bims-mibica 2025-05-11 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–05–11
eighteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Functional mitochondrial respiration is essential for glioblastoma tumour growth.
GPX1 confers resistance to metabolic stress in BCR/ABL-T315I mutant chronic myeloid leukemia cells.
The oncoprotein SET promotes serine-derived one-carbon metabolism by regulating SHMT2 enzymatic activity.
Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.
Metabolic reprogramming driven by Ant2 deficiency augments T Cell function and anti-tumor immunity in mice.
m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability.
Cryo-EM of Mitochondrial Complex I and ATP Synthase.
Scavenging Reactive Oxygen Species by Cerium Oxide Nanoparticles Prevents Death in a Peripheral T Cell Lymphoma Preclinical Mouse Model.
The m5C methyltransferase NSUN2 promotes progression of acute myeloid leukemia by regulating serine metabolism.
Lipid-degrading small molecule kills cancer cells by ferroptosis.
Aneuploidy generates enhanced nucleotide dependency and sensitivity to metabolic perturbation.
Small-scale protocols to characterize mitochondrial Complex V activity and assembly in peripheral blood mononuclear cells.
Role of ANT2 in mitochondrial function and cancer cell survival: a target for therapeutic intervention.
Transient increase in mitochondrial respiration in blood cells from breast cancer patients following chemo- and radiotherapy.
NDUFA8 promotes cell viability and inhibits ferroptosis and cisplatin sensitivity by stabilizing Fe-S clusters in cervical cancer.
The Curated Cancer Cell Atlas provides a comprehensive characterization of tumors at single-cell resolution.
Kinome screening identifies integrated stress response kinase EIF2AK1/HRI as a negative regulator of PINK1 mitophagy signaling.
GPX4-dependent ferroptosis sensitivity is a fitness trade-off for cell enlargement.

Oncogene. 2025 May 05.

Functional mitochondrial respiration is essential for glioblastoma tumour growth.

Petra Brisudova, Dana Stojanovic, Jaromir Novak, Zuzana Nahacka, Gabriela Lopes Oliveira, Ondrej Vanatko, Sarka Dvorakova, Berwini Endaya, Jaroslav Truksa, Monika Kubiskova, Alice Foltynova, Daniel Jirak, Natalia Jirat-Ziolkowska, Lukas Kucera, Karel Chalupsky, Krystof Klima, Jan Prochazka, Radislav Sedlacek, Francesco Mengarelli, Patrick Orlando, Luca Tiano, Paulo Oliveira, Carole Grasso, Michael V Berridge, Renata Zobalova, Miroslava Anderova, Jiri Neuzil.

Horizontal transfer of mitochondria from the tumour microenvironment to cancer cells to support proliferation and enhance tumour progression has been shown for various types of cancer in recent years. Glioblastoma, the most aggressive adult brain tumour, has proven to be no exception when it comes to dynamic intercellular mitochondrial movement, as shown in this study using an orthotopic tumour model of respiration-deficient glioblastoma cells. Although confirmed mitochondrial transfer was shown to facilitate tumour progression in glioblastoma, we decided to investigate whether the related electron transport chain recovery is necessary for tumour formation in the brain. Based on experiments using time-resolved analysis of tumour formation by glioblastoma cells depleted of their mitochondrial DNA, we conclude that functional mitochondrial respiration is essential for glioblastoma growth in vivo, because it is needed to support coenzyme Q redox cycling for de novo pyrimidine biosynthesis controlled by respiration-linked dihydroorotate dehydrogenase enzyme activity. We also demonstrate here that astrocytes are key mitochondrial donors in this model.

DOI: https://doi.org/10.1038/s41388-025-03429-6
Cell Death Discov. 2025 May 09. 11(1): 229

GPX1 confers resistance to metabolic stress in BCR/ABL-T315I mutant chronic myeloid leukemia cells.

Jun-Dan Wang, Jin-Xing Wang, Zhi-Li Lin, Na Xu, Ling Zhang, Jia-Jun Liu, Rui Gao, Zi-Jie Long.

