bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–06–29
nineteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Microprotein SMIM26 drives oxidative metabolism via serine-responsive mitochondrial translation.
  2. Cancer cells get power boost by stealing mitochondria from nerves.
  3. The Identification of a Key Regulator of Mitochondrial Metabolism, the LRPPRC Protein, as a Novel Therapeutic Target in SDHA-Overexpressing Ovarian Tumors.
  4. Steroid Sulfatase Regulates Metabolic Reprogramming in Advanced Prostate Cancer.
  5. An NADH-controlled gatekeeper of ATP synthase.
  6. MICOS.
  7. Unlocking the Distinct Roles of the Three Mammalian VDAC Isoforms in Mitochondrial Respiration and Cancer Cell Metabolism.
  8. The mitochondrial methylation potential gates mitoribosome assembly.
  9. Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes.
  10. Nerve-to-cancer transfer of mitochondria during cancer metastasis.
  11. PLK1-mediated PDHA1 phosphorylation drives mitochondrial dysfunction, mitophagy, and cancer progression in Cr(VI)-associated lung cancer.
  12. Crotonoside induces ferroptosis and mitochondrial dysfunction in AML.
  13. Neuronal transfer of mitochondria to tumour cells promotes cancer spread.
  14. Mitochondrial proteome landscape unveils key insights into melanoma severity and treatment strategies.
  15. Posttranscriptional depletion of ribosome biogenesis factors engenders therapeutic vulnerabilities in NPM1-mutant AML.
  16. 3-mercaptopyruvate sulfurtransferase resides on the inner mitochondrial membrane.
  17. A nuclear branched-chain amino acid catabolism pathway controls histone propionylation in pancreatic cancer.
  18. Sirtuin 5 inhibits mitochondrial metabolism in liver cancer cells and promotes apoptosis by mediating the desuccinylation of CS.
  19. Mutations and translocations associated with venetoclax resistance in chronic lymphocytic leukemia.
  1. Mol Cell. 2025 Jun 20. pii: S1097-2765(25)00472-1. [Epub ahead of print]
    Microprotein SMIM26 drives oxidative metabolism via serine-responsive mitochondrial translation.
    Jiemin Nah, Sreya Mahendran, Baptiste Kerouanton, Liang Cui, Daniella H Hock, Alfredo Cabrera-Orefice, Kyle Dunlap, David Robinson, Desmond W H Tung, Sze Huey Leong, Kiat-Yi Tan, Sonia P Chothani, Jingjing Sun, Agnieszka Dziegowska, Grazyna Leszczynska, Owen J L Rackham, Ilka Wittig, Peter Dedon, Gregory S Ducker, David A Stroud, Lena Ho.
      Mitochondrial small open reading frame (ORF)-encoded microproteins (SEPs) are key regulators and components of the electron transport chain (ETC). Although ETC complex I assembly is tightly coupled to nutrient availability, including serine, the coordinating mechanism remains unknown. A genome-wide CRISPR screen targeting SEPs revealed that deletion of the LINC00493-encoded microprotein SMIM26 sensitizes cells to one-carbon restriction. SMIM26 interacts with mitochondrial serine transporters SFXN1/2 and the mitoribosome, forming a functional triad that facilitates translation of the complex I subunit mt-ND5. SMIM26 loss impairs serine import, reduces folate intermediates, and disrupts key mitochondrial tRNA modifications (τm5U and τm5s²U), resulting in ND5 translation failure and complex I deficiency. SMIM26 deletion is embryonic lethal in mice and impedes tumor growth in a xenograft model of folate-dependent acute myeloid leukemia. These findings define SMIM26 as a critical integrator of one-carbon flux and complex I biogenesis and establish a paradigm for localized mitochondrial translation through transporter-ribosome interactions.
    Keywords:  complex I; electron transport chain; micropeptides; mitochondria; mitochondrial translation; one-carbon pathway; oxidative phosphorylation; small ORF-encoded peptides
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.033
  2. Nature. 2025 Jun 25.
    Cancer cells get power boost by stealing mitochondria from nerves.
    Traci Watson.
      
    Keywords:  Cancer; Cell biology; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-01941-z
  3. Cancers (Basel). 2025 Jun 11. pii: 1942. [Epub ahead of print]17(12):
    The Identification of a Key Regulator of Mitochondrial Metabolism, the LRPPRC Protein, as a Novel Therapeutic Target in SDHA-Overexpressing Ovarian Tumors.
