO was administered in the low micromolar range. The potent inhibitory effect of MitoSNO was comparable to 2-keto-3-methyl-valeric acid (KMV) and valproic acid (VA), selective inhibitors for KGDH-mediate mH2O2 production. S1QEL 1.1 (S1) and S3QEL (S3), which are known to selectively suppress mtH2O2 genesis through inhibition of complex I and complex III respectively, without disrupting respiration, had little to no effect on mtH2O2 production by liver mitochondria. We also identified it was a major mtH2O2 source as well but MitoSNO and MitoNAP did not affect mtH2O2 production by this ETC-linked enzyme. The MitoSNO also suppressed mtH2O2 production and partially rescued mitochondrial respiration in Huh-7 cells subjected to palmitate (PA) and fructose (Fruc) induced lipotoxicity. MitoSNO also prevented cell death and abrogated intrahepatic lipid accumulation in these Huh-7 cells. MitoSNO nullified mtH2O2 overgeneration and partially rescued OxPhos in liver mitochondria from mice fed a high fat diet (HFD). Our findings demonstrate that MitoSNO interferes with mtH2O2 production through KGDH S-nitrosation and may be useful in alleviating non-alcoholic fatty liver disease (NAFLD).

DOI: https://doi.org/10.1016/j.jbc.2025.108510
Nat Commun. 2025 Apr 16. 16(1): 3306

Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.

Kira A Young, Mohsen Hosseini, Jayna J Mistry, Claudia Morganti, Taylor S Mills, Xiurong Cai, Brandon T James, Griffin J Nye, Natalie R Fournier, Veronique Voisin, Ali Chegini, Aaron D Schimmer, Gary D Bader, Grace Egan, Marc R Mansour, Grant A Challen, Eric M Pietras, Kelsey H Fisher-Wellman, Keisuke Ito, Steven M Chan, Jennifer J Trowbridge.

The competitive advantage of mutant hematopoietic stem and progenitor cells (HSPCs) underlies clonal hematopoiesis (CH). Drivers of CH include aging and inflammation; however, how CH-mutant cells gain a selective advantage in these contexts is an unresolved question. Using a murine model of CH (Dnmt3aR878H/+), we discover that mutant HSPCs sustain elevated mitochondrial respiration which is associated with their resistance to aging-related changes in the bone marrow microenvironment. Mutant HSPCs have DNA hypomethylation and increased expression of oxidative phosphorylation gene signatures, increased functional oxidative phosphorylation capacity, high mitochondrial membrane potential (Δψm), and greater dependence on mitochondrial respiration compared to wild-type HSPCs. Exploiting the elevated Δψm of mutant HSPCs, long-chain alkyl-TPP molecules (MitoQ, d-TPP) selectively accumulate in the mitochondria and cause reduced mitochondrial respiration, mitochondrial-driven apoptosis and ablate the competitive advantage of HSPCs ex vivo and in vivo in aged recipient mice. Further, MitoQ targets elevated mitochondrial respiration and the selective advantage of human DNMT3A-knockdown HSPCs, supporting species conservation. These data suggest that mitochondrial activity is a targetable mechanism by which CH-mutant HSPCs gain a selective advantage over wild-type HSPCs.

DOI: https://doi.org/10.1038/s41467-025-57238-2
Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2421953122

Active control of mitochondrial network morphology by metabolism-driven redox state.

Gaurav Singh, Vineeth Vengayil, Aayushee Khanna, Swagata Adhikary, Sunil Laxman.

  Mitochondria are dynamic organelles that constantly change morphology. What controls mitochondrial morphology however remains unresolved. Using actively respiring yeast cells growing in distinct carbon sources, we find that mitochondrial morphology and activity are unrelated. Cells can exhibit fragmented or networked mitochondrial morphology in different nutrient environments independent of mitochondrial activity. Instead, mitochondrial morphology is controlled by the intracellular redox state, which itself depends on the nature of electron entry into the electron transport chain (ETC)-through complex I/II or directly to coenzyme Q/cytochrome c. In metabolic conditions where direct electron entry is high, reactive oxygen species (ROS) increase, resulting in an oxidized cytosolic environment and rapid mitochondrial fragmentation. Decreasing direct electron entry into the ETC by genetic or chemical means, or reducing the cytosolic environment rapidly restores networked morphologies. Using controlled disruptions of electron flow to alter ROS and redox state, we demonstrate minute-scale, reversible control between networked and fragmented forms in an activity-independent manner. Mechanistically, the fission machinery through Dnm1 responds in minute-scale to redox state changes, preceding the change in mitochondrial form. Thus, the metabolic state of the cell and its consequent cellular redox state actively control mitochondrial form.

Keywords:  electron transport chain; mitochondrial network; reactive oxygen species; redox state

DOI:  https://doi.org/10.1073/pnas.2421953122
Cell Chem Biol. 2025 Apr 17. pii: S2451-9456(25)00097-2. [Epub ahead of print]32(4): 620-630.e6

Genetically encoded tool for manipulation of ΔΨm identifies its role as the driver of ISR induced by ATP synthase dysfunction.

Mangyu Choe, Alex E Ekvik, Gretchen Stalnaker, Hijai R Shin, Denis V Titov.

  Mitochondrial membrane potential (ΔΨm) is one of the key parameters controlling cellular bioenergetics. Investigation of the role of ΔΨm in live cells is complicated by a lack of tools for its direct manipulation without off-target effects. Here, we adopted the uncoupling protein UCP1 from brown adipocytes as a genetically encoded tool for direct manipulation of ΔΨm. We validated the ability of exogenously expressed UCP1 to induce uncoupled respiration and lower ΔΨm in mammalian cells. UCP1 expression lowered ΔΨm to the same extent as chemical uncouplers but did not inhibit cell proliferation, suggesting that it manipulates ΔΨm without the off-target effects of chemical uncouplers. Using UCP1, we revealed that elevated ΔΨm is the driver of the integrated stress response induced by ATP synthase inhibition in mammalian cells.

Keywords:  ATP synthase inhibition; GEMMs; ISR; UCP1; genetically encoded tools for manipulation of metabolism; integrated stress response,; mitochondrial membrane potential; ΔΨm

DOI:  https://doi.org/10.1016/j.chembiol.2025.03.007
Nature. 2025 Apr 16.

Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis.

Malgorzata Gozdecka, Monika Dudek, Sean Wen, Muxin Gu, Richard J Stopforth, Justyna Rak, Aristi Damaskou, Guinevere L Grice, Matthew A McLoughlin, Laura Bond, Rachael Wilson, George Giotopoulos, Vijaya Mahalingam Shanmugiah, Rula Bany Bakar, Eliza Yankova, Jonathan L Cooper, Nisha Narayan, Sarah J Horton, Ryan Asby, Dean C Pask, Annalisa Mupo, Graham Duddy, Ludovica Marando, Theodoros Georgomanolis, Paul Carter, Amirtha Priya Ramesh, William G Dunn, Clea Barcena, Paolo Gallipoli, Kosuke Yusa, Slavé Petrovski, Penny Wright, Pedro M Quiros, Christian Frezza, James A Nathan, Arthur Kaser, Siddhartha Kar, Konstantinos Tzelepis, Jonathan Mitchell, Margarete A Fabre, Brian J P Huntly, George S Vassiliou.

Somatic DNMT3A R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk1,2. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3aR882H/+ HSPCs. Amongst the 640 vulnerability genes identified, many were involved in mitochondrial metabolism and metabolic flux analysis confirmed enhanced oxidative phosphorylation usage in Dnmt3aR882H/+ vs Dnmt3a+/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies. In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin, suppressed post-transplantation clonal expansion of Dnmt3aR882H/+, but not WT, LT-HSC. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank (UKB) participants revealed that individuals taking metformin had markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.