Chronic myeloid leukemia (CML) harboring BCR/ABL-T315I mutation has been a challenging obstacle for targeted therapy due to the acquired resistance to tyrosine kinase inhibitor (TKI)-based therapy. Thus, it is especially urgent to investigate more effective therapeutic targets to overcome T315I-induced resistance. Here, we reported that BCR/ABL-T315I mutant CML cells possessed a long-term proliferative capacity and tolerance to metabolic stress. Importantly, we also found that selenoamino acid metabolism was increased in the bone marrows of BCR/ABL-T315I patients compared with non-T315I patients by GSEA from RNA-Seq data. Indeed, GPX1 was highly expressed in T315I mutant cells, while knockout of GPX1 significantly suppressed cell proliferation and triggered apoptosis under glucose-deprived condition. GPX1 knockout showed decreased cell metabolism signaling as well as mitochondrial gene expression by RNA-Seq. Mechanistically, GPX1 maintained mitochondrial activity and oxygen consumption rate (OCR), retaining mitochondrial redox homeostasis and oxidative phosphorylation (OXPHOS). Additionally, mercaptosuccinic acid (MSA), a GPX inhibitor, inhibited CML colony formation and induced cell apoptosis under glucose-free condition. Therefore, GPX1 is a promising therapeutic target to overcome drug resistance induced by the T315I mutation, which provides a novel approach for BCR/ABL-T315I CML treatment by disturbing mitochondrial OXPHOS.

DOI: https://doi.org/10.1038/s41420-025-02502-z
Proc Natl Acad Sci U S A. 2025 May 13. 122(19): e2412854122

The oncoprotein SET promotes serine-derived one-carbon metabolism by regulating SHMT2 enzymatic activity.

Zishan Jiao, Mi Zhang, Jingyuan Ning, Han Yao, Xiaojun Yan, Zhen Wu, Dexuan Wu, Yajing Liu, Meng Zhang, Lin Wang, Donglai Wang.

  Cancer cells frequently reprogram one-carbon metabolic pathways to fulfill their vigorous demands of biosynthesis and antioxidant defense for survival and proliferation. Dysfunction of oncogenes or tumor suppressor genes is critically involved in this process, but the precise mechanisms by which cancer cells actively trigger one-carbon metabolic alterations remain incompletely elucidated. Here, by using untargeted metabolomic analysis, we identify the oncoprotein SE translocation (SET) as a key regulator of one-carbon metabolism in cancer cells. SET physically interacts with mitochondrial SHMT2 and facilitates SHMT2 enzymatic activity. Loss of SET profoundly suppresses serine-derived one-carbon metabolic flux, whereas reexpression of ectopic SET leads to the opposite effect. Notably, although the presence of SHMT2 is critical for SET-mediated one-carbon metabolic alterations, the depletion of SHMT2 alone is insufficient to antagonize SET-induced tumor growth, probably due to functional compensation by its cytosolic isozyme SHMT1 upon SHMT2 knockdown. Instead, pharmacological targeting of cellular SHMT (including both SHMT1 and SHMT2) activity results in dramatic suppression of SET-induced tumor growth. Moreover, by using a Kras/Lkb1 mutation-driven lung tumor mouse model, we demonstrate that the loss of SET compromises both tumor formation and intratumoral SHMT2 enzymatic activity. Clinically, the overexpression of SET and SHMT2 is observed in lung tumors, both of which correlate with poor prognosis. Our study reveals a SET-SHMT2 axis in regulating serine-derived one-carbon metabolism and uncovers one-carbon metabolic reprogramming as a mechanism for SET-driven tumorigenesis.

Keywords:  SET; SHMT2; enzymatic activity; one-carbon metabolism; tumor

DOI:  https://doi.org/10.1073/pnas.2412854122
Aging Cell. 2025 May 02. e70085

Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.

Hiroaki Tamashiro, Kaori Ishikawa, Koichi Sadotomo, Emi Ogasawara, Kazuto Nakada.

