bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–12–21
sixteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Pharmacological Inhibition of miR-126 Enhances Venetoclax Activity in Acute Myeloid Leukemia.
  2. Transporting the transporter: TIM22 translocates mitoferrins to enable mitochondrial iron-sulfur cluster synthesis.
  3. Lactate mitochondrial oxidation drives stemness potential in metastatic breast cancer.
  4. Stochasticity contributes to explaining minority and majority MOMP during apoptosis.
  5. NAMPT inhibition uncovers therapeutic vulnerabilities to venetoclax and chemotherapy in acute myelogenous leukemia.
  6. The TIM22 carrier translocase supports cell proliferation by facilitating mitochondrial iron uptake for Fe-S biogenesis.
  7. MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.
  8. Redox-dependent protein S-glutathionylation governs azacitidine sensitivity and resistance in AML.
  9. Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
  10. Niclosamide nanoparticles enhance pancreatic cancer sensitivity to gemcitabine via HIF-1α inhibition.
  11. The fate of pyruvate dictates cell growth by modulating cellular redox potential.
  12. Drp1 Interaction with BIP Maintains Mitochondrial Dynamic Equilibrium to Promote Anoikis Resistance and Metastasis in Nasopharyngeal Carcinoma.
  13. Mitochondrial complex II orchestrates divergent effects in CD4+ and CD8+ T cells.
  14. The cytochrome c oxidase subunit COX6B1 is required for redox-sensitive early assembly and late stabilization of complex IV.
  15. Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
  16. Mechanistically informed machine learning links non-canonical TCA cycle activity to Warburg metabolism and hallmarks of malignancy.
  1. Blood. 2025 Dec 15. pii: blood.2025029875. [Epub ahead of print]
    Pharmacological Inhibition of miR-126 Enhances Venetoclax Activity in Acute Myeloid Leukemia.
    Lianjun Zhang, HyunJun Kang, Melissa Valerio, Dinh Hoa Hoang, Khyatiben V Pathak, Krystine Garcia-Mansfield, Xiyuan Lu, Wancheng Guo, Yu-Hsuan Fu, Xin He, Ying-Chieh Chen, Zhenhua Chen, Lucy Y Ghoda, Ralf Buettner, Zhuo Li, Amanda Blackmon, Ling Li, Bin Zhang, Patrick Pirrotte, Guido Marcucci, Ya-Huei Kuo, Le Xuan Truong Nguyen.
      Leukemic stem cells (LSCs) in acute myeloid leukemia (AML) depend on oxidative phosphorylation (OXPHOS) sustained by fatty acid oxidation (FAO) and mitochondrial fusion (mitofusion). We demonstrate that miR-126 maintains LSC function by promoting BCL-2-dependent FAO, OXPHOS, and mitofusion, whereas its inhibition disrupts mitochondrial metabolism, induces mitochondrial fission (mitofission), and triggers apoptosis. Mechanistically, miR-126 stabilizes BCL-2 via the SPRED1/ERK axis, which upregulates CPT1B (FAO) and NRF2 (antioxidant response) while regulating mitochondrial dynamics through DRP1 phosphorylation (inhibiting mitofission) and MFN1/2 phosphorylation (enhancing mitofusion). miRisten, a CpG-conjugated anti-miR-126 oligonucleotide now in clinical trials (NCT07025564), synergized with venetoclax (VEN) to suppress FAO/OXPHOS, promote mitofission, and impair LSC homeostasis. In vivo, miRisten potentiated the VEN/azacitidine (AZA) regimen, an FDA-approved therapy for older or unfit AML patients, significantly prolonging survival in patient-derived xenograft models. VEN/miRisten combination also reduced LSC burden and restored VEN sensitivity, establishing miR-126 inhibition as a transformative therapeutic strategy in AML.
    DOI:  https://doi.org/10.1182/blood.2025029875
  2. Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00943-8. [Epub ahead of print]85(24): 4483-4484
    Transporting the transporter: TIM22 translocates mitoferrins to enable mitochondrial iron-sulfur cluster synthesis.