    Anna Szulta, Lin Wang, Ameera Hasan, Michael Kinter, Atul Pranay, Jie Zhu, Kenneth M Humphries, Brooke Loveland, Timothy M Griffin, Magdalena Bieniasz.
      Background: Ovarian cancer is the deadliest of all gynecologic malignancies due to limited therapeutic options. Our data show that the tumor-specific metabolism of ovarian cancer could be effectively targetable, which highlights a path for new anti-cancer therapies. Methods and Results: Our work shows that the upregulation of mitochondrial enzyme SDHA is particularly prevalent in ovarian carcinoma. SDHA overexpression significantly induced orthotopic ovarian tumor growth, reducing mouse survival. We showed that SDHA-overexpressing tumors depend on glutaminolysis and increased activity of the tricarboxylic acid (TCA) cycle coupled with mitochondrial oxidative phosphorylation (OXPHOS), which are essential for high-energy metabolism and cell survival. We identified a distinctive vulnerability of SDHA-overexpressing tumors to agents targeting regulators of the OXPHOS pathway, particularly the LRPPRC protein. LRPPRC is a key regulator of mitochondrial energy metabolism, promoting OXPHOS and ATP generation. However, when overexpressed, the LRPPRC acts as a tumor oncogene. Our analysis of SDHA and LRPPRC gene and protein expression patterns in precursor lesions and established ovarian cancer demonstrated that the upregulation of SDHA is accompanied by LRPPRC overexpression, notably in advanced tumors. Our novel findings highlight for the first time a potential functional interaction between SDHA and LRPPRC in the development and progression of ovarian malignancy. Importantly, our in vivo data showed that pharmacological inhibition of LRPPRC results in a lasting therapeutic benefit and can be an effective therapy in SDHA- and LRPPRC-overexpressing ovarian tumors. Conclusions: Overall, our study underlines an understudied role of concomitant overexpression of SDHA and LRPPRC in ovarian cancer pathogenesis, highlighting new paths for therapeutic development.
    Keywords:  LRPPRC; OXPHOS; SDHA; high-grade serous ovarian cancer; metabolism; ovarian cancer; patient-derived xenograft; shikonin; succinate dehydrogenase
    DOI:  https://doi.org/10.3390/cancers17121942
  4. Cancers (Basel). 2025 Jun 12. pii: 1959. [Epub ahead of print]17(12):
    Steroid Sulfatase Regulates Metabolic Reprogramming in Advanced Prostate Cancer.
    Masuda Sharifi, Cameron M Armstrong, Shu Ning, Amy R Leslie, Zachary A Schaaf, James P Maine, Wei Lou, Pui-Kai Li, Hongyu Xu, Chengfei Liu, Allen C Gao.
       BACKGROUND/OBJECTIVE: The expression of human steroid sulfatase (STS) is upregulated in castration-resistant prostate cancer (CRPC) and is associated with resistance to anti-androgen drugs, such as enzalutamide (Enza) and abiraterone (Abi). Despite the known link between STS overexpression and therapeutic unresponsiveness, the mechanism by which STS confers this phenotype remains incompletely understood. In this study, we sought to understand how STS induces treatment resistance in advanced prostate cancer (PCa) cells by exploring its role in altering mitochondrial activity.
    METHODS: To examine the effects of increased STS expression on mitochondrial respiration and programming, we performed RNA sequencing (RNA-seq) analysis, the Seahorse XF Mito Stress Test, and a mitochondrial Complex I enzyme activity assay in STS-overexpressing cells (C4-2B STS) and in enzalutamide-resistant CPRC cells (C4-2B MDVR). We employed SI-2, the specific chemical inhibitor of STS, on C4-2B STS and C4-2B MDVR cells and evaluated STS activity inhibition on mitochondrial molecular pathways and mitochondrial respiration. Lastly, we examined the effects of dehydroepiandrosterone sulfate (DHEAS) supplementation on C4-2B STS organoids.
    RESULTS: We present evidence from the transcriptomic profiling of C4-2B STS cells that there are enriched metabolic pathway signatures involved in oxidative phosphorylation, the electron transport chain, and mitochondrial organization. Moreover, upon STS inhibition, signaling in the electron transport chain and mitochondrial organization pathways is markedly attenuated. Findings from the Seahorse XF Mito Stress Test and mitochondrial Complex I enzyme activity assay demonstrate that STS overexpression increases mitochondrial respiration, whereas the inhibition of STS by SI-2 significantly reduces the oxygen consumption rate (OCR) and Complex I enzyme activity in C4-2B STS cells. Similarly, an increased OCR and electron transport chain Complex I enzymatic activity are observed in C4-2B MDVR cells and a decreased OCR upon SI-2 inhibition. Lastly, we show that STS overexpression promotes organoid growth upon DHEAS treatment.