  mtDNA mutator mice (Polgmut/mut mice) have reinforced the mitochondrial theory of aging. These mice accumulate multiple mutations in mtDNA with age due to a homozygous proofreading-deficient mutation in mtDNA polymerase gamma (Polg), resulting in mitochondrial respiratory dysfunction and premature aging phenotypes. However, whether the accumulation of multiple mutations in Polgmut/mut mice induces mitochondrial respiratory dysfunction remains unclear. Here, we determined the accurate mtDNA genotype, including the frequency of total mutations and the number of non-synonymous substitutions and pathogenic mutations, using next-generation sequencing in the progeny of all three genotypes obtained from the mating of heterozygous mtDNA mutator mice (Polg+/mut mice) and examined their correlation with mitochondrial respiratory activity. Although Polg+/mut mice showed equivalent mtDNA genotype to Polg+/+ (wild-type) mice, the mitochondrial respiratory activity in the Polg+/mut mice was mildly reduced. To further investigate the causal relationship between mtDNA genotype and mitochondrial respiratory activity, we experimentally varied the mtDNA genotype in Polg mice. However, mitochondrial respiratory activity was mildly reduced in Polg+/mut mice and severely reduced in Polgmut/mut mice, regardless of the mtDNA genotype. Moreover, by varying the mtDNA genotype, some Polg+/+ mice showed mtDNA genotype equivalent to those of Polgmut/mut mice, but mitochondrial respiratory activity in Polg+/+ mice was normal. These results indicate that the mitochondrial respiratory dysfunction observed in mice with proofreading-deficient mutation in Polg is correlated with the nuclear genotype of Polg rather than the mtDNA genotype. Thus, the mitochondrial theory of aging in Polgmut/mut mice needs further re-examination.

Keywords:  aging; mitochondria; mitochondrial DNA

DOI:  https://doi.org/10.1111/acel.70085
Nat Commun. 2025 May 08. 16(1): 4292

Metabolic reprogramming driven by Ant2 deficiency augments T Cell function and anti-tumor immunity in mice.

Omri Yosef, Leonor Cohen-Daniel, Oded Shamriz, Zahala Bar-On, Wajeeh Salaymeh, Amijai Saragovi, Ifat Abramovich, Bella Agranovich, Veronika Lutz, Joseph Tam, Anna Permyakova, Eyal Gottlieb, Magdalena Huber, Michael Berger.

T cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generate T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT in wild-type T cells recapitulates the Ant2-/- phenotype and improves adoptive T cell therapy of cancer in mouse models. Our findings thus suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T cell function and highlighting the therapeutic potential of targeting ANT for immune modulation.

DOI: https://doi.org/10.1038/s41467-025-59310-3
Nat Commun. 2025 May 06. 16(1): 4214

m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability.

Feng Huang, Yushuai Wang, Xiuxin Zhang, Weiwei Gao, Jingwen Li, Ying Yang, Hongjie Mo, Emily Prince, Yifei Long, Jiacheng Hu, Chuang Jiang, Yalin Kang, Zhenhua Chen, Yueh-Chiang Hu, Chengwu Zeng, Lu Yang, Chun-Wei Chen, Jianjun Chen, Huilin Huang, Hengyou Weng.

Metabolic reprogramming of amino acids represents a vulnerability in cancer cells, yet the mechanisms underlying serine metabolism in acute myeloid leukemia (AML) and leukemia stem/initiating cells (LSCs/LICs) remain unclear. Here, we identify RNA N6-methyladenosine (m6A) modification as a key regulator of serine biosynthesis in AML. Using a CRISPR/Cas9 screen, we find that depletion of m6A regulators IGF2BP3 or METTL14 sensitizes AML cells to serine and glycine (SG) deprivation. IGF2BP3 recognizies m6A on mRNAs of key serine synthesis pathway (SSP) genes (e.g., ATF4, PHGDH, PSAT1), stabilizing these transcripts and sustaining serine production to meet the high metabolic demand of AML cells and LSCs/LICs. IGF2BP3 silencing combined with dietary SG restriction potently inhibits AML in vitro and in vivo, while its deletion spares normal hematopoiesis. Our findings reveal the critical role of m6A modification in the serine metabolic vulnerability of AML and highlight the IGF2BP3/m6A/SSP axis as a promising therapeutic target.

DOI: https://doi.org/10.1038/s41467-025-58966-1
Annu Rev Biophys. 2025 May;54(1): 209-226

Cryo-EM of Mitochondrial Complex I and ATP Synthase.

Werner Kühlbrandt, Luis A M Carreira, Özkan Yildiz.