    Erdem M Terzi, Richard Possemato.
      Iron is a critical nutrient, especially to power mitochondrial iron-sulfur cofactor synthesis. In this issue of Molecular Cell, Liu et al.1 engineer a fluorescent iron sensor, enabling them to define a critical function of the mitochondrial translocase, TIM22, in powering mitochondrial iron use by proper targeting of the mitochondrial iron importers, the mitoferrins.
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.026
  3. Nat Commun. 2025 Dec 18.
    Lactate mitochondrial oxidation drives stemness potential in metastatic breast cancer.
    Jia-Jia Zhang, Ruo-Fei Tian, Chang-Geng Song, Rui Liu, Duo He, Gai-Qin Zhang, Xin-Yu Fan, Zi-Chuan Duan, Kun Zhang, Tian-Jiao Zhang, Ya-Tong Chen, Jian Zhang, Ke Wang, Ju-Mei Zhao, Xiang-Min Yang, Zhi-Nan Chen, Ling Li.
      Metastatic cancer cells, originating from cancer stem cells with metastatic capacity, utilize nutrient flexibility to navigate the challenges of the metastatic cascade. However, the nutrient required to maintain the stemness potentials of metastatic cancer cells remains unclear. Here, we reveal that metastatic breast cancer cells sustain stemness and initiate metastasis upon detachment by taking up and oxidizing lactate. In detached metastasizing breast cancer cells, lactate is incorporated into the tricarboxylic acid cycle, boosting oxidative phosphorylation, and promoting the stemness potentials via α-KG-DNMT3B-mediated SOX2 hypomethylation. Moreover, lactate is taken up and oxidized in mitochondria by the CD147/MCT1/LDHB complex, which correlates with stemness potentials and tumor metastasis in patients with breast cancer. An intracellularly expressed single-chain variable fragment targeting mitochondrial CD147 (mito-CD147 scFv) effectively disrupts the mitochondrial CD147/MCT1/LDHB complex, inhibits lactate-induced stemness potential, depletes circulating breast cancer cells, and reduces metastatic burden, suggesting promising clinical applications in reducing lactate-fueled metastasis.
    DOI:  https://doi.org/10.1038/s41467-025-67091-y
  4. Cell Death Dis. 2025 Dec 19. 16(1): 893
    Stochasticity contributes to explaining minority and majority MOMP during apoptosis.
    Jenny Geiger, Fabian Klötzer, Nadine Pollak, Gavin Fullstone, Markus Rehm.
      Apoptosis dysfunction is linked to diseases like cancer and neurodegenerative disorders. A key event during apoptosis is mitochondrial outer membrane permeabilization (MOMP), which typically proceeds in a rapid all-or-none fashion. If MOMP occurs only in a subset of mitochondria (minority MOMP), it can be sublethal and contribute to tumorigenesis and cancer progression. Similarly, individual mitochondria escaping widespread MOMP (majority MOMP) can allow cancer cells to recover if apoptosis execution fails. How such heterogeneities in mitochondrial MOMP responsiveness arise within cells is incompletely understood. In particular, whether stochasticity in subcellular protein distributions and interactions across cytosol and mitochondria can realistically contribute to mitochondrial MOMP heterogeneity has not yet been studied. To assess this, we sequentially built and experimentally parameterized a particle-based, cell-sized model including cytosolic and mitochondrial compartments, and that featured a reduced interactome of MCL-1, BAK and tBID. High-performance computing enabled cell-scale simulations of protein distributions and interactions to understand how and under which conditions stochasticity could contribute to heterogeneity in MOMP susceptibility. Our results show that stochastic effects strongly predispose sub-pools of fragmented mitochondria to MOMP under low apoptotic stress. At higher apoptotic stress, fractions of small mitochondria were more likely to escape MOMP than large mitochondria. Retrospective quantification of mitochondrial sizes in experimental scenarios of minority and majority MOMP confirmed these findings. We therefore conclude that stochasticity substantially contributes to enabling small or fragmented mitochondria to undergo MOMP in minority MOMP scenarios and to escape MOMP in majority MOMP scenarios.