DOI: https://doi.org/10.1038/s41586-025-08980-6
Nat Cancer. 2025 Apr 18.

UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples.

Amy X Xie, Wesley Tansey, Ed Reznik.

Comprehensively studying metabolism requires metabolite measurements. Such measurements, however, are often unavailable in large cohorts of tissue samples. To address this basic barrier, we propose a Bayesian framework ('UnitedMet') that leverages RNA-metabolite covariation to impute otherwise unmeasured metabolite levels from widely available transcriptomic data. UnitedMet is equally capable of imputing whole pool sizes and outcomes of isotope tracing experiments. We apply UnitedMet to investigate the metabolic impact of driver mutations in kidney cancer, identifying an association between BAP1 and a highly oxidative tumor phenotype. We similarly apply UnitedMet to determine that advanced kidney cancers upregulate oxidative phosphorylation relative to early-stage disease, that oxidative metabolism in kidney cancer is associated with inferior outcomes to anti-angiogenic therapy and that kidney cancer metastases demonstrate elevated oxidative phosphorylation. UnitedMet provides a scalable tool for assessing metabolic phenotypes when direct measurements are infeasible, facilitating unexplored avenues for metabolite-focused hypothesis generation.

DOI: https://doi.org/10.1038/s43018-025-00943-0
Biochim Biophys Acta Mol Cell Res. 2025 Apr 15. pii: S0167-4889(25)00060-6. [Epub ahead of print] 119955

In vivo composition of the mitochondrial nucleoid in mice.

Rodolfo García-Villegas, Franka Odenthal, Yvonne Giannoula, Nina A Bonekamp, Inge Kühl, Chan Bae Park, Henrik Spåhr, Elisa Motori, Fredrik Levander, Nils-Göran Larsson.

  Mitochondrial DNA (mtDNA) is compacted into dynamic structures called mitochondrial nucleoids (mt-nucleoids), with the mitochondrial transcription factor A (TFAM) as the core packaging protein. We generated bacterial artificial chromosome (BAC) transgenic mice expressing FLAG-tagged TFAM protein (Tfam-FLAGBAC mice) to investigate the mt-nucleoid composition in vivo. Importantly, we show that the TFAM-FLAG protein is functional and complements the absence of the wild-type TFAM protein in homozygous Tfam knockout mice. We performed immunoprecipitation experiments from different mouse tissues and identified 12 proteins as core mt-nucleoid components by proteomics analysis. Among these, eight proteins correspond to mtDNA replication and transcription factors, while the other four are involved in the mitoribosome assembly. In addition, we used the Tfam-FLAGBAC mice to identify ten proteins that may stabilize TFAM-FLAG upon depletion of the mitochondrial RNA polymerase despite the absence of mtDNA and induction of the LONP1 protease. Finally, we evaluated the changes in mt-nucleoids caused by very high levels of TFAM unraveling nine interactors that could counteract the high TFAM levels to maintain active mtDNA transcription. Altogether, we demonstrate that the Tfam-FLAGBAC mice are a valuable tool for investigating the mt-nucleoid composition in vivo.

Keywords:  Mitochondrial nucleoid; Mitochondrial translation; TFAM; Transgenic mice; mtDNA expression

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119955
Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2417477122

The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability.

Josefin M E Forslund, Tran V H Nguyen, Vimal Parkash, Andreas Berner, Steffi Goffart, Jaakko L O Pohjoismäki, Paulina H Wanrooij, Erik Johansson, Sjoerd Wanrooij.

  Mitochondrial DNA (mtDNA) stability, essential for cellular energy production, relies on DNA polymerase gamma (POLγ). Here, we show that the POLγ Y951N disease-causing mutation induces replication stalling and severe mtDNA depletion. However, unlike other POLγ disease-causing mutations, Y951N does not directly impair exonuclease activity and only mildly affects polymerase activity. Instead, we found that Y951N compromises the enzyme's ability to efficiently toggle between DNA synthesis and degradation, and is thus a patient-derived mutation with impaired polymerase-exonuclease switching. These findings provide insights into the intramolecular switch when POLγ proofreads the newly synthesized DNA strand and reveal a new mechanism for causing mitochondrial DNA instability.

Keywords:  DNA polymerases; mitochondria; mitochondrial disease; mtDNA; mtDNA replication

DOI:  https://doi.org/10.1073/pnas.2417477122
bioRxiv. 2025 Apr 10. pii: 2025.04.03.647084. [Epub ahead of print]

STAR/STARD1: a mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.

Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.

The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the acidic pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet swift mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process has remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This newfound mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.

DOI: https://doi.org/10.1101/2025.04.03.647084
J Cell Sci. 2025 Apr 14. pii: jcs.263665. [Epub ahead of print]

Spatial regulation of mitochondrial membrane potential by 𝛂5ꞵ1 integrin engagement in collective cell migration.

Gustavo G Pacheco, Bette J Dzamba, Wakako Endo, Benjamin C Edwards, Minah Khan, Tien Comlekoglu, David R Shook, Keri Quasey, Maureen A Bjerke, Glen D Hirsh, David F Kashatus, Douglas W DeSimone.

  The mechanistic links between mechanical forces and bioenergetics remain elusive. We report an increase in mitochondrial membrane potential (MMP) along the leading row of collectively migrating Xenopus laevis mesendoderm cells at sites where fibronectin- a5b1 integrin substrate traction stresses are greatest. Real-time metabolic analyses reveal a5b1 integrin-dependent increases in respiration efficiency in cells on fibronectin substrates. Elevation of metabolic activity is reduced following pharmacologic inhibition of focal adhesion kinase (FAK) signaling. Attachment of mesendoderm cells to fibronectin fragments that support differing a5b1 integrin conformational and ligand-binding affinity states, increases MMP when both the Arg-Gly-Asp (RGD) and Pro-Pro-Ser-Arg-Asn (PPSRN) synergy sites of fibronectin are engaged by the receptor. Cell stretch on deformable fibronectin substrates also results in a FAK-dependent increase in MMP. Inhibition of MMP or ATP-synthase activity slows collective cell migration velocity in vivo, further suggesting that integrin-dependent adhesion and signaling contribute to metabolic changes. These data highlight an underexplored link between ECM-integrin adhesion and metabolic activity in embryonic cell migration. We propose that fibronectin-integrin adhesion and signaling help shape the metabolic landscape of collectively migrating cells.

Keywords:  Adhesion; Cell migration; Extracellular matrix; Integrin; Mitochondria; Morphogenesis

DOI:  https://doi.org/10.1242/jcs.263665
Free Radic Biol Med. 2025 Apr 14. pii: S0891-5849(25)00229-1. [Epub ahead of print]

Inhibition of mitochondrial genome-encoded mitomiR-3 contributes to ZEB1 mediated GPX4 downregulation and pro-ferroptotic lipid metabolism to induce ferroptosis in breast cancer cells.

Amoolya Kandettu, Joydeep Ghosal, Jesline Shaji Tharayil, Raviprasad Kuthethur, Sandeep Mallya, Rekha Koravadi Narasimhamurthy, Kamalesh Dattaram Mumbrekar, Yashwanth Subbannayya, Naveena An Kumar, Raghu Radhakrishnan, Shama Prasada Kabekkodu, Sanjiban Chakrabarty.

  Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, represents a unique vulnerability in cancer cells. However, current ferroptosis-inducing therapies face clinical limitations due to poor cancer cell specificity, systemic toxicity, and off-target effects. Therefore, a deeper understanding of molecular regulators of ferroptosis sensitivity is critical for developing targeted therapies. The metabolic plasticity of cancer cells determines their sensitivity to ferroptosis. While mitochondrial dysfunction contributes to metabolic reprogramming in cancer, its role in modulating ferroptosis remains poorly characterized. Previously, studies have identified that mitochondrial genome also encodes several noncoding RNAs. We identified 13 novel mitochondrial genome-encoded miRNAs (mitomiRs) that are aberrantly overexpressed in triple-negative breast cancer (TNBC) cell lines and patient tumors. We observed higher levels of mitomiRs in basal-like triple-negative breast cancer (TNBC) cells compared to mesenchymal stem-like TNBC cells. Strikingly, 11 of these mitomiRs directly target the 3'UTR of ZEB1, a master regulator of epithelial-to-mesenchymal transition (EMT). Using mitomiR-3 mimic, inhibitor and sponges, we demonstrated its role as a key regulator of ZEB1 expression in TNBC cells. Inhibition of mitomiR-3 via sponge construct in basal-like TNBC, MDA-MB-468 cells, promoted ZEB1 upregulation and induced a mesenchymal phenotype. Further, mitomiR-3 inhibition in TNBC cells contributed to reduced cancer cell proliferation, migration, and invasion. Mechanistically, mitomiR-3 inhibition in TNBC cells promote metabolic reprogramming toward pro-ferroptotic pathways, including iron accumulation, increased polyunsaturated fatty acid (PUFA) metabolites, and lipid peroxidation, contributing to ferroptotic cell death via ZEB1-mediated downregulation of GPX4, a critical ferroptosis defense enzyme. We observed that mitomiR-3 inhibition significantly suppressed tumor growth in vivo. Our identified mitomiR-3 has low expression in normal breast cells, minimizing potential off-target toxicity, making them a promising target for pro-ferroptotic cancer therapy. Our study reveals a novel link between mitochondrial miRNAs and ferroptosis sensitivity in TNBC paving a way for miRNA-based therapeutics.

Keywords:  GPX4; PUFA; TNBC; ZEB1; ferroptosis; lipid peroxidation; miRNA; mitochondria

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.019
Sci Adv. 2025 Apr 18. 11(16): eads1842

Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.

Kristina Bubb, Julia Etich, Kristina Probst, Tanvi Parashar, Maximilian Schuetter, Frederik Dethloff, Susanna Reincke, Janica L Nolte, Marcus Krüger, Ursula Schlötzer-Schrehard, Julian Nüchel, Constantinos Demetriades, Patrick Giavalisco, Jan Riemer, Bent Brachvogel.

Decline of mitochondrial respiratory chain (mtRC) capacity is a hallmark of mitochondrial diseases. Patients with mtRC dysfunction often present reduced skeletal growth as a sign of premature cartilage degeneration and aging, but how metabolic adaptations contribute to this phenotype is poorly understood. Here we show that, in mice with impaired mtRC in cartilage, reductive/reverse TCA cycle segments are activated to produce metabolite-derived amino acids and stimulate biosynthesis processes by mechanistic target of rapamycin complex 1 (mTORC1) activation during a period of massive skeletal growth and biomass production. However, chronic hyperactivation of mTORC1 suppresses autophagy-mediated organelle recycling and disturbs extracellular matrix secretion to trigger chondrocytes death, which is ameliorated by targeting the reductive metabolism. These findings explain how a primarily beneficial metabolic adaptation response required to counterbalance the loss of mtRC function, eventually translates into profound cell death and cartilage tissue degeneration. The knowledge of these dysregulated key nutrient signaling pathways can be used to target skeletal aging in mitochondrial disease.

DOI: https://doi.org/10.1126/sciadv.ads1842
bioRxiv. 2025 Apr 01. pii: 2025.03.31.646474. [Epub ahead of print]

Mitochondrial function regulates cell growth kinetics to actively maintain mitochondrial homeostasis.

Leeba Ann Chacko, Hidenori Nakaoka, Richard Morris, Wallace Marshall, Vaishnavi Ananthanarayanan.

Mitochondria are not produced de novo in newly divided daughter cells, but are inherited from the mother cell during mitosis. While mitochondrial homeostasis is crucial for living cells, the feedback responses that maintain mitochondrial volume across generations of dividing cells remain elusive. Here, using a microfluidic yeast 'mother machine', we tracked several generations of fission yeast cells and observed that cell size and mitochondrial volume grew exponentially during the cell cycle. We discovered that while mitochondrial homeostasis relied on the 'sizer' mechanism of cell size maintenance, mitochondrial function was a critical determinant of the timing of cell division: cells born with lower than average amounts of mitochondria grew slower and thus added more mitochondria before they divided. Thus, mitochondrial addition during the cell cycle was tailored to the volume of mitochondria at birth, such that all cells ultimately contained the same mitochondrial volume at cell division. Quantitative modelling and experiments with mitochondrial DNA-deficient rho0 cells additionally revealed that mitochondrial function was essential for driving the exponential growth of cells. Taken together, we demonstrate a central role for mitochondrial activity in dictating cellular growth rates and ensuring mitochondrial volume homeostasis.

DOI: https://doi.org/10.1101/2025.03.31.646474
J Mater Chem B. 2025 Apr 17.

A red-shifted donor-acceptor hemicyanine-based probe for mitochondrial pH in live cells.

Fouzia Kalim, Gandhi Sivaraman, Himanshu Vankhede, Arati Ramesh, Sufi O Raja, Akash Gulyani.

pH dynamically regulates diverse cellular functions and processes. At the inner mitochondrial membrane (IMM), nanoscale pH gradients generated by the electron transport chain (ETC) play a critical role in contributing to mitochondrial membrane potential that drives ATP synthesis and thermogenesis. However, tools to decouple pH gradients from the overall IMM potential in living cells are limited. This study integrates a fluorescent "benzo-indole" chromophore with a pH-sensitive "phenol" moiety into a single covalent skeleton to build a sensitive, red-shifted, cell-permeable pH probe (Mito-pH2). Mito-pH2 localizes inside mitochondria with high specificity presumably to the mitochondrial inner membrane by virtue of being an amphiphilic cation and can report dynamic changes in mitochondrial pH in living cells. Our design ensures that Mito-pH2 exhibits pH-sensitive dual-excitation and dual-emission peaks enabling ratiometric pH-sensing. Furthermore, Mito-pH2 reports an increase in pH in the pH range of 3-9 through a striking colour change from yellow to purple making it a sensitive all-purpose colorimetric pH probe. A combination of DFT calculations and spectroscopy shed light on likely sensing mechanisms including photophysics. Quantitative live-cell fluorescence imaging reveals that Mito-pH2 can detect dynamic changes in mitochondrial pH upon extracellular pH modulation with little or no measurable cytotoxicity during live imaging. Red-emitting Mito-pH2 opens new avenues of quantitative mapping of physiological mitochondrial membrane pH and significantly enhances the repertoire of environment-sensitive and low-toxicity mitochondrial probes that link mitochondrial state and micro-environment.

DOI: https://doi.org/10.1039/d4tb01839g
Nat Commun. 2025 Apr 17. 16(1): 3401

Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering.