    CONCLUSIONS: Our study demonstrates STS as a key driver of metabolic reprogramming and flexibility in advanced prostate cancer. Disrupting enhanced mitochondrial respiration via STS presents a promising strategy in improving CRPC treatment.
    Keywords:  metabolic reprogramming; prostate cancer; steroid sulfatase; therapeutic resistance
    DOI:  https://doi.org/10.3390/cancers17121959
  5. Mol Cell. 2025 Jun 24. pii: S1097-2765(25)00507-6. [Epub ahead of print]
    An NADH-controlled gatekeeper of ATP synthase.
    Fabian Schildhauer, Petra S J Ryl, Simon M Lauer, Swantje Lenz, Ayşe Berçin Barlas, Vasileios R Ouzounidis, Kate Jeffrey, Daniel-Cosmin Marcu, Francis J O'Reilly, Andrea Graziadei, Marchel Stuiver, Kita Schmidt, Helge Ewers, Christian M T Spahn, Ezgi Karaca, Karl Emanuel Busch, Dhanya Cheerambathur, David Schwefel, Juri Rappsilber.
      ATP fuels crucial cellular processes and is obtained mostly by oxidative phosphorylation (OXPHOS) at the inner mitochondrial membrane. While significant progress has been made in mechanistic understanding of ATP production, critical aspects surrounding its substrate supply logistics are poorly understood. We identify an interaction between mitochondrial apoptosis-inducing factor 1 (AIFM1) and adenylate kinase 2 (AK2) as gatekeeper of ATP synthase. This interaction is NADH dependent and influenced by glycolysis, linking it to the cell's metabolic state. Genetic interference with AIFM1/AK2 association impedes the ability of Caenorhabditis elegans animals to handle altered metabolic rates and nutrient availability. Together, the results imply AIFM1 as a cellular NADH sensor, placing AK2 next to the OXPHOS complexes for local ADP regeneration as the substrate for ATP synthesis. This metabolic signal relay balances ATP synthase substrate supply against ATP conservation, enabling cells to adapt to fluctuating energy availability, with possible implications for AIFM1-related mitochondrial diseases.
    Keywords:  AIFM1; AK2; ATP synthesis; OXPHOS; adenylate kinase 2; apoptosis-inducing factor 1; cell signaling; crosslinking mass spectrometry; energy metabolism; mitochondria; mitochondrial; oxidative phosphorylation; protein structure; protein-protein interaction
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.007
  6. Curr Biol. 2025 Jun 23. pii: S0960-9822(25)00576-7. [Epub ahead of print]35(12): R595-R597
    MICOS.
    Karina von der Malsburg, Anastasiia Maitova, Martin van der Laan.
      von der Malsburg et al. introduce the mitochondrial contact site and cristae organizing system, a complex that localises to the inner mitochondrial membrane at crista junctions and stabilises these curved membrane domains.
    DOI:  https://doi.org/10.1016/j.cub.2025.05.001
  7. bioRxiv. 2025 Apr 07. pii: 2025.02.20.639106. [Epub ahead of print]
    Unlocking the Distinct Roles of the Three Mammalian VDAC Isoforms in Mitochondrial Respiration and Cancer Cell Metabolism.
    Megha Rajendran, William M Rosencrans, Wendy Fitzgerald, Diana Huynh, Bethel G Beyene, Baiyi Quan, Julie Hwang, Nina A Bautista, Tsui-Fen Chou, Sergey M Bezrukov, Tatiana K Rostovtseva.
      The Voltage Dependent Anion Channel (VDAC) is the most ubiquitous protein in the mitochondrial outer membrane. This channel facilitates the flux of water-soluble metabolites and ions like calcium across the mitochondrial outer membrane. Beyond this canonical role, VDAC has been implicated, through interactions with protein partners, in several cellular processes such as apoptosis, calcium signaling, and lipid metabolism. There are three VDAC isoforms in mammalian cells, VDAC 1, 2, and 3, with varying tissue-specific expression profiles. From a biophysical standpoint, all three isoforms can conduct metabolites and ions with similar efficiency. However, isoform knockouts (KOs) in mice lead to distinct phenotypes, which may be due to differences in VDAC isoform interactions with partner proteins. To understand the functional role of each VDAC isoform within a single cell type, we created functional KOs of each isoform in HeLa cells and performed a comparative study of their metabolic activity and proteomics. We found that each isoform KO alters the proteome differently, with VDAC3 KO dramatically downregulating key members of the electron transport chain (ETC) while shifting the mitochondria into a glutamine-dependent state. Importantly, this unexpected dependence of mitochondrial function on the VDAC3 isoform is not compensated by the more ubiquitously expressed VDAC1 and VDAC2 isoforms. In contrast, VDAC2 KO did not affect respiration but upregulated ETC components and decreased key enzymes in the glutamine metabolic pathway. VDAC1 KO specifically reduced glycolytic activity linked to decreased hexokinase localization to mitochondria. These results reveal non-redundant roles of VDAC isoforms in cancer cell metabolic adaptability.