    DOI:  https://doi.org/10.1038/s41419-025-08258-9
  5. Leuk Lymphoma. 2025 Dec 16. 1-11
    NAMPT inhibition uncovers therapeutic vulnerabilities to venetoclax and chemotherapy in acute myelogenous leukemia.
    John R Sanchez, Chaomei Liu, Vishakha Pawar, Yanqing Huang, Daisy Diaz-Rohena, Jyotsana Singh, Priya Koppikar, Tzung-Huei Lai, Lisa St John, Vinay Puduvalli, Jeffrey Molldrem, Palaniraja Thandapani, Nitin Jain, Rosa Lapalombella, Deepa Sampath.
      Acute myeloid leukemia (AML) cells depend on nicotinamide adenine dinucleotide (NAD+) biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) for survival. Single-cell RNA sequencing revealed robust NAMPT expression across diverse AML subtypes. Proteomic profiling showed that NAMPT inhibition with KPT-9274 induced adaptive upregulation of BCL2, an anti-apoptotic protein, highlighting a survival mechanism. BH3 profiling confirmed that AML cells hierarchically depend on BCL2, followed by MCL1 and BCLxL, for survival. Combining KPT9274 with the BCL2 inhibitor venetoclax synergistically enhanced mitochondrial dysfunction, cytochrome C release, and apoptotic death in AML blasts. Additionally, NAMPT inhibition reduced PARP activity and impaired DNA repair pathways, sensitizing AML cells to cytarabine and hypomethylating agents. Together, these results demonstrate that NAMPT inhibition both potentiates venetoclax activity and enhances the cytotoxic effects of standard chemotherapies by targeting metabolic and DNA repair vulnerabilities. These findings provide strong preclinical support for evaluating NAMPT and BCL2 dual inhibition strategies in future AML clinical trials.
    Keywords:  AML; BCL-2 dependency; DNA repair impairment; KPT-9274; NAMPT inhibition; metabolic vulnerability
    DOI:  https://doi.org/10.1080/10428194.2025.2571199
  6. Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00939-6. [Epub ahead of print]85(24): 4587-4601.e7
    The TIM22 carrier translocase supports cell proliferation by facilitating mitochondrial iron uptake for Fe-S biogenesis.
    Shuai Liu, Qingyu Li, Mengye Cao, Zefang Bimo Zhao, Cong Liu, Zhuoran Zhen, Jiankun Ren, Chengyang Liu, Danyang Ruan, Luna Zhang, Wenjuan Zhang, Hao Gong, Xiaolong Liu, Xuejie Zhang, Deng Pan, Weijun Pan, Jiajun Zhu.
      Mitochondria host a number of reductive biosynthetic pathways and rely on extensive metabolite exchanges with the cytosol to support cellular anabolic metabolism. Mitochondrial iron-sulfur cluster (Fe-S) biogenesis is essential for multiple cellular functions, and its disruption causes various inborn genetic diseases. How mammalian cells regulate Fe-S biogenesis remains incompletely understood. Here, mitochondria-focused CRISPR screening and DepMap-based gene co-essentiality analysis consistently reveal that components of the carrier translocase of the inner mitochondrial membrane (TIM22) complex, including TIMM29, are selectively required for Fe-S biogenesis. Mechanistically, loss of TIM22 complex function reduced iron transporter presence on mitochondria, thereby impairing iron uptake from the cytosol. Reconstituting mitochondrial iron level was sufficient to restore Fe-S biogenesis and proliferation of TIMM29-deficient cells or rescue the embryonic development of timm29-deficient zebrafish. Thus, a primary function of the TIM22 carrier translocase is to facilitate transporter-mediated iron uptake required for Fe-S biogenesis, underscoring a biosynthetic role of mitochondria in cellular anabolism.
    Keywords:  TIM22 carrier translocase; cellular metabolism; iron-sulfur cluster; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.022
  7. Nat Cell Biol. 2025 Dec 15.
    MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.
