bims-cytox1 2026-01-11 papers

bims-cytox1

Biomed News

on Cytochrome oxidase subunit 1

Issue of 2026–01–11
eight papers selected by
Gavin McStay, Liverpool John Moores University

Mitochondrial presequences harbor variable strengths to maintain organellar function.
LRPPRC-Driven Oxidative Phosphorylation Is Associated with Elesclomol-Induced Cuproptosis in Ovarian Cancer.
Integrative Multi-Omics Analysis and Experiments Validation Identify COX5B as a Novel Therapeutic Target for Lung Adenocarcinoma.
Combined Proteomics and Transcriptomics Analysis: Revealing the Antibacterial Mechanism of 1,3,4-Thiadiazole Metal Complexes.
Local mitochondrial physiology defined by mtDNA quality guides purifying selection.
Therapeutic targeting LRPPRC-Mediated OXPHOS synthesis for cancer intervention.
RLRL Therapeutic Feasibility and Potential Mechanism on Myopia.
When heme is low, copper kills cancer.

J Cell Biol. 2026 Apr 06. pii: e202507116. [Epub ahead of print]225(4):

Mitochondrial presequences harbor variable strengths to maintain organellar function.

Youmian Yan, Baigalmaa Erdenepurev, Thiago N Menezes, Ian Collinson, Natalie M Niemi.

Hundreds of mitochondrial proteins rely on N-terminal presequences for organellar targeting and import. While generally described as positively charged amphiphilic helices, presequences lack a consensus motif and thus likely promote protein import into mitochondria with variable efficiencies. Indeed, the concept of presequence strength underlies biological models such as stress sensing, yet a quantitative analysis of what dictates strong versus weak presequences is lacking. Furthermore, the extent to which presequence strength affects mitochondrial function and cellular fitness remains unclear. Here, we capitalize on the MitoLuc protein import assay to define multiple aspects of presequence strength. We find that select presequences, including those that regulate the mitochondrial unfolded protein response (UPRmt), impart differential import efficiencies during mitochondrial uncoupling. Surprisingly, we find that presequences beyond those associated with stress signaling promote highly variable import efficiency in vitro, suggesting presequence strength may influence a broader array of processes than currently appreciated. We exploit this variability to demonstrate that only presequences that promote robust in vitro import can fully rescue defects in respiratory growth in complex IV-deficient yeast, suggesting that presequence strength dictates metabolic potential. Collectively, our findings demonstrate that presequence strength can describe numerous metrics, such as total imported protein, maximal import velocity, or sensitivity to uncoupling, suggesting that the annotation of presequences as weak or strong requires more nuanced characterization than typically performed. Importantly, we find that such variability in presequence strength meaningfully affects cellular fitness beyond stress signaling, suggesting that organisms may broadly exploit presequence strength to fine-tune mitochondrial import and thus organellar homeostasis.

DOI: https://doi.org/10.1083/jcb.202507116
Int J Mol Sci. 2025 Dec 31. pii: 451. [Epub ahead of print]27(1):

LRPPRC-Driven Oxidative Phosphorylation Is Associated with Elesclomol-Induced Cuproptosis in Ovarian Cancer.

Ying Wu, Wenda