    DOI:  https://doi.org/10.1101/2025.02.20.639106
  8. Nat Commun. 2025 Jun 25. 16(1): 5388
    The mitochondrial methylation potential gates mitoribosome assembly.
    Ruth I C Glasgow, Vivek Singh, Lucía Peña-Pérez, Alissa Wilhalm, Marco F Moedas, David Moore, Florian A Rosenberger, Xinping Li, Ilian Atanassov, Mira Saba, Miriam Cipullo, Joanna Rorbach, Anna Wedell, Christoph Freyer, Alexey Amunts, Anna Wredenberg.
      S-adenosylmethionine (SAM) is the principal methyl donor in cells and is essential for mitochondrial gene expression, influencing RNA modifications, translation, and ribosome biogenesis. Using direct long-read RNA sequencing in mouse tissues and embryonic fibroblasts, we show that processing of the mitochondrial ribosomal gene cluster fails in the absence of mitochondrial SAM, leading to an accumulation of unprocessed precursors. Proteomic analysis of ribosome fractions revealed these precursors associated with processing and assembly factors, indicating stalled biogenesis. Structural analysis by cryo-electron microscopy demonstrated that SAM-dependent methylation is required for peptidyl transferase centre formation during mitoribosome assembly. Our findings identify a critical role for SAM in coordinating mitoribosomal RNA processing and large subunit maturation, linking cellular methylation potential to mitochondrial translation capacity.
    DOI:  https://doi.org/10.1038/s41467-025-60977-x
  9. Cell Death Differ. 2025 Jun 23.
    Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes.
    Jan Dreute, Julia Stengel, Jonas Becher, David van den Borre, Maximilian Pfisterer, Marek Bartkuhn, Vanessa M Beutgen, Benardina Ndreshkjana, Ulrich Gärtner, Johannes Graumann, Michael Huck, Stephan Klatt, Chloe Leff, Henner F Farin, Andrea Nist, Roland Schmitz, Thorsten Stiewe, Julia Teply-Szymanski, Jochen Wilhelm, Alfredo Cabrera-Orefice, M Lienhard Schmitz.
      As cancer cell specific rewiring of metabolic networks creates potential therapeutic opportunities, we conducted a synthetic lethal screen utilizing inhibitors of metabolic pathways. Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, BMS-986205, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), also restricts oxidative phosphorylation (OXPHOS), as revealed here. BMS-986205, which is being tested in multiple Phase III clinical trials, inhibits the ubiquinone reduction site of respiratory complex I and thus compromises mitochondrial ATP production. The energetic catastrophe caused by simultaneous interference with glycolysis and OXPHOS resulted in either cell death or the induction of senescence in tumor cells, with the latter being eliminated by senolytics. The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.
    DOI:  https://doi.org/10.1038/s41418-025-01532-5
  10. Nature. 2025 Jun 25.
    Nerve-to-cancer transfer of mitochondria during cancer metastasis.
    Gregory Hoover, Shila Gilbert, Olivia Curley, Clémence Obellianne, Mike T Lin, William Hixson, Terry W Pierce, Joel F Andrews, Mikhail F Alexeyev, Yi Ding, Ping Bu, Fariba Behbod, Daniel Medina, Jeffrey T Chang, Gustavo Ayala, Simon Grelet.
      The nervous system has a pivotal role in cancer biology, and pathological investigations have linked intratumoural nerve density to metastasis1. However, the precise impact of cancer-associated neurons and the communication channels at the nerve-cancer interface remain poorly understood. Previous cancer denervation models in rodents and humans have highlighted robust cancer dependency on nerves, but the underlying mechanisms that drive nerve-mediated cancer aggressivity remain unknown2,3. Here we show that cancer-associated neurons enhance cancer metabolic plasticity by transferring mitochondria to cancer cells. Breast cancer denervation and nerve-cancer coculture models confirmed that neurons significantly improve tumour energetics. Neurons cocultured with cancer cells undergo metabolic reprogramming, resulting in increased mitochondrial mass and subsequent transfer of mitochondria to adjacent cancer cells. To precisely track the fate of recipient cells, we developed MitoTRACER, a reporter of cell-to-cell mitochondrial transfer that permanently labels recipient cancer cells and their progeny. Lineage tracing and fate mapping of cancer cells acquiring neuronal mitochondria in primary tumours revealed their selective enrichment at metastatic sites following dissemination. Collectively, our data highlight the enhanced metastatic capabilities of cancer cells that receive mitochondria from neurons in primary tumours, shedding new light on how the nervous system supports cancer metabolism and metastatic dissemination.