    Yue Zhang, Yuchen Xia, Xinhui Wang, Yueqin Xia, Shang Wu, Jianshuang Li, Xuan Guo, Qinghua Zhou, Li He.
      Mitochondrial dynamics and mtDNA homeostasis have been linked to specialized mitochondrial subdomains known as small MTFP1-enriched mitochondria (SMEM), though the underlying molecular mechanisms remain unclear. Here we identified MISO (mitochondrial inner membrane subdomain organizer), a conserved protein that regulates both mitochondrial dynamics and SMEM formation in Drosophila and mammalian cells. MISO inhibits fusion by recruiting MTFP1 and promotes fission through FIS1-DRP1. Furthermore, MISO drives SMEM biogenesis and facilitates their peripheral fission that promotes lysosomal degradation of mtDNA. Genetic ablation of MISO abolishes SMEM generation, confirming that MISO is both necessary and sufficient for SMEM formation. Inner mitochondrial membrane stresses, including mtDNA damages, OXPHOS dysfunction and cristae disruption, stabilize the otherwise short-lived MISO protein, thereby triggering SMEM assembly. This process depends on the C-terminal domain of MISO, likely mediated by oligomerization. Together, our findings reveal a molecular pathway through which inner mitochondrial membrane stresses modulate mitochondrial dynamics and mtDNA homeostasis via MISO-orchestrated SMEM organization.
    DOI:  https://doi.org/10.1038/s41556-025-01829-0
  8. Redox Biol. 2025 Dec 04. pii: S2213-2317(25)00471-9. [Epub ahead of print]89 103958
    Redox-dependent protein S-glutathionylation governs azacitidine sensitivity and resistance in AML.
    Dušan Nemes, Michaela Myšáková, Lubomír Minařík, Anna Jonášová, Tomáš Stopka, Kristýna Gloc Pimková.
      Disruption of redox metabolism is a hallmark of drug-resistant cancer cells, representing a major obstacle to the effective treatment of acute myeloid leukemia (AML). While recent studies have highlighted the importance of redox balance in AML therapy, the specific contribution of protein redox signaling to resistance remains poorly understood. Defining these mechanisms could uncover therapeutic vulnerabilities of resistant AML cells and guide the development of novel combination strategies. Here, we performed comprehensive mass spectrometry-based redox and quantitative proteomic profiling of AML cell lines and patient samples sensitive or resistant to the hypomethylating agent azacitidine (AZA). We demonstrate that AZA disrupts redox homeostasis, which inactivates the glyoxalase system and DNA damage response, and thereby induces cell death. In contrast, AZA resistance is associated with a redox reset characterized by elevated glutathione levels and diminished protein S-glutathionylation. Importantly, AZA failed to induce oxidation of proteins in these pathways in resistant cells and patient-derived AML samples. Pharmacological inhibition of glutathione synthesis restored protein S-glutathionylation and resensitized resistant AML cells to AZA.
    Keywords:  Acute myeloid leukemia; Azacitidine; Cysteine oxidation; DNA damage; Drug resistance; Glyoxalase system; Hypomethylation therapy; Redox proteomics; S-glutathionylation
    DOI:  https://doi.org/10.1016/j.redox.2025.103958
  9. Nat Cell Biol. 2025 Dec 19.
    Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
    Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B Compeer, Felix C Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L Dustin, Linda V Sinclair, Pekka Katajisto, Anna Katharina Simon.
      T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function.
    DOI:  https://doi.org/10.1038/s41556-025-01835-2
  10. iScience. 2025 Dec 19. 28(12): 114088
    Niclosamide nanoparticles enhance pancreatic cancer sensitivity to gemcitabine via HIF-1α inhibition.
    Susheel Kumar Nethi, Venugopal Gunda, Nagabhishek Sirpu Natesh, Brianna M White, Adam S Mullis, Balaji Narasimhan, Surinder K Batra, Surya K Mallapragada, Satyanarayana Rachagani.