  Cryo-electron microscopy (cryo-EM) is the method of choice for investigating the structures of membrane protein complexes at high resolution under near-native conditions. This review focuses on recent cryo-EM work on mitochondrial complex I and ATP synthase. Single-particle cryo-EM structures of complex I from mammals, plants, and fungi extending to a resolution of 2 Å show different functional states, indicating consistent conformational changes of loops near the Q binding site, clusters of internal water molecules in the membrane arm, and an α-π transition in a membrane-spanning helix that opens and closes the proton transfer path. Cryo-EM structures of ATP synthase dimers from mammalian, yeast, and Polytomella mitochondria show several rotary states at a resolution of 2.7 to 3.5 Å. The new structures of complex I and ATP synthase are important steps along the way toward understanding the detailed molecular mechanisms of both complexes. Cryo-electron tomography and subtomogram averaging have the potential to resolve their high-resolution structures in situ.

Keywords:  ATP synthase; complex I; cryo-electron microscopy; cryo-electron tomography; mitochondria; respiratory chain

DOI:  https://doi.org/10.1146/annurev-biophys-060724-110838
ACS Nano. 2025 May 09.

Scavenging Reactive Oxygen Species by Cerium Oxide Nanoparticles Prevents Death in a Peripheral T Cell Lymphoma Preclinical Mouse Model.

Adrien Krug, Lena M Ernst, Rana Mhaidly, Joana Ramis, Muriel F Gusta, Neus G Bastus, Adriana Martinez-Turtos, Marie Tosolini, Léa Di Mascio, Gamze Tari, Laurent Boyer, Philippe Gaulard, François Lemonnier, Jean-Ehrland Ricci, Els Verhoeyen, Victor Puntes.

  Cancer cell survival and proliferation are correlated with increased metabolic activity and consequent oxidative stress, driving metabolic shifts that interfere with the immune response to malignant cells. This is the case of high-energy-demanding angioimmunoblastic T cell lymphoma (AITL), a highly aggressive cancer with poor survival rates, where malignant CD4+ PD-1high T cells show increased mitochondrial activity and Reactive oxygen species (ROS) accumulation. Here, we report that administration of ROS scavenging cerium oxide (CeO2) nanoparticles in an AITL preclinical mouse model leads to their preferential accumulation in the spleen, where the CD4+ PD-1high T cells driving malignancy were significantly reduced. This was accompanied by activation of previously exhausted cytotoxic CD8+ T cells, restoring their potent antitumor function. As a result, survival rates dramatically increase with no observed toxicity to healthy cells or tissues. Overall, it highlights the correlation between increased energy demand, increased mitochondrial mass, increased PD-1 expression, increased ROS production, and immune suppression and how this vicious loop can be stopped by scavenging ROS.

Keywords:  AITL preclinical model; ROS; T cell lymphoma; antioxidant; cancer; cerium oxide nanoparticles; mitochondria

DOI:  https://doi.org/10.1021/acsnano.5c02860
Cell Rep. 2025 May 07. pii: S2211-1247(25)00432-2. [Epub ahead of print]44(5): 115661

The m5C methyltransferase NSUN2 promotes progression of acute myeloid leukemia by regulating serine metabolism.

Songyu Li, Ya Liu, Xiang Wu, Minjia Pan, Hongxia Zhao, Yunguang Hong, Qinghua Zhang, Shushu Hu, Aorong Ouyang, Guangru Li, Minhui Wu, Shanshan Fan, Zhirong Jia, Shanchao Zhao, Guocai Wu, Xiangwei Gao, Zhigang Yang, Zhanghui Chen.

  Acute myeloid leukemia (AML) is one of the most prevalent heterogeneous hematologic malignancies with a complicated etiology. RNA post-transcriptional modifications have been linked to the incidence and progression of AML, while the detailed mechanism remains to be elucidated. In this study, we find that NOP2/Sun domain family member 2 (NSUN2), a methyltransferase of 5-methylcytosine (m5C) RNA methylation, is upregulated in AML and predicts a poor prognosis for patients with AML. Knockdown of NSUN2 in AML cells inhibits proliferation and colony formation and promotes apoptosis. Depletion of NSUN2 in AML mice reduces the tumor burden and prolongs survival. Mechanistically, NSUN2 promotes the expression of phosphoglycerate dehydrogenase (PHGDH) and serine hydroxymethyltransferase 2 (SHMT2), two key enzymes in the serine/glycine biosynthesis pathway, by stabilizing the corresponding mRNAs through regulation of m5C modifications. Overall, our findings demonstrate a critical role of NSUN2 in AML development and highlight the therapeutic potential of targeting the NSUN2/m5C axis for the treatment of this cancer.