    DOI:  https://doi.org/10.1038/s41586-025-09176-8
  11. J Biol Chem. 2025 Jun 20. pii: S0021-9258(25)02256-2. [Epub ahead of print] 110406
    PLK1-mediated PDHA1 phosphorylation drives mitochondrial dysfunction, mitophagy, and cancer progression in Cr(VI)-associated lung cancer.
    Qiongsi Zhang, Jia Peng, Zhiguo Li, Xiongjian Rao, Derek B Allison, Qi Qiao, Zhuangzhuang Zhang, Yifan Kong, Yanquan Zhang, Ruixin Wang, Jinghui Liu, Xinyi Wang, Chaohao Li, Fengyi Mao, Qing Shao, Tianyan Gao, Xiaoqi Liu.
      Hexavalent chromium (Cr(VI)) is a class I environmental carcinogen that induces lung epithelial cell transformation and promotes lung cancer progression by altering cell cycle regulation and cellular energy metabolism. In this study, we investigated the role of polo-like kinase 1 (PLK1) in Cr(VI)-transformed (CrT) bronchial epithelial cells (BEAS-2B) and found that PLK1 expression was significantly upregulated in these cells, leading to impaired mitochondrial function and enhanced mitophagy, which in turn stimulated cell proliferation both in vitro and in vivo. Mechanistically, we demonstrated that PLK1 directly phosphorylates the pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) at Thr57, leading to its destabilization and disruption of pyruvate dehydrogenase complex (PDHc) integrity. This modification inhibits oxidative phosphorylation (OXPHOS) and induces mitochondrial dysfunction. Furthermore, mitochondrial dysfunction triggers mitophagy and accelerates PDHA1 degradation, establishing a positive feedback loop that amplifies mitochondrial impairment and mitophagy, ultimately promoting cancer cell proliferation. These findings underscore the pivotal role of PLK1 in Cr(VI)-associated cancer progression and offer new insights into potential therapeutic targets to inhibit Cr(VI)-induced tumorigenesis.
    Keywords:  Hexavalent Chromium (Cr(VI)); Mitochondrial Dysfunction; Mitophagy; Polo-like Kinase 1 (PLK1)
    DOI:  https://doi.org/10.1016/j.jbc.2025.110406
  12. Eur J Pharmacol. 2025 Jun 17. pii: S0014-2999(25)00613-2. [Epub ahead of print] 177859
    Crotonoside induces ferroptosis and mitochondrial dysfunction in AML.
    Chenchen Ma, Jinxin Wang, Siyuan Cui, Ruirong Xu.
      Crotonoside, an isomer of guanine, has demonstrated inhibitory activity against various acute myeloid leukemia (AML) cell lines. Transcriptome sequencing analyses indicate that the mechanism by which crotonoside inhibits AML cell activity is not singular. This study examines the impact of crotonoside on mitochondrial function and the induction of ferroptosis. By assessing mitochondrial respiration capacity, mitochondrial membrane potential, mitochondrial mass, and several ferroptosis-related parameters in both KG-1a and Molm-13 cell lines, we observed that crotonoside induces mitochondrial damage, leading to dysfunction and the accumulation of reactive oxygen species (ROS), which subsequently triggers ferroptosis in AML cells. Molecular docking simulations, informed by the structural characteristics of crotonoside, suggest that its mitochondrial damage is mediated through the inhibition of mitochondrial DNA polymerase γ. Furthermore, this ferroptosis is intricately linked to crotonoside's modulation of AML cell autophagy via the p62/KEAP1 signaling pathway. Nonetheless, the precise mechanisms underlying the inhibition of mitochondrial DNA polymerase γ and the subsequent induction of ferroptosis following crotonoside intervention remain to be fully elucidated.
    Keywords:  AML; Crotonoside; DNA polymerse γ; ferroptosis; mitochondrial dysfunction; mt DNA
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177859
  13. Nature. 2025 Jun 25.
    Neuronal transfer of mitochondria to tumour cells promotes cancer spread.