      Pancreatic cancer (PC) exhibits profound metabolic adaptations that support tumor progression, survival, and therapy resistance. Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of these processes, promoting metabolic reprogramming and chemoresistance. Given that mitochondrial metabolites modulate HIF-1α stability, targeting mitochondrial metabolism offers a promising therapeutic strategy. Niclosamide (Nic), a clinically approved anthelmintic, disrupts mitochondrial function but is limited by poor bioavailability. To overcome this, we developed polyanhydride-based Nic nanoparticles (NicNps) to enhance bioavailability and efficacy. NicNps impaired mitochondrial function, suppressed metabolism, downregulated HIF-1α, and inhibited growth of PC cells and orthotopic gemcitabine (Gem)-resistant mouse tumor models. Notably, NicNps combined with Gem overcame therapy resistance by synergistically reducing tumor hypoxia and HIF-1α-driven metabolic reprogramming. These findings highlight NicNps as a mitochondria-targeted, nanoparticle-based therapy that enhances Nic's bioavailability while suppressing HIF-1α-driven adaptations. NicNps in combination with Gem offer a promising strategy to overcome therapy resistance and improve treatment outcomes in patients with pancreatic cancer.
    Keywords:  Cancer; Metabolomics; Pharmacology
    DOI:  https://doi.org/10.1016/j.isci.2025.114088
  11. Elife. 2025 Dec 16. pii: RP103705. [Epub ahead of print]13
    The fate of pyruvate dictates cell growth by modulating cellular redox potential.
    Ashish G Toshniwal, Geanette Lam, Alex J Bott, Ahmad A Cluntun, Rachel Skabelund, Hyuck-Jin Nam, Dona R Wisidagama, Carl S Thummel, Jared Rutter.
      Pyruvate occupies a central node in carbohydrate metabolism such that how it is produced and consumed can optimize a cell for energy production or biosynthetic capacity. This has been primarily studied in proliferating cells, but observations from the post-mitotic Drosophila fat body led us to hypothesize that pyruvate fate might dictate the rapid cell growth observed in this organ during development. Indeed, we demonstrate that augmented mitochondrial pyruvate import prevented cell growth in fat body cells in vivo as well as in cultured mammalian hepatocytes and human hepatocyte-derived cells in vitro. We hypothesize that this effect on cell size was caused by an increase in the NADH/NAD+ ratio, which rewired metabolism toward gluconeogenesis and suppressed the biomass-supporting glycolytic pathway. Amino acid synthesis was decreased, and the resulting loss of protein synthesis prevented cell growth. Surprisingly, this all occurred in the face of activated pro-growth signaling pathways, including mTORC1, Myc, and PI3K/Akt. These observations highlight the evolutionarily conserved role of pyruvate metabolism in setting the balance between energy extraction and biomass production in specialized post-mitotic cells.
    Keywords:  D. melanogaster; cell biology; cell growth; genetics; hepatocytes; human; pyruvate metabolism; redox state; translation
    DOI:  https://doi.org/10.7554/eLife.103705
  12. Cancer Res. 2025 Dec 15.
    Drp1 Interaction with BIP Maintains Mitochondrial Dynamic Equilibrium to Promote Anoikis Resistance and Metastasis in Nasopharyngeal Carcinoma.
    Lili Bao, Keying Li, Yue Fan, Zhen Ge, Yang Zeng, Tian Xia, Qicheng Zhang, Si Pan, Wenhui Chen, Haimeng Yin, Bo You.
      Anoikis resistance is a phenomenon wherein cells survive under anchorage-independent conditions, which is critical for cancer cell dissemination and metastasis. To identify strategies to overcome anoikis resistance, we employed a 3D suspension culture model combined with proteomic screening, identifying a relationship between the dynamin-like protein Drp1 and anoikis resistance in nasopharyngeal carcinoma (NPC). Drp1 facilitated the generation of new mitochondria and the removal of damaged ones by regulating fission and mitophagy, thereby enabling tumor cells to overcome anoikis. Furthermore, the interaction of Drp1 and BIP was enhanced during anoikis resistance, which increased formation of mitochondria-associated endoplasmic reticulum membranes (MAMs) to maintain mitochondrial dynamic equilibrium. Mechanistically, CaMKKβ activated the AMPK-MFF-Drp1 and AMPK-mTOR-Drp1 pathways through O-GlcNAcylation modification, thus recruiting Drp1 to MAMs. Notably, the Drp1-BIP complex served as a prognostic indicator for NPC clinical outcome and metastatic risk. Collectively, these results elucidate a mechanism by which Drp1 regulates anoikis resistance through mitochondrial dynamics and provide a feasible treatment strategy for managing NPC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0622
  13. J Clin Invest. 2025 Dec 15. pii: e194134. [Epub ahead of print]135(24):
    Mitochondrial complex II orchestrates divergent effects in CD4+ and CD8+ T cells.