Koki Nakamura, Saeko Aoyama-Ishiwatari, Takahiro Nagao, Mohammadreza Paaran, Christopher J Obara, Yui Sakurai-Saito, Jake Johnston, Yudan Du, Shogo Suga, Masafumi Tsuboi, Makoto Nakakido, Kouhei Tsumoto, Yusuke Kishi, Yukiko Gotoh, Chulhwan Kwak, Hyun-Woo Rhee, Jeong Kon Seo, Hidetaka Kosako, Clint Potter, Bridget Carragher, Jennifer Lippincott-Schwartz, Franck Polleux, Yusuke Hirabayashi.

Mitochondria-ER membrane contact sites (MERCS) represent a fundamental ultrastructural feature underlying unique biochemistry and physiology in eukaryotic cells. The ER protein PDZD8 is required for the formation of MERCS in many cell types, however, its tethering partner on the outer mitochondrial membrane (OMM) is currently unknown. Here we identify the OMM protein FKBP8 as the tethering partner of PDZD8 using a combination of unbiased proximity proteomics, CRISPR-Cas9 endogenous protein tagging, Cryo-electron tomography, and correlative light-electron microscopy. Single molecule tracking reveals highly dynamic diffusion properties of PDZD8 along the ER membrane with significant pauses and captures at MERCS. Overexpression of FKBP8 is sufficient to narrow the ER-OMM distance, whereas independent versus combined deletions of these two proteins demonstrate their interdependence for MERCS formation. Furthermore, PDZD8 enhances mitochondrial complexity in a FKBP8-dependent manner. Our results identify a novel ER-mitochondria tethering complex that regulates mitochondrial morphology in mammalian cells.

DOI: https://doi.org/10.1038/s41467-025-58538-3
Cell Death Dis. 2025 Apr 17. 16(1): 309

SLC25A42 promotes gastric cancer growth by conferring ferroptosis resistance through enhancing CPT2-mediated fatty acid oxidation.

Haoying Wang, Weijia Dou, Mengxiao Liu, Weifang Wang, Ying Yang, Jibin Li, Zhenxiong Liu, Nan Wang.

Accumulating evidence has shown that the dysfunction of mitochondria, the multifunctional organelles in various cellular processes, is a pivotal event in the development of various diseases, including human cancers. Solute Carrier Family 25 Member 42 (SLC25A42) is a mitochondrial protein governing the transport of coenzyme A (CoA). However, the biological roles of SLC25A42 in human cancers are still unexplored. Here we uncovered that SLC25A42 is upregulated and correlated with a worse prognosis in GC patients. SLC25A42 promotes the proliferation of gastric cancer (GC) cells while suppresses apoptosis in vitro and in vivo. Mechanistically, SLC25A42 promotes the growth and inhibits apoptosis of GC cells by reprograming lipid metabolism. On the one hand, SLC25A42 enhances fatty acid oxidation-mediated mitochondrial respiration to provide energy for cell survival. On the other hand, SLC25A42 decreases the levels of free fatty acids and ROS to inhibit ferroptosis. Moreover, we found that SLC25A42 reprograms lipid metabolism in GC cells by upregulating the acetylation and thus the expression of CPT2. Collectively, our data reveal a critical oncogenic role of SLC25A42 in GCs and suggest that SLC25A42 represent a promising therapeutic target for GC.

DOI: https://doi.org/10.1038/s41419-025-07644-7
Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2419881122

Mechanism of allosteric activation in human mitochondrial ClpP protease.

Monica M Goncalves, Adwaith B Uday, Taylor J B Forrester, S Quinn W Currie, Angelina S Kim, Yue Feng, Yulia Jitkova, Algirdas Velyvis, Robert W Harkness, Matthew S Kimber, Aaron D Schimmer, Natalie Zeytuni, Siavash Vahidi.

  Human ClpP protease contributes to mitochondrial protein quality control by degrading misfolded proteins. ClpP is overexpressed in cancers such as acute myeloid leukemia (AML), where its inhibition leads to the accumulation of damaged respiratory chain subunits and cell death. Conversely, hyperactivating ClpP with small-molecule activators, such as the recently discovered ONC201, disrupts mitochondrial protein degradation and impairs respiration in cancer cells. Despite its critical role in human health, the mechanism underlying the structural and functional properties of human ClpP remains elusive. Notably, human ClpP is paradoxically activated by active-site inhibitors. All available structures of human ClpP published to date are in the inactive compact or compressed states, surprisingly even when ClpP is bound to an activator molecule such as ONC201. Here, we present structures of human mitochondrial ClpP in the active extended state, including a pair of structures where ClpP is bound to an active-site inhibitor. We demonstrate that amino acid substitutions in the handle region (A192E and E196R) recreate a conserved salt bridge found in bacterial ClpP, stabilizing the extended active state and significantly enhancing ClpP activity. We elucidate the ClpP activation mechanism, highlighting a hormetic effect where substoichiometric inhibitor binding triggers an allosteric transition that drives ClpP into its active extended state. Our findings link the conformational dynamics of ClpP to its catalytic function and provide high-resolution structures for the rational design of potent and specific ClpP inhibitors, with implications for targeting AML and other disorders with ClpP involvement.

Keywords:  ClpP protease; HDX–MS; allostery; cryo-EM; intracellular protein degradation

DOI:  https://doi.org/10.1073/pnas.2419881122
J Cell Sci. 2025 Apr 16. pii: jcs.263925. [Epub ahead of print]

Approaches to reduce succinate accumulation by restoration of succinate dehydrogenase activity in cultured adrenal cells.

Fatimah Al Khazal, Leili Rahimi, Fan Feng, Nicole A Becker, Clifford D Folmes, Judith Favier, L James Maher.

  The rare human neuroendocrine tumors pheochromocytoma and paraganglioma (PPGL) can result from loss of mitochondrial succinate dehydrogenase. The resulting succinate accumulation is tumorigenic in certain neuroendocrine cells. Here we explore two theoretical approaches to mitigate tumorigenic succinate accumulation in a cell culture model of PPGL. We first study a gene replacement strategy using transposition technology and conclude that many aspects of mitochondrial morphology, oxidative cell metabolism and succinate accumulation are reversible by this process. We then investigate if riboflavin supplementation has the potential to rescue succinate dehydrogenase activity in the intact SDHA catalytic subunit to suppress succinate accumulation even in the absence of SDHB. We show that this latter strategy is not successful.

Keywords:  Paraganglioma; Pheochromocytoma; Riboflavin; Succinate dehydrogenase

DOI:  https://doi.org/10.1242/jcs.263925
Nat Microbiol. 2025 Apr 18.

Metabolic remodelling produces fumarate via the aspartate-argininosuccinate shunt in macrophages as an antiviral defence.

Wenjun Xia, Youxiang Mao, Ziyan Xia, Jie Cheng, Peng Jiang.

Metabolic remodelling underpins macrophage effector functions in response to various stimuli, but the mechanisms involved are unclear. Here we report that viral-infection-induced inflammatory stimulation causes a rewiring of the urea cycle and the tricarboxylic acid cycle metabolism in macrophages to form a cyclic pathway called the aspartate-argininosuccinate (AAS) shunt. Using RNA sequencing, unbiased metabolomics and stable isotope tracing, we found that fumarate generated from the AAS shunt is driven by argininosuccinate synthase (ASS1) in the cytosol and potentiates inflammatory effects. Genetic ablation of ASS1 reduces intracellular fumarate levels and interferon-β production, and mitochondrial respiration is also suppressed. Notably, viral challenge or fumarate esters enhance interferon-β production via direct succination of the mitochondrial antiviral signalling protein and activation of the retinoic acid-inducible gene-I-like receptor signalling. In addition to the vesicular stomatitis virus, the Sendai virus and influenza A virus can also exert these effects. In addition, patients with Ebola virus disease have increased ASS1 expression and ASS1-deficient mice show suppressed macrophage interferon responses to vesicular stomatitis virus infection. These findings reveal that fumarate can be produced from the viral inflammation-induced AAS shunt and is essential for antiviral innate immunity.