    Anand K Singh, Yuan Pan.
      
    Keywords:  Cancer; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-01718-4
  14. Cancer. 2025 Jul 01. 131(13): e35897
    Mitochondrial proteome landscape unveils key insights into melanoma severity and treatment strategies.
    Yonghyo Kim, Viktória Doma, Uğur Çakır, Magdalena Kuras, Lazaro Hiram Betancourt, Indira Pla, Aniel Sanchez, Yutaka Sugihara, Roger Appelqvist, Henriett Oskolas, Boram Lee, Jéssica Guedes, Gustavo Monnerat, Gabriel Reis Alves Carneiro, Fábio C S Nogueira, Gilberto B Domont, Johan Malm, Bo Baldetorp, Elisabet Wieslander, István Balázs Németh, A Marcell Szász, Runyu Hong, Krzysztof Pawłowski, Melinda Rezeli, Ho Jeong Kwon, Jozsef Timar, David Fenyö, Sarolta Kárpáti, György Marko-Varga, Jeovanis Gil.
       BACKGROUND: Melanoma, the deadliest form of skin cancer, exhibits resistance to conventional therapies, particularly in advanced and metastatic stages. Mitochondrial pathways, including oxidative phosphorylation and mitochondrial translation, have emerged as critical drivers of melanoma progression and therapy resistance. This study investigates the mitochondrial proteome in melanoma to uncover novel therapeutic vulnerabilities.
    METHODS: Quantitative proteomics was performed on 151 melanoma-related samples from a prospective cohort and postmortem tissues. Differential expression analysis identified mitochondrial proteins linked to disease aggression and treatment resistance. Functional enrichment analyses and in vitro validation using mitochondrial inhibitors were conducted to evaluate therapeutic potential.
    RESULTS: Mitochondrial translation and oxidative phosphorylation (OXPHOS) were significantly upregulated in aggressive melanomas, particularly in BRAF-mutant and metastatic tumors. Inhibition of mitochondrial pathways using antibiotics (doxycycline, tigecycline, and azithromycin) and OXPHOS inhibitors (VLX600, IACS-010759, and BAY 87-2243) demonstrated dose-dependent antiproliferative effects in melanoma cell lines, sparing noncancerous melanocytes. These treatments disrupted mitochondrial function, suppressed key metabolic pathways, and induced apoptosis, highlighting the clinical relevance of targeting these pathways.
    CONCLUSIONS: This study reveals mitochondrial pathways as critical drivers of melanoma progression and resistance, providing a rationale for targeting mitochondrial translation and OXPHOS in advanced melanoma. Combining mitochondrial inhibitors with existing therapies could overcome treatment resistance and improve patient outcomes.
    Keywords:  BRAF mutation; MCM complex; melanoma; mitochondrial metabolism; mitochondrial proteome; mitoribosomes; oxidative phosphorylation; proteomics
    DOI:  https://doi.org/10.1002/cncr.35897
  15. Blood. 2025 Jun 25. pii: blood.2024026113. [Epub ahead of print]
    Posttranscriptional depletion of ribosome biogenesis factors engenders therapeutic vulnerabilities in NPM1-mutant AML.
    Aristi Damaskou, Rachael Wilson, Malgorzata Gozdecka, George Giotopoulos, Ryan Asby, Maria Eleftheriou, Muxin Gu, Christian Récher, Véronique Mansat-De Mas, Francois Vergez, Ambrine Sahal, Binje Vick, Evangelia K Papachristou, Ashley Sawle, Eliza Yankova, Monika Dudek, Xiaoxuan Liu, James Russell, Justyna Rak, Christine Hilcenko, Clive S D'Santos, Irmela Jeremias, Jean-Emmanuel Sarry, Konstantinos Tzelepis, Brian Jp Huntly, Alan J Warren, Omid Tavana, George S Vassiliou.
