bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2026–07–05
two papers selected by
Gavin McStay, Liverpool John Moores University
  1. Disrupted Mitochondrial Copper Homeostasis Promotes Ferroptotic Stress, Senescence and MASLD Progression.
  2. Nucleo-mitochondrial asymmetry profiles the proliferative engine and spatial niche reconstruction in clear cell renal cell carcinoma.
  1. bioRxiv. 2026 Jun 17. pii: 2026.06.15.731916. [Epub ahead of print]
    Disrupted Mitochondrial Copper Homeostasis Promotes Ferroptotic Stress, Senescence and MASLD Progression.
    Niansheng Ren, Liuyang Wang, Rajesh K Dutta, David S Umbaugh, Qiaojuan Zhang, Seh Hoon Oh, Dennis C Ko, Ming Song, Anna Mae Diehl, Kuo Du.
       Background & Aims: Systemic metabolic dysfunction promotes degenerative diseases in many organs, including liver and kidney. The liver is a master regulator of systemic metal ion homeostasis. Hepatic copper deficiency is increasingly observed in metabolic dysfunction associated steatotic liver disease (MASLD) and is associated with greater disease severity and poor outcomes. However, mechanisms linking copper dysregulation to MASLD and its co-morbidities remain poorly defined. We investigated whether impaired mitochondrial copper homeostasis contributes to MASLD-related pathobiology and represents a modifiable therapeutic axis.
    Methods & Results: Using dietary mouse models of MASLD and in vitro systems, we found that dietary copper deficiency induces lipotoxicity and suppresses mitochondrial metabolic programs. MASLD livers exhibited marked depletion of copper, impaired cytochrome c oxidase integrity, and bioenergetic failure. Targeted restoration of mitochondrial copper with the copper ionophore elesclomol normalized copper-handling programs, improved mitochondrial function, and suppressed ferroptotic stress, hepatocyte senescence, and fibroinflammatory remodeling. Mechanistically, reduced expression of the mitochondrial copper transporter SLC25A3 and MT-CO1 disrupted the SLC25A3-SCO1-MT-CO1-CTR1 axis, limited copper uptake and destabilized copper-iron balance, promoting maladaptive cell fate changes. Across multiple human cohorts and mouse models, copper-iron imbalance tracks with MASLD progression, clinical outcomes, and multiple extrahepatic comorbidities; restoring copper homeostasis in mice with MASLD attenuates both liver and kidney inflammation and fibrosis.
    Conclusions: Mitochondrial copper deficiency is a mechanistically actionable driver of MASLD that promotes bioenergetic failure, ferroptosis, senescence and fibroinflammatory damage in the liver and other organs. Targeting copper-centered mitochondrial regulation represents a novel biomarker and therapeutic strategy for MASLD and its systemic complications.
    DOI:  https://doi.org/10.64898/2026.06.15.731916
  2. Front Immunol. 2026 ;17 1838182
    Nucleo-mitochondrial asymmetry profiles the proliferative engine and spatial niche reconstruction in clear cell renal cell carcinoma.
    Shansen Peng, Zhouzhou Xie, Ting Hu, Xia Li, Chunmei Yan, Chuyang Jiang, Huiming Jiang, Guihao Zhang, Nanhui Chen.
       Background: Tumor heterogeneity is the key driver of disease progression and therapeutic resistance in clear cell renal cell carcinoma (ccRCC). Within this landscape, mitochondrial (MT) heterogeneity has emerged as a critical but poorly understood feature. This study identified a specific manifestation of MT heterogeneity termed "nucleo-mitochondrial expression asymmetry (NMA)". It is characterized by a dysregulated burst of mitochondrial DNA (mtDNA)-encoded genes compared to the nuclear genome, marking a pivotal tipping point in tumor proliferation and spatial reconstruction.
    Methods: We employed an integrative multi-omics approach combining single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (stRNA-seq), and mass spectrometry imaging (MSI)-based spatial metabolomics from the Tongji Renal Cell Carcinoma (TJ-RCC) cohort. To identify and characterize the profound NMA malignant subpopulations, we utilized Gaussian Mixture Model (GMM) clustering, CytoTRACE 2 for differentiation potential, and scFEA for metabolic flux inference. We implemented neighborhood and pseudo-spatiotemporal map (pSM) analyses to quantify spatial reconstruction. We validated these findings through mitochondrially encoded cytochrome c oxidase I (MT-CO1) immunohistochemistry (IHC) in an independent cohort of 53 patients.
    Results: We identified a unique malignant subpopulation (C0) defined by NMA, where nucleo-mitochondrial coordination significantly decreased to R = 0.30 compared to R = 0.50 in other clusters. C0 functioned as a proliferative engine, exhibiting the highest ribosomal activity, peak differentiation potential, and concentrated G2M/S-phase activity. Metabolic modeling and MSI revealed that C0-dominant regions act as metabolic hubs, correlating with total metabolic flux (R = 0.631) and the physical accumulation of tricarboxylic acid (TCA) cycle intermediates. Spatially, C0 abundance was highly predictive of global MT gene scores (R = 0.852). As ccRCC progressed, NMA-driven niches underwent a dramatic reconstruction: transitioning from an "immune-active core" in the early stages to stroma-shielded "metabolic islands" in the advanced stages. Furthermore, we observed a resurgence of NMA and the C0 subpopulation in metastatic lesions. Clinical validation confirmed that MT-CO1 protein levels-a histological proxy for NMA-positively correlated with the proliferation marker Ki67 (r = 0.702) and served as an independent prognostic factor for overall survival.
    Conclusion: This study characterized NMA as a hallmark of ccRCC progression and spatial niche reconstruction, offering a novel, clinically actionable framework for metabolic risk stratification via MT-CO1.
    Keywords:  MT-CO1; clear cell renal cell carcinoma; nucleo- mitochondrial asymmetry; scRNA-seq; stRNA-seq
    DOI:  https://doi.org/10.3389/fimmu.2026.1838182
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