Keywords:  5-methylcytosine; AML; Acute myeloid leukemia; CP: Cancer; CP: Metabolism; NOP2/Sun RNA methyltransferase 2; NSUN2; m(5)C; serine metabolism

DOI:  https://doi.org/10.1016/j.celrep.2025.115661
Nature. 2025 May 07.

Lipid-degrading small molecule kills cancer cells by ferroptosis.

Mike Lange, James A Olzmann.



Keywords:  Cancer; Cell biology

DOI:  https://doi.org/10.1038/d41586-025-01337-z
Genes Dev. 2025 May 05.

Aneuploidy generates enhanced nucleotide dependency and sensitivity to metabolic perturbation.

Rayna Y Magesh, Arshia N Kaur, Faith N Keller, Abdulrazak Frederick, Tenzin Tseyang, John A Haley, Alejandra M Rivera-Nieves, Anthony C Liang, David A Guertin, Jessica B Spinelli, Stephen J Elledge, Emma V Watson.

  Despite the general detriment of aneuploidy to cellular fitness, >90% of solid tumors carry an imbalanced karyotype. This existing paradox and the molecular responses to aneuploidy remain poorly understood. Here, we explore these cellular stresses and unique vulnerabilities of aneuploidy in human mammary epithelial cells (HMECs) enriched for breast cancer-associated copy number alterations (CNAs). To uncover the genetic dependencies specific to aneuploid cells, we conducted a comprehensive, genome-wide CRISPR knockout screen in isogenic aneuploid and diploid HMEC lines. Our study reveals that aneuploid HMECs exhibit an increased reliance on pyrimidine biosynthesis and mitochondrial oxidative phosphorylation genes and demonstrate heightened fitness advantages upon loss of tumor suppressor genes. Using an integrative multiomic analysis, we confirmed nucleotide pool insufficiency as a key contributor to widespread cellular dysfunction in aneuploid HMECs with net copy number gain. Although diploid cells can switch seamlessly between pyrimidine synthesis and salvage, cells with increased chromosomal content exhibit p53 activation and S-phase arrest when relying on salvage alone, alongside increased sensitivity to DNA-damaging chemotherapeutics. This work advances our understanding of the consequences of aneuploidy and uncovers potential avenues for patient stratification and therapeutic intervention based on tumor ploidy.

Keywords:  CRISPR; aneuploidy; cancer; genomics; metabolism

DOI:  https://doi.org/10.1101/gad.352512.124
PLoS One. 2025 ;20(5): e0323136

Small-scale protocols to characterize mitochondrial Complex V activity and assembly in peripheral blood mononuclear cells.

Kai-Yin Chau, Jan-Willem Taanman, Anthony H V Schapira.

Complex V of the mitochondrial oxidative phosphorylation system is an ATP synthase that plays a pivotal role in the cell's energy transduction. Mutations in genes encoding the multiple protein subunits that constitute complex V cause severe metabolic and neurodegenerative diseases. We present here three complementary assays to assess Complex V activity and assembly in peripheral blood mononuclear cells (PBMCs). The assays involve spectrophotometric and in-gel activity measurements, cytochemical assessment of the mitochondrial transmembrane electrochemical gradient (∆Ѱm) to determine if the enzyme acts forward as an ATP synthase or in reverse as an ATPase, and western blot analysis of clear native gels to evaluate Complex V assembly. The whole process can be performed with 2 × 106 PBMCs isolated from ~2 ml of blood. Our study suggests that PBMCs can serve as a platform for small-scale, minimally invasive investigations of patients suspected of Complex V deficiency or in biomarker research of mitochondrial function.

DOI: https://doi.org/10.1371/journal.pone.0323136
Cell Death Discov. 2025 May 08. 11(1): 225

Role of ANT2 in mitochondrial function and cancer cell survival: a target for therapeutic intervention.

Klara Bohacova, Zuzana Nahacka, Jana Dudova, Jaromira Kovarova, Jakub Rohlena, Michaela Rennerova, Barbora Judita Kasperova, Jan Stursa, Lukas Werner, Martin Haluzik, Jiri Neuzil, Sona Stemberkova Hubackova.