      NPM1 is a multifunctional phosphoprotein with key roles in ribosome biogenesis amongst its many functions. NPM1 gene mutations drive 30% of acute myeloid leukemia (AML) cases. The mutations disrupt a nucleolar localization signal (NoLS) and create a novel nuclear export signal (NES), leading to cytoplasmic displacement of the protein (NPM1c). NPM1c mutations prime hematopoietic progenitors to leukemic transformation, but their precise molecular consequences remain elusive. Here, we first examine the effects of isolated NPM1c mutations on the global proteome of pre-leukemic hematopoietic stem and progenitor cells (HSPCs) using conditional knock-in Npm1cA/+ mice. We discover that many proteins involved in ribosome biogenesis are significantly depleted in these murine HSPCs, but also importantly in human NPM1-mutant AMLs. In line with this, we found that pre-leukemic Npm1cA/+ HSPCs display higher sensitivity to RNA polymerase I inhibitors, including Actinomycin D (ActD), compared to Npm1+/+ cells. Combination treatment with ActD and Venetoclax inhibited the growth and colony forming ability of pre-leukemic and leukemic NPM1c+ cells, whilst low-dose ActD treatment was able to re-sensitize resistant NPM1c+ cells to Venetoclax. Furthermore, using data from CRISPR dropout screens, we identified and validated TSR3, a 40S ribosomal maturation factor whose knock-out preferentially inhibited the proliferation of NPM1c+ AML cells by activating a p53-dependent apoptotic response. Similarly to low-dose ActD treatment, TSR3 depletion could partially restore sensitivity to Venetoclax in therapy-resistant NPM1c+ AML models. Our findings propose that targeted disruption of ribosome biogenesis should be explored as a therapeutic strategy against NPM1-mutant AML.
    DOI:  https://doi.org/10.1182/blood.2024026113
  16. Nitric Oxide. 2025 Jun 20. pii: S1089-8603(25)00059-X. [Epub ahead of print]158 67-75
    3-mercaptopyruvate sulfurtransferase resides on the inner mitochondrial membrane.
    Antonia Katsouda, Eleni Vasilaki, Markos Fountoulakis, Ioanna Tremi, Sophia Havaki, Vassilios Myrianthopoulos, Vassilis G Gorgoulis, Emmanuel Mikros, Andreas Papapetropoulos.
      3-mercaptopyruvate sulfurtransferase (MPST) is an enzyme implicated in the generation of the gasotransmitter hydrogen sulfide (H2S). Unlike, the other two H2S-synthesizing enzymes cystathionine gamma lyase (CSE) and cystathionine beta synthase (CBS), MPST is found in the mitochondria. However, the mechanisms through which MPST gains access to the mitochondria and its exact localization within this organelle remain unclear. Using immunogold electron microscopy staining, we localized MPST on the inner mitochondrial membrane. To study the pathway of mitochondrial entry for MPST, pharmacological inhibitors of different components of the translocase of outer/inner membrane were used. In line with the observation that ΜPST is found on the inner mitochondrial membrane, inhibition of TIM23 blocked MPST mitochondrial entry. Generation of N-terminally truncated forms of ΜPST did not interfere with the ability of the enzyme to gain access into the mitochondria, suggesting that an N-terminal pre-sequence does not mediate MPST mitochondrial entry. In agreement to this finding, cytosolic and mitochondrial MPST had a similar molecular weight. Interestingly, N-terminally deleted MPST exhibited reduced expression levels, indicating that this part of the enzyme is required for protein stability. Molecular dynamics simulations confirmed that deletion of the first 39 amino acids of the enzyme destabilizes the protein. Our findings reveal that MPST is present on the inner mitochondrial membrane and that its entry into mitochondria does not involve the N-terminus of the protein.
    Keywords:  3-mercaptopyruvate sulfurtransferase; Cristae; Mitochondria; TIM/TOM; TIM23
    DOI:  https://doi.org/10.1016/j.niox.2025.06.004
  17. bioRxiv. 2025 Apr 26. pii: 2025.04.23.650241. [Epub ahead of print]
    A nuclear branched-chain amino acid catabolism pathway controls histone propionylation in pancreatic cancer.
    Christina Demetriadou, Michael Noji, Austin L Good, Erick Mitchell-Velasquez, Sharan Venkatesh, Daniel S Kantner, Jennifer Pennise, Pedro Costa-Pinheiro, Laura V Pinheiro, Taku Harada, Phuong T T Nguyen, Adam Chatoff, Emily Megill, Claudia V Da Silva Crispim, Mariola M Marcinkiewicz, Jordan L Meier, Zoltan Arany, Irfan Asangani, Emma E Furth, Ben Z Stanger, Nathaniel W Snyder, Kathryn E Wellen.