    Keisuke Seike, Shih-Chun A Chu, Yuichi Sumii, Takashi Ikeda, Meng-Chih Wu, Laure Maneix, Dongchang Zhao, Yaping Sun, Marcin Cieslik, Pavan Reddy.
      Mitochondrial metabolism orchestrates T cell functions, yet the role of specific mitochondrial components in distinct T cell subsets remains poorly understood. Here, we explored the role of mitochondrial complex II (MC II), the only complex from the electron transport chain (ETC) that plays a role in both ETC and metabolism, in regulating T cell functions. Surprisingly, MC II exerts divergent effects on CD4+ and CD8+ T cell activation and function. Using T cell-specific MC II subunit, succinate dehydrogenase A-deficient (SDHA-deficient) mice, we integrated single-cell RNA-seq and metabolic profiling, with in vitro and in vivo T cell functional assays to illuminate these differences. SDHA deficiency induced metabolic changes and remodeled gene expression exclusively in activated T cells. In CD4+ T cells, SDHA loss dampened both oxidative phosphorylation (OXPHOS) and glycolysis, impaired cytokine production, proliferation, and reduced CD4+ T cell-mediated graft-versus-host disease after allogeneic stem cell transplantation (SCT). In contrast, SDHA deficiency in CD8+ T cells reduced OXPHOS but paradoxically upregulated glycolysis and demonstrated enhanced cytotoxic functions in vitro and in vivo. This metabolic reprogramming endowed SDHA-KO CD8+ T cells with superior in vivo antitumor efficacy after immune checkpoint inhibitor therapy and allogeneic SCT. These findings reveal MC II as a bifurcation point for metabolic and functional specialization in CD4+ and CD8+ T cells.
    Keywords:  Bone marrow transplantation; Hematology; Immunology; Metabolism; Mitochondria; T cells
    DOI:  https://doi.org/10.1172/JCI194134
  14. J Biol Chem. 2025 Dec 17. pii: S0021-9258(25)02922-9. [Epub ahead of print] 111070
    The cytochrome c oxidase subunit COX6B1 is required for redox-sensitive early assembly and late stabilization of complex IV.
    Kristýna Čunátová, Marek Vrbacký, Michal Knězů, Alena Pecinová, Lukáš Alán, Josef Houštěk, Erika Fernández-Vizarra, Tomáš Mráček, Petr Pecina.
      COX6B1 is a nuclear-encoded subunit of the human mitochondrial cytochrome c oxidase (cIV) located in its intermembrane space-facing region. The relevance of COX6B1 in mitochondrial physiopathology was highlighted by the missense pathogenic variants associated with cIV deficiency. Despite the assigned COX6B1 role as a late incorporation subunit, the COX6B1 human cell line knock-out (KO) exhibited a total loss of cIV. To get a deeper insight into the mechanisms driving the lack of cIV assembly or destabilization in the absence of COX6B1, we used the COX6B1 KO cell background to express alternative oxidase and COX6B1 pathogenic variants. These analyses uncovered that the COX6B1 subunit is indispensable for redox-sensitive early cIV assembly steps, besides its contribution to the stabilization of cIV in the late assembly stages. In addition, we have evidenced the incorporation of partially assembled cIV modules directly into supercomplex structures, supporting the 'cooperative assembly' model for respiratory chain biogenesis.