DOI: https://doi.org/10.1038/s41420-025-02510-z
Clin Exp Med. 2025 May 08. 25(1): 142

Transient increase in mitochondrial respiration in blood cells from breast cancer patients following chemo- and radiotherapy.

Marie-Louise Abrahamsen, Ida Bager Christensen, Linda Laizāne, Haboon Ismail Ahmed, Kristian Buch-Larsen, Djordje Marina, Michael Andersson, Peter Schwarz, Flemming Dela, Linn Gillberg.

  Mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) has previously been shown to increase after chemo- and radiotherapy in early-stage breast cancer (BC) patients, but the persistence of the increase remains unknown. This study assessed whether changes in mitochondrial respiration and content in PBMCs from postmenopausal BC patients persist up to 1 year after treatment. Thirty-four early-stage BC patients were studied before, shortly after, and six- and twelve-months post-treatment along with 20 healthy controls. Mitochondrial respiration was measured using high-resolution respirometry of intact and permeabilized PBMCs. Mitochondrial content was estimated by quantifying mitochondrial DNA relative to nuclear DNA via qPCR. The mitochondrial respiratory capacity of intact and permeabilized PBMCs from BC patients significantly increased after adjuvant chemo- and radiotherapy (+ 33% and + 30% for the maximal capacity of the electron transport system, ETS), consistent with previous findings. Importantly, the respiratory capacity returned to pre-treatment levels six months after treatment completion in both intact and permeabilized cells (- 23% and - 26% for the ETS). Healthy controls exhibited similar mitochondrial respiration but had increased mitochondrial content (+ 20%) compared to BC patients before treatment. In summary, chemo- and radiotherapy transiently increased mitochondrial respiration in PBMCs, returning to baseline within six months after treatment completion. This temporary rise in oxygen demand may reflect immune system activation.

Keywords:  Adjuvant therapy; Breast cancer; High-resolution respirometry; Inflammation; Mitochondria; Peripheral blood mononuclear cells

DOI:  https://doi.org/10.1007/s10238-025-01665-4
Naunyn Schmiedebergs Arch Pharmacol. 2025 May 08.

NDUFA8 promotes cell viability and inhibits ferroptosis and cisplatin sensitivity by stabilizing Fe-S clusters in cervical cancer.

Huaguo Xiang, Junfang Sun, Lingyue Kong, Yingzhen Wang, Xiaorou Qiu, Jinting Zeng, Guo Li, Jiehong He.

  Cervical cancer (CC) ranks among the primary causes of cancer fatalities in women, with cisplatin (DDP) resistance significantly impacting clinical outcomes. NADH dehydrogenase (ubiquinone) FA8 (NDUFA8) is significantly upregulated in CC tissues and correlates with lower survival rates, but its role in cisplatin sensitivity in CC is still unclear. NDUFA8 silencing inhibited CC cell viability, promoted ferroptosis, evidenced by increased Fe2+ and lipid ROS levels, along with decreased levels of ATP and reduced activities of complex I, aconitase (ACO), and xanthine oxidase (XO). However, overexpression of NDUFA8 promoted CC cell viability, inhibited ferroptosis, and increased levels of ATP and activities of complex I, ACO, and XO in ferric ammonium citrate (FAC) or rotenone-treated CC cells. NDUFA8 expression showed a negative correlation with the DDP therapy response in CC tissues and cell lines. However, in CC tissues, NDUFA8 expression was positively associated with ACO and XO activities. In in vivo experiments, the overexpression of NDUFA8 diminished the anti-tumor effects of DDP, which was counteracted by FAC. NDUFA8 promotes cell viability and inhibits ferroptosis and DDP sensitivity by stabilizing Fe-S clusters in CC.

Keywords:  Cervical cancer; Cisplatin; Fe-S clusters; Ferroptosis; NDUFA8

DOI:  https://doi.org/10.1007/s00210-025-04237-1
Nat Cancer. 2025 May 08.

The Curated Cancer Cell Atlas provides a comprehensive characterization of tumors at single-cell resolution.

Michael Tyler, Avishai Gavish, Chaya Barbolin, Roi Tschernichovsky, Rouven Hoefflin, Michael Mints, Sidharth V Puram, Itay Tirosh.