      Branched-chain amino acid (BCAA) catabolism contributes prominently to the TCA cycle in the healthy pancreas but is suppressed in pancreatic ductal adenocarcinoma (PDA). The impact of this metabolic remodeling on cancer phenotypes remains poorly understood. Here, we find that the BCAA isoleucine is a primary source of propionyl-CoA in PDA cells. Reduction of propionyl-CoA availability by either genetic perturbation or isoleucine and valine starvation decreases histone propionylation (Kpr) without impacting histone acetylation on specific lysine sites, correlating with reduced transcription of certain lipid- and immune-related genes. Mechanistically, we find that multiple enzymes of isoleucine catabolism unexpectedly localize to and carry out multi-step isoleucine oxidation within the nuclei of PDA cells. Importantly, nuclear localization of the rate-limiting branched-chain alpha ketoacid dehydrogenase (BCKDH) complex is essential for isoleucine-dependent Kpr and gene regulation. Moreover, we demonstrate that isoleucine-sensitive Kpr and its associated gene expression are driven by the MYST family of lysine acyltransferases (KATs), and that the BCKDHA subunit of the BCKDH complex interacts with KAT7 within the nuclear compartment. BCAA catabolism enzymes are apparent in the nuclei of PanIN lesions in mice and PDA tumors in patients, contrasting that in healthy pancreatic acinar and ductal cells. Collectively, these findings unveil a nuclear isoleucine catabolism pathway and highlight its role in controlling histone Kpr and tumorigenic transcriptional programs in PDA.
    DOI:  https://doi.org/10.1101/2025.04.23.650241
  18. Front Immunol. 2025 ;16 1560989
    Sirtuin 5 inhibits mitochondrial metabolism in liver cancer cells and promotes apoptosis by mediating the desuccinylation of CS.
    Huimin Cao, Dongsheng Wei, Han Li, Mei Zhao, Yixin Ma, Liang Kong, Guoyuan Sui, Lianqun Jia.
       Background: Citrate synthase (CS) is a key rate-limiting enzyme in the tricarboxylic acid (TCA) cycle and plays a crucial role in cancer progression. However, the mechanism by which CS promotes liver cancer growth remains unclear. The aim of this study is to elucidate the role of CS and its post-translational modifications (PTMs) in the initiation and progression of hepatocellular carcinoma (HCC).
    Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to detect protein lysine succinylation in human liver cancer and adjacent non-cancerous tissues. A HCC model was established in male C57BL/6 mice through intraperitoneal injection of DEN. The expression of SIRT5 and CS in HCC mice was assessed by RT-qPCR, immunohistochemistry, and Western blotting. HepG2 cells were cultured, and co-immunoprecipitation (Co-IP) was performed to evaluate the interaction between SIRT5 and CS. Western blotting was used to measure the succinylation levels of CS. In addition, Mito-Tracker Red CMXRos staining, reactive oxygen species (ROS) measurement, ATP level assay, EdU cell proliferation assay, colony formation assay, TUNEL staining, and flow cytometry were used to investigate the effects of CS succinylation and desuccinylation on mitochondrial function and cell proliferation in hepatocellular carcinoma cells.
    Results: A total of 358 differentially modified proteins were identified in human liver cancer tissues. These differentially modified proteins were primarily enriched in the mitochondria, and CS exhibited high levels of succinylation in HCC tissues. In mouse liver cancer tissues, SIRT5 expression was reduced while CS expression was increased. Furthermore, SIRT5 was found to interact with CS, mediating the de-succinylation of CS at the lysine 375 site. Additionally, succinylation at the K375 site of CS was shown to enhance mitochondrial activity and ATP content in HepG2 cells, while reducing intracellular ROS levels and promoting cell proliferation. In contrast, de-succinylation of CS at the K375 site significantly impaired mitochondrial function and ATP levels, increased ROS levels, and induced apoptosis in HepG2 cells.
    Conclusion: Succinylation of CS is crucial for maintaining mitochondrial function and promoting cell proliferation in liver cancer cells. Targeting SIRT5-mediated de-succinylation of CS may represent a promising therapeutic strategy for the treatment of hepatocellular carcinoma.
    Keywords:  PTMs (post-translational modifications); apoptosis; citrate synthase; hepatocellular carcinoma; mitochondrial metabolism; succinylation
    DOI:  https://doi.org/10.3389/fimmu.2025.1560989
  19. Leukemia. 2025 Jun 23.
    Mutations and translocations associated with venetoclax resistance in chronic lymphocytic leukemia.
    Kiyomi Mashima, Yanan Kuang, Stacey M Fernandes, Shidong Xu, Benjamin Hanna, Samantha Shupe, Mariia Mikhaleva, Roberta Azevedo Santos, Paulina Predko, Rayan Fardoun, Ava Bidgoli, Stephen P Martindale, Aishath Naeem, Matthew S Davids, Cloud Paweletz, Jennifer R Brown.
      
    DOI:  https://doi.org/10.1038/s41375-025-02611-9
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