DOI: https://doi.org/10.1038/s41564-025-01985-x
Cell Metab. 2025 Apr 08. pii: S1550-4131(25)00149-4. [Epub ahead of print]

Cytosolic cytochrome c represses ferroptosis.

Xinxin Song, Zhuan Zhou, Jiao Liu, Jingbo Li, Chunhua Yu, Herbert J Zeh, Daniel J Klionsky, Brent R Stockwell, Jiayi Wang, Rui Kang, Guido Kroemer, Daolin Tang.

  The release of cytochrome c, somatic (CYCS) from mitochondria to the cytosol is an established trigger of caspase-dependent apoptosis. Here, we unveil an unexpected role for cytosolic CYCS in inhibiting ferroptosis-a form of oxidative cell death driven by uncontrolled lipid peroxidation. Mass spectrometry and site-directed mutagenesis revealed the existence of a cytosolic complex composed of inositol polyphosphate-4-phosphatase type I A (INPP4A) and CYCS. This CYCS-INPP4A complex is distinct from the CYCS-apoptotic peptidase activating factor 1 (APAF1)-caspase-9 apoptosome formed during mitochondrial apoptosis. CYCS boosts INPP4A activity, leading to increased formation of phosphatidylinositol-3-phosphate, which prevents phospholipid peroxidation and plasma membrane rupture, thus averting ferroptotic cell death. Unbiased screening led to the identification of the small-molecule compound 10A3, which disrupts the CYCS-INPP4A interaction. 10A3 sensitized cultured cells and tumors implanted in immunocompetent mice to ferroptosis. Collectively, these findings redefine our understanding of cytosolic CYCS complexes that govern diverse cell death pathways.

Keywords:  apoptosis; cytochrome c; ferroptosis; protein complex

DOI:  https://doi.org/10.1016/j.cmet.2025.03.014
Nature. 2025 Apr 16.

Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs.

Mohsen Hosseini, Veronique Voisin, Ali Chegini, Angelica Varesi, Severine Cathelin, Dhanoop Manikoth Ayyathan, Alex C H Liu, Yitong Yang, Vivian Wang, Abdula Maher, Eric Grignano, Julie A Reisz, Angelo D'Alessandro, Kira Young, Yiyan Wu, Martina Fiumara, Samuele Ferrari, Luigi Naldini, Federico Gaiti, Shraddha Pai, Grace Egan, Aaron D Schimmer, Gary D Bader, John E Dick, Stephanie Z Xie, Jennifer J Trowbridge, Steven M Chan.

Clonal haematopoiesis arises when a haematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type HSCs, resulting in its clonal expansion. Individuals with clonal haematopoiesis are at increased risk of developing haematologic neoplasms and other age-related inflammatory illnesses1-4. Suppressing the expansion of mutant HSCs may prevent these outcomes; however, such interventions have not yet been identified. The most common clonal haematopoiesis driver mutations are in the DNMT3A gene, with arginine 882 (R882) being a mutation hotspot1-3,5-7. Here we show that mouse haematopoietic stem and progenitor cells (HSPCs) carrying the Dnmt3aR878H/+ mutation, equivalent to human DNMT3AR882H/+, have increased mitochondrial respiration compared with wild-type cells and are dependent on this metabolic reprogramming for their competitive advantage. Treatment with metformin, an anti-diabetic drug that inhibits mitochondrial respiration8, reduced the competitive advantage of Dnmt3aR878H/+ HSCs. Through a multi-omics approach, we found that metformin acts by enhancing methylation potential in Dnmt3aR878H/+ HSPCs and reversing the aberrant DNA CpG methylation and histone H3 K27 trimethylation profiles in these cells. Metformin also reduced the competitive advantage of human DNMT3AR882H HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against DNMT3A R882 mutation-driven clonal haematopoiesis in humans.

DOI: https://doi.org/10.1038/s41586-025-08871-w
Nat Commun. 2025 Apr 17. 16(1): 3641

Coupling of ribosome biogenesis and translation initiation in human mitochondria.

Marleen Heinrichs, Anna Franziska Finke, Shintaro Aibara, Angelique Krempler, Angela Boshnakovska, Peter Rehling, Hauke S Hillen, Ricarda Richter-Dennerlein.

Biogenesis of mitoribosomes requires dedicated chaperones, RNA-modifying enzymes, and GTPases, and defects in mitoribosome assembly lead to severe mitochondriopathies in humans. Here, we characterize late-step assembly states of the small mitoribosomal subunit (mtSSU) by combining genetic perturbation and mutagenesis analysis with biochemical and structural approaches. Isolation of native mtSSU biogenesis intermediates via a FLAG-tagged variant of the GTPase MTG3 reveals three distinct assembly states, which show how factors cooperate to mature the 12S rRNA. In addition, we observe four distinct primed initiation mtSSU states with an incompletely matured rRNA, suggesting that biogenesis and translation initiation are not mutually exclusive processes but can occur simultaneously. Together, these results provide insights into mtSSU biogenesis and suggest a functional coupling between ribosome biogenesis and translation initiation in human mitochondria.

DOI: https://doi.org/10.1038/s41467-025-58827-x
Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2503531122

RRM2B deficiency causes dATP and dGTP depletion through enhanced degradation and slower synthesis.

Ololade Folajimi Awoyomi, Choco Michael Gorospe, Biswajit Das, Pradeep Mishra, Sushma Sharma, Olena Diachenko, Anna Karin Nilsson, Phong Tran, Paulina H Wanrooij, Andrei Chabes.

  Mitochondrial DNA (mtDNA) replication requires a steady supply of deoxyribonucleotides (dNTPs), synthesized de novo by ribonucleotide reductase (RNR). In nondividing cells, RNR consists of RRM1 and RRM2B subunits. Mutations in RRM2B cause mtDNA depletion syndrome, linked to muscle weakness, neurological decline, and early mortality. The impact of RRM2B deficiency on dNTP pools in nondividing tissues remains unclear. Using a mouse knockout model, we demonstrate that RRM2B deficiency selectively depletes dATP and dGTP, while dCTP and dTTP levels remain stable or increase. This depletion pattern resembles the effects of hydroxyurea, an inhibitor that reduces overall RNR activity. Mechanistically, we propose that the depletion of dATP and dGTP arises from their preferred degradation by the dNTPase SAMHD1 and the lower production rate of dATP by RNR. Identifying dATP and dGTP depletion as a hallmark of RRM2B deficiency provides insights for developing nucleoside bypass therapies to alleviate the effects of RRM2B mutations.

Keywords:  dNTP metabolism; genome stability; mtDNA stability; ribonucleotide reductase

DOI:  https://doi.org/10.1073/pnas.2503531122
bioRxiv. 2025 Apr 02. pii: 2025.04.02.646853. [Epub ahead of print]

Interleukin-13-mediated alterations in esophageal epithelial mitochondria contribute to tissue remodeling in eosinophilic esophagitis.

Jazmyne L Jackson, Reshu Saxena, Mary Grace Murray, Abigail J Staub, Alena Klochkova, Travis H Bordner, Courtney Worrell, Annie D Fuller, John M Crespo, Andres J Klein-Szanto, John Elrod, Tatiana A Karakasheva, Melanie Ruffner, Amanda B Muir, Kelly A Whelan.