Recent years have seen a rapid proliferation of single-cell cancer studies, yet most of these studies profiled few tumors, limiting their statistical power. Combining data and results across studies holds great promise but also involves various challenges. We recently began to address these challenges by curating a large collection of cancer single-cell RNA-sequencing datasets, leveraging it for systematic analyses of tumor heterogeneity. Here we greatly extend this repository to 124 datasets for over 40 cancer types, together comprising 2,836 samples, with improved data annotations, visualizations and exploration. Using this vast cohort, we generate an updated map of recurrent expression programs in malignant cells and systematically quantify context-dependent gene expression and cell-cycle patterns across cell types and cancer types. These data, annotations and analysis results are all freely available for exploration and download through the Curated Cancer Cell Atlas, a central community resource that opens new avenues in cancer research.

DOI: https://doi.org/10.1038/s43018-025-00957-8
Sci Adv. 2025 May 09. 11(19): eadn2528

Kinome screening identifies integrated stress response kinase EIF2AK1/HRI as a negative regulator of PINK1 mitophagy signaling.

Pawan K Singh, Shalini Agarwal, Ilaria Volpi, Léa P Wilhelm, Giada Becchi, Andrew Keenlyside, Thomas Macartney, Rachel Toth, Adrien Rousseau, Glenn R Masson, Ian G Ganley, Miratul M K Muqit.

Loss-of-function mutations in the PINK1 kinase lead to early-onset Parkinson's disease (PD). PINK1 is activated by mitochondrial damage to phosphorylate ubiquitin and Parkin, triggering mitophagy. PINK1 also indirectly phosphorylates Rab GTPases, such as Rab8A. Using an siRNA library targeting human Ser/Thr kinases in HeLa cells, we identified EIF2AK1 [heme-regulated inhibitor (HRI) kinase], a branch of the integrated stress response (ISR), as a negative regulator of PINK1. EIF2AK1 knockdown enhances mitochondrial depolarization-induced PINK1 stabilization and phosphorylation of ubiquitin and Rab8A. These results were confirmed in SK-OV-3, U2OS, and ARPE-19 cells. Knockdown of DELE1, an activator of EIF2AK1, produced similar effects. Notably, the ISR inhibitor ISRIB also enhanced PINK1 activation. In human cells with mito-QC mitophagy reporters, EIF2AK1 knockdown or ISRIB treatment increased PINK1-dependent mitophagy without affecting deferiprone-induced mitophagy. These findings suggest that the DELE1-EIF2AK1 ISR pathway is a negative regulator of PINK1-dependent mitophagy. Further evaluation in PD-relevant models is needed to assess the therapeutic potential of targeting this pathway.

DOI: https://doi.org/10.1126/sciadv.adn2528
iScience. 2025 May 16. 28(5): 112363

GPX4-dependent ferroptosis sensitivity is a fitness trade-off for cell enlargement.

Kuan Yoow Chan, Yini Yu, Yidi Kong, Ling Cheng, Renzhi Yao, Phoebe Sha Yin Chair, Ping Wang, Rong Wang, Wan-Yang Sun, Rong-Rong He, Junxia Min, Fudi Wang, Mikael Björklund.

  Despite wide variation, each cell type has an optimal size. Maintaining optimal size is essential for cellular fitness and function but the biological basis for this remains elusive. Here, we performed fitness analysis involving genome-wide CRISPR-Cas9 knockout data from tens of human cell lines and identified that cell size influences the essentiality of genes related to mitochondria and membrane repair. These genes also included glutathione peroxidase 4 (GPX4), which safeguards membranes from oxidative damage and prevents ferroptosis-iron-dependent death. Growth beyond normal size, with or without cell-cycle arrest, increased lipid peroxidation, resulting in a ferroptosis-sensitive state. Proteomic analysis revealed cell-cycle-independent superscaling of endoplasmic reticulum, accumulation of iron, and lipidome remodeling. Even slight increases from normal cell size sensitized proliferating cells to ferroptosis as evidenced by deep-learning-based single-cell analysis. Thus, lipid peroxidation may be a fitness trade-off that constrains cell enlargement and contributes to the establishment of an optimal cell size.

Keywords:  Biochemistry; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.112363