    Keywords:  COX; COX6B1; COX6B2; OXPHOS assembly; alternative oxidase; cIV; complex IV; cytochrome c oxidase; mitochondrial deficiency; respiratory chain supercomplexes
    DOI:  https://doi.org/10.1016/j.jbc.2025.111070
  15. EMBO Mol Med. 2025 Dec 19.
    Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
    Márcio Augusto Campos-Ribeiro, Erminia Donnarumma, Hendrik Nolte, Paul Cobine, Elodie Vimont, Dusanka Milenkovic, Juan Diego Hernandez-Camacho, Francina Langa-Vives, Etienne Kornobis, Esthel Pénard, Sonny Yde, Thomas Langer, Véronique Paquis-Flucklinger, Timothy Wai.
      Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause mitochondrial disease. Knock-in mice modeling the human CHCHD10S59L variant associated with ALS-FTD develop a mitochondrial cardiomyopathy driven by CHCHD10 aggregation and activation of the mitochondrial integrated stress response (mtISR). We show that cardiac dysfunction is associated with dual defects originating at the onset of disease: (1) bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using protease-inactive Oma1E324Q/E324Q knock-in mice, we show that blunting mtISR in Chchd10S55L/+ mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment. Proteomic profiling of insoluble mitochondrial proteins in Chchd10S55L/+ mice reveals widespread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria is rescued by the addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Thus, mutant CHCHD10 insolubility compromises metabolic resilience by impairing bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.
    Keywords:  CHCHD10; Cardiomyopathy; Cytochrome c; Mitochondrial Disease; OMA1
    DOI:  https://doi.org/10.1038/s44321-025-00358-5
  16. PLoS Comput Biol. 2025 Dec 18. 21(12): e1013384
    Mechanistically informed machine learning links non-canonical TCA cycle activity to Warburg metabolism and hallmarks of malignancy.
    Lihao Lin, Francesco Lapi, Bruno Giovanni Galuzzi, Marco Vanoni, Lilia Alberghina, Chiara Damiani.
      Cancer cells undergo extensive metabolic rewiring to support growth, survival, and phenotypic plasticity. A non-canonical variant of the tricarboxylic acid (TCA) cycle, characterized by mitochondrial-to-cytosolic citrate export, has emerged as critical for embryonic stem cell differentiation. However, its role in cancer remains poorly understood. Here, we present a two-step computational framework to systematically analyze the activity of this non-canonical TCA cycle across over 500 cancer cell lines and investigate its role in shaping hallmarks of malignancy. First, we applied constraint-based modeling to infer cycle activity, defining two complementary metrics: Cycle Propensity, measuring the likelihood of its engagement in each cell line, and Cycle Flux Intensity, quantifying average flux through the reaction identified as rate-limiting. We identified distinct tumor-specific patterns of pathway utilization. Notably, cells with high Cycle Propensity preferentially reroute cytosolic citrate via aconitase 1 (ACO1) and isocitrate dehydrogenase 1 (IDH1), promoting [Formula: see text]-ketoglutarate ([Formula: see text]KG) and NADPH production. Elevated engagement of this cycle strongly correlated with Warburg-like metabolic shifts, including decreased oxygen consumption and increased lactate secretion. In the second step, to uncover non-metabolic transcriptional signatures associated with non-canonical TCA cycle activity, we performed machine learning-based feature selection using ElasticNet and XGBoost, identifying robust gene signatures predictive of cycle activity. Over-representation analysis revealed enrichment in genes involved in metastatic behavior, angiogenesis, stemness, and key oncogenic signaling. SHapley Additive exPlanations (SHAP) further prioritized genes with the strongest predictive contributions, highlighting candidates for experimental validation. Correlation analysis of DepMap gene-dependency profiles revealed distinct vulnerability patterns associated with non-canonical TCA cycle activity, outlining a characteristic landscape of genetic dependencies. Together, our integrative framework uniting constraint-based metabolic modeling and machine learning systematically reveals how non-canonical TCA cycle dynamics underpin metabolic plasticity and promote malignant traits.
    DOI:  https://doi.org/10.1371/journal.pcbi.1013384
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