Background: The significance of mitochondria in EoE pathobiology remains elusive.
Objective: To determine the impact of EoE inflammatory mediators upon mitochondrial biology in esophageal epithelium, the mechanisms mediating these effects, and their functional significance to EoE pathobiology.
Methods: Mitochondria were evaluated in human biopsies, MC903/Ovalbumin-induced murine EoE, and human esophageal keratinocytes. Esophageal keratinocytes were treated with EoE-relevant cytokines and JAK/STAT inhibitor ruxolitinib. To deplete mitochondria, 3D organoids generated from TFAM loxp/loxp mice were subjected ex vivo to Cre or siRNA against Transcription factor A, mitochondria (TFAM) was transfected into esophageal keratinocytes. Mitochondrial respiration, membrane potential, and superoxide levels were measured.
Results: We find evidence of increased mitochondria in esophageal epithelium of patients with EoE and mice with EoE-like inflammation. In esophageal keratinocytes, IL-4 and IL-13 increase mitochondrial mass. IL-13 increases mitochondrial biogenesis in a JAK/STAT-dependent manner. In 3D organoids, IL-13 limits squamous cell differentiation (SCD), and this is blunted upon TFAM depletion. IL-13 decreases mitochondrial respiration and superoxide level, although mitochondria remain intact. IL-13-mediated suppression of superoxide was abrogated upon TFAM depletion in esophageal keratinocytes.
Conclusions: We report that increased mitochondrial mass is a feature of EoE. Among EoE-relevant cytokines, IL-13 is the primary driver of increased mitochondrial mass in esophageal keratinocytes by promoting mitochondrial biogenesis in a JAK/STAT-dependent manner. IL-13-mediated accumulation of mitochondria impairs SCD in esophageal keratinocytes and also suppresses oxidative stress, a factor that is known to induce SCD. These findings identify a novel mechanism through which IL-13 promotes EoE-associated epithelial remodeling.
Clinical Implication: These findings further lay a foundation for exploration of level of esophageal epithelial mitochondria as a predictive biomarker for response to dupilumab.
Capsule summary: IL-13 promotes mitochondrial biogenesis in esophageal epithelium, contributing to impaired squamous cell differentiation.

DOI: https://doi.org/10.1101/2025.04.02.646853
iScience. 2025 Apr 18. 28(4): 112219

Supinoxin blocks small cell lung cancer progression by inhibiting mitochondrial respiration through DDX5.

Subhadeep Das, Maria P Zea, Matthew P Russon, Zheng Xing, Sandra Torregrosa-Allen, Heidi E Cervantes, Haley Anne Harper, Bennett D Elzey, Elizabeth J Tran.

  DDX5 is a DEAD-box RNA helicase that is overexpressed and implicated in the progression of several cancers, including small cell lung cancer (SCLC). Our laboratory has demonstrated that DDX5 is essential for the invasive growth of SCLC and mitochondrial respiration. SCLC is an extremely lethal, recalcitrant tumor, and currently lacking effective treatments. Supinoxin (RX 5902), a compound having anti-cancer activity, is a known target of phosphor-DDX5. We now report that Supinoxin inhibits the proliferation of chemo-sensitive and chemo-resistant SCLC lines, H69 and H69AR, respectively. Additionally, Supinoxin mitigates both the growth of H69AR xenograft tumors and SCLC PDX tumors in vivo. Finally, we find that Supinoxin inhibits expression of mitochondrial genes and effectively blocks respiration. These studies suggest that Supinoxin functions in anti-tumor progression by reducing cellular energy levels through DDX5.

Keywords:  Cancer; Molecular biology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2025.112219
Nature. 2025 Apr 16.

Age-related blood condition counteracted with a common diabetes drug.

Elmira Khabusheva, Margaret A Goodell.



Keywords:  Ageing; Cancer; Metabolism; Stem cells

DOI:  https://doi.org/10.1038/d41586-025-01129-5
Hematol Transfus Cell Ther. 2025 Apr 12. pii: S2531-1379(25)00026-4. [Epub ahead of print]47(2): 103758

A common ground: an in silico assessment of the sources of intrinsic ex vivo resistance to venetoclax in acute myeloid leukemia.

Brunno Gilberto Santos de Macedo, Manuela Albuquerque de Melo, Diego Antonio Pereira-Martins, João Agostinho Machado-Neto, Fabiola Traina.

  Venetoclax is a promising alternative for patients with acute myeloid leukemia who are considered unfit for conventional chemotherapy; however, its employment still faces challenges mostly related to drug resistance. Here, we provide further biological mechanisms underlying the previously described and potentially novel intrinsic sources of poor response to venetoclax departing from ex vivo response data. Acute myeloid leukemia data including FLT3 mutation status, gene expression data, and ex vivo response data were extracted from the publicly available BeatAML 1.0 study database and aided sample categorization that supported differential gene expression analysis that, in turn, supported gene set enrichment analysis. CIBERSORTx-based bulk RNA sequencing deconvolution of BeatAML 1.0 data allowed us to categorize samples according to their cell type content. We observed that inflammation-related gene sets, such as cytokines and inflammatory response, NLRP3 inflammasome activation, and activation of adaptive immune response, were concordantly positively enriched across all the conditions reported to be associated with poor ex vivo venetoclax response, whereas samples from good ex vivo responders' mostly enriched gene sets related to mitochondrial activity, and early myeloid progenitor cell molecular programs. Besides the alternative reliance on BCL2A1, we highlight inflammation as a common element present across multiple sources of venetoclax ex vivo response modulation in acute myeloid leukemia samples. Hence, a potential key modulator for venetoclax response.

Keywords:  Acute myeloid leukemia; Drug resistance; Targeted molecular therapies; Venetoclax

DOI:  https://doi.org/10.1016/j.htct.2025.103758
Biol Chem. 2025 Apr 17.

The mitochondrial unfolded protein response: acting near and far.

Nikolaos Charmpilas, Qiaochu Li, Thorsten Hoppe.

  Mitochondria are central hubs of cellular metabolism and their dysfunction has been implicated in a variety of human pathologies and the onset of aging. To ensure proper mitochondrial function under misfolding stress, a retrograde mitochondrial signaling pathway known as UPRmt is activated. The UPRmt ensures that mitochondrial stress is communicated to the nucleus, where gene expression for several mitochondrial proteases and chaperones is induced, forming a protective mechanism to restore mitochondrial proteostasis and function. Importantly, the UPRmt not only acts within cells, but also exhibits a conserved cell-nonautonomous activation across species, where mitochondrial stress in a defined tissue triggers a systemic response that affects distant organs. Here, we summarize the molecular basis of the UPRmt in the invertebrate model organism Caenorhabditis elegans and in mammals. We also describe recent findings on cell-nonautonomous activation of the UPRmt in worms, flies and mice, and how UPRmt activation in specific tissues affects organismal metabolism and longevity.

Keywords:  cell-nonautonomous regulation; integrated stress response; mitochondria; mitochondrial unfolded protein response; stress signaling

DOI:  https://doi.org/10.1515/hsz-2025-0107
Stem Cell Res Ther. 2025 Apr 15. 16(1): 180

Mitochondrial quality control in hematopoietic stem cells: mechanisms, implications, and therapeutic opportunities.

Yun Liao, Stacia Octaviani, Zhen Tian, Samuel R Wang, Chunlan Huang, Jian Huang.

  Mitochondrial quality control (MQC) is a critical mechanism for maintaining mitochondrial function and cellular metabolic homeostasis, playing an essential role in the self-renewal, differentiation, and long-term stability of hematopoietic stem cells (HSCs). Recent research highlights the central importance of MQC in HSC biology, particularly the roles of mitophagy, mitochondrial biogenesis, fission, fusion and mitochondrial transfer in regulating HSC function. Mitophagy ensures the removal of damaged mitochondria, maintaining low levels of reactive oxygen species (ROS) in HSCs, thereby preventing premature aging and functional decline. Concurrently, mitochondrial biogenesis adjusts key metabolic regulators such as mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) to meet environmental demands, ensuring the metabolic needs of HSCs are met. Additionally, mitochondrial transfer, as an essential form of intercellular material exchange, facilitates the transfer of functional mitochondria from bone marrow stromal cells to HSCs, contributing to damage repair and metabolic support. Although existing studies have revealed the significance of MQC in maintaining HSC function, the precise molecular mechanisms and interactions among different regulatory pathways remain to be fully elucidated. Furthermore, the potential role of MQC dysfunction in hematopoietic disorders, including its involvement in disease progression and therapeutic resistance, is not yet fully understood. This review discusses the molecular mechanisms of MQC in HSCs, its functions under physiological and pathological conditions, and its potential therapeutic applications. By summarizing the current progress in this field, we aim to provide insights for further research and the development of innovative treatment strategies.

Keywords:  Hematopoietic stem cell; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial metabolism; Mitochondrial quality control; Mitochondrial transfer; Mitophagy

DOI:  https://doi.org/10.1186/s13287-025-04304-7
Expert Rev Hematol. 2025 Apr 17.

Real-world (RW) study of outcomes for acute myeloid leukemia (AML) patients treated with glasdegib or venetoclax in US community oncology practices.

Kristin M Zimmerman Savill, Jonathan K Kish, Choo Hyung Lee, Prathamesh Pathak, Paul D'Amico, Alexander Russell-Smith, Ajeet Gajra.

   BACKGROUND: Glasdegib (GLAS) and venetoclax (VEN) are approved in the US for treating AML in patients aged 75+ or with comorbidities precluding intensive induction chemotherapy. Community oncology outcomes for these therapies are limited.
RESEARCH DESIGN AND METHODS: This retrospective chart review summarized characteristics, treatment patterns, and outcomes of US patients treated with first-line (1 L) GLAS or VEN for AML using descriptive statistics. The study was not designed or powered to compare GLAS and VEN cohorts.
RESULTS: Among 50 patients receiving 1 L GLAS (82.0% with low-dose cytarabine), 50.0% achieved complete remission (CR), morphological leukemia-free state (MLFS), or partial response (PR). Median overall survival (OS) was 6.9 months (95% CI: 5.4-8.9). A trial-matched GLAS cohort represented 80.0% of all GLAS-treated patients in the study. Among 83 patients receiving 1 L VEN (94.0% with a hypomethylating agent), 51.8% achieved CR, MLFS, or PR, median OS was 8.4 months (95% CI: 5.7-16.2), and 31.3% met pivotal trial eligibility criteria.
CONCLUSIONS: This observational study supports the clinical benefit of GLAS and VEN in treating AML patients in the real-world setting.

Keywords:  AML; BCL-2; RWE; glasdegib; hedgehog; venetoclax

DOI:  https://doi.org/10.1080/17474086.2025.2492886
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 10. pii: S0925-4439(25)00184-X. [Epub ahead of print] 167839

Mitochondrial classic metabolism and its often-underappreciated facets.

João P Moura, Paulo J Oliveira, Ana M Urbano.

  For many decades, mitochondria were essentially regarded as the main providers of the adenosine triphosphate (ATP) required to maintain the viability and function of eukaryotic cells, thus the widely popular metaphor "powerhouses of the cell". Besides ATP generation - via intermediary metabolism - these organelles have also traditionally been known, albeit to a lesser degree, for their notable role in biosynthesis, both as generators of biosynthetic intermediates and/or as the sites of biosynthesis. From the 1990s onwards, the concept of mitochondria as passive organelles providing the rest of the cell, from which they were otherwise isolated, with ATP and biomolecules on an on-demand basis has been challenged by a series of paradigm-shifting discoveries. Namely, it was shown that mitochondria act as signaling effectors to upregulate ATP generation in response to growth-promoting stimuli and that they are actively engaged, through signaling and epigenetics, in the regulation of a plethora of cellular processes, ultimately deciding cell function and fate. With the focus of mitochondrial research increasingly placed in these "non-classical" functions, the centrality of mitochondrial intermediary metabolism to biosynthesis and other mitochondrial functions tends to be overlooked. In this article, we revisit mitochondrial intermediary metabolism and illustrate how its intermediates, by-products and molecular machinery underpin other mitochondrial functions. A certain emphasis is given to frequently overlooked functions, namely the biosynthesis of iron‑sulfur (FeS) clusters, the only known function shared by all mitochondria and mitochondrion-related organelles. The generation of reactive oxygen species (ROS) and their putative role in signaling is also discussed in detail.

Keywords:  Educational article; Intermediary metabolism; Iron‑sulfur clusters; Metabolic energy; Mitochondrion-related organelles; ROS signaling

DOI:  https://doi.org/10.1016/j.bbadis.2025.167839
Sci Adv. 2025 Apr 18. 11(16): eadw1489

Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.

Maximilian Sichrovsky, Denis Lacabanne, Jonathan J Ruprecht, Jessica J Rana, Klaudia Stanik, Mariangela Dionysopoulou, Alice P Sowton, Martin S King, Scott A Jones, Lee Cooper, Steven W Hardwick, Giulia Paris, Dimitri Y Chirgadze, Shujing Ding, Ian M Fearnley, Shane M Palmer, Els Pardon, Jan Steyaert, Vanessa Leone, Lucy R Forrest, Sotiria Tavoulari, Edmund R S Kunji.

The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the mitochondrial matrix, as a crucial transport step in eukaryotic energy metabolism. The carrier is a drug target for the treatment of cancers, diabetes mellitus, neurodegeneration, and metabolic dysfunction-associated steatotic liver disease. We have solved the structure of the human MPC1L/MPC2 heterodimer in the inward- and outward-open states by cryo-electron microscopy, revealing its alternating access rocker-switch mechanism. The carrier has a central binding site for pyruvate, which contains an essential lysine and histidine residue, important for its ΔpH-dependent transport mechanism. We have also determined the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state by mimicking pyruvate interactions and by using aromatic stacking interactions.

DOI: https://doi.org/10.1126/sciadv.adw1489
Free Radic Biol Med. 2025 Apr 11. pii: S0891-5849(25)00227-8. [Epub ahead of print]

3-Bromopyruvate boosts the effect of chemotherapy in acute myeloid leukemia by a pro-oxidant mechanism.

Joana Pereira-Vieira, Sara Granja, Sónia Pires Celeiro, Catarina Barbosa-Matos, Ana Preto, Odília Queirós, Young Hee Ko, Margarida Casal, Fátima Baltazar.

  Acute myeloid leukemia (AML) comprises a diverse group of blood cancers with varying genetic, phenotypic, and clinical traits, making development of targeted therapy challenging. Metabolic reprogramming in AML has been described as relevant for chemotherapy effectiveness. 3-Bromopyruvate (3-BP) is an anticancer agent that undermines energy metabolism of cancer cells. However, the effect of 3-BP in hematologic malignancies, such as AML, needs further investigation. Thus, we aimed to explore 3-BP as a chemo-sensitizing agent in AML. Different approaches of combining 3-BP with classical chemotherapy (daunorubicin and cytarabin) were tested in diverse AML cell lines. Cell sensitivity to the different drug combinations was analyzed by Trypan blue staining. The effect of pre-treatment with a non-toxic concentration of 3-BP was assessed on the AML cell metabolic profile (Western blot and immunofluorescence), mitochondrial activity (cytometry flow), and antioxidant capacity (colorimetric detection kit). KG-1 and MOLM13 cells showed increased sensitivity to chemotherapy (decreased EC50 values) after exposure to a non-toxic concentration (5 μM) of 3-BP. In both cell lines, 5 μM 3-BP decreased glucose consumption without changing extracellular lactate levels. 5 μM 3-BP treatment increased reactive oxygen species levels and decreased cell antioxidant capacity by depleting reduced glutathione levels in both KG-1 and MOLM13 cells. Our results demonstrate that non-toxic concentrations of 3-BP enhance the effect of classical chemotherapy in AML cells through a pro-oxidant mechanism. These data unveiled a new approach for AML treatment, using 3-BP or other pro-oxidant agents as co-adjuvants of chemotherapy, subsiding chemotherapy-induced side effects.

Keywords:  Blood Cancer; Cancer Metabolism; Cytarabine; Daunorubicin; Oxidative Stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.017
Eur J Med Chem. 2025 Apr 15. pii: S0223-5234(25)00389-7. [Epub ahead of print]291 117624

Discovery of XZ338, a highly potent BCL-XL degrader.

Xuan Zhang, Dinesh Thummuri, Wanyi Hu, Xingui Liu, Peiyi Zhang, Shuo Zhou, Daohong Zhou, Guangrong Zheng.

  BCL-XL is a crucial anti-apoptotic protein involved in tumorigenesis and resistance to cancer chemotherapy. Transitioning from conventional inhibitors to PROTAC degraders has shown promising potential, particularly in minimizing the on-target thrombocytopenia linked to BCL-XL inhibition. However, reported BCL-XL degraders were mostly derived from BCL-XL/BCL-2 dual inhibitor ABT-263, which also inhibits or degrades BCL-2 and can potentially cause neutropenia when combined with conventional chemotherapy as seen with ABT-263 in the clinic. The goal of the present study is to develop a highly specific BCL-XL degrader without BCL-2 inhibition/degradation. In this study, XZ338, a highly potent and selective BCL-XL degrader derived from BCL-XL specific inhibitor A-1331852, was generated. XZ338 is 70-fold more potent than ABT-263 against MOLT-4 T-ALL cells, with over 89-fold selectivity for MOLT-4 cells over human platelets.

Keywords:  Apoptosis; BCL-2; BCL-X(L); PROTAC; Platelet

DOI:  https://doi.org/10.1016/j.ejmech.2025.117624
Stem Cell Reports. 2025 Apr 05. pii: S2213-6711(25)00080-3. [Epub ahead of print] 102476

CD37 regulates the self-renewal of leukemic stem cells via integrin-mediated signaling in acute myeloid leukemia.

Jinyuan Lu, Lixin Lv, Xiaoxue Tian, Zheng Li, Yuting Ma, Nannan Li, Jian Wang, Guangming Wang, Yu Zeng, Wenjun Zhang, Jun Xu, Aibin Liang.

  Leukemic stem cells (LSCs) are a small subset of leukemia cells that drive leukemia initiation and maintenance. Herein, we report that CD37, a member of transmembrane 4 superfamily (TM4SF), regulates the survival of acute myeloid leukemia (AML) cells as well as the self-renewal of AML LSCs. The downregulation of CD37 retarded proliferation and increased apoptosis in human AML cell lines THP-1 and OCI-AML2. Deficiency of CD37 in vivo had a minimal effect on normal hematopoiesis but significantly impeded leukemia maintenance and propagation, which led to increased apoptosis and decreased cell cycle entry in AML blasts as well as impaired colony formation and declined frequency of AML LSCs in the serial transplantation. Furthermore, CD37 interacted with integrin α4β7 and activated the phosphatidylinositol 3-kinase (PI3K)-AKT pathway mediated by integrin signaling. Our study provides novel insights for targeted therapy of AML, indicating CD37 as a safe and effective target for immunotherapy.

Keywords:  CD37; acute myeloid leukemia; integrin; leukemic stem cell; tetraspanin

DOI:  https://doi.org/10.1016/j.stemcr.2025.102476
Cell Death Dis. 2025 Apr 13. 16(1): 282

Dysregulation of sphingolipid metabolism contributes to the pathogenesis of chronic myeloid leukemia.

Yinyin Xie, Qinghua Zeng, Zhiwei Chen, Jiachun Song, Fuhui Wang, Dan Liu, Xiaojian Sun, Yuanliang Zhang, Qiuhua Huang.

Chronic myeloid leukemia (CML) is primarily driven by the BCR::ABL1 oncoprotein, which has potent tyrosine kinase activity. BCR::ABL1 has been shown to facilitate several metabolic processes, including glycolysis, lipid synthesis, and protein synthesis in vitro. However, the altered metabolic profile in vivo remains poorly understood. Using Scl/tTA-BCR::ABL1 mice as a model, we conducted an analysis of plasma metabolites at different stages following BCR::ABL1 induction. Metabolites involved in sphingolipid and thiamine metabolism were significantly altered at the early stage of CML, while the tricarboxylic acid (TCA) cycle metabolites were altered during disease progression. Among these metabolic changes, sphingolipid metabolism is of particular significance. Inhibition of sphingolipid metabolism had a more pronounced effect on the growth and survival fate of K562 cells compared to thiamine metabolism inhibition. Furthermore, knockdown of sphingosine kinase 1 (SPHK1) resulted in extensive metabolic remodeling, affecting lipid, energy, and heme metabolism. Pharmacological targeting of sphingolipid metabolism appeared to attenuate the development of CML. Our study also demonstrated that BCR::ABL1 triggers ERK-dependent phosphorylation of SphK1, leading to aberrant activation of sphingolipid metabolism, which in turn has a positive feedback effect on BCR/ABL expression. These findings highlight the dominant role of sphingolipid metabolism in BCR::ABL1-induced metabolic reprogramming in CML.

DOI: https://doi.org/10.1038/s41419-025-07594-0
Mol Cell. 2025 Apr 17. pii: S1097-2765(25)00196-0. [Epub ahead of print]85(8): 1487-1508

Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis.

Brandon Chen, Costas A Lyssiotis, Yatrik M Shah.

  Mitochondria serve as central hubs in cellular metabolism by sensing, integrating, and responding to metabolic demands. This integrative function is achieved through inter-organellar communication, involving the exchange of metabolites, lipids, and signaling molecules. The functional diversity of metabolite exchange and pathway interactions is enabled by compartmentalization within organelle membranes. Membrane contact sites (MCSs) are critical for facilitating mitochondria-organelle communication, creating specialized microdomains that enhance the efficiency of metabolite and lipid exchange. MCS dynamics, regulated by tethering proteins, adapt to changing cellular conditions. Dysregulation of mitochondrial-organelle interactions at MCSs is increasingly recognized as a contributing factor in the pathogenesis of multiple diseases. Emerging technologies, such as advanced microscopy, biosensors, chemical-biology tools, and functional genomics, are revolutionizing our understanding of inter-organellar communication. These approaches provide novel insights into the role of these interactions in both normal cellular physiology and disease states. This review will highlight the roles of metabolite transporters, lipid-transfer proteins, and mitochondria-organelle interfaces in the coordination of metabolism and transport.

Keywords:  endoplasmic reticulum; inter-organellar communication; mitochondria; organellar metabolism; organelle membrane contact sites

DOI:  https://doi.org/10.1016/j.molcel.2025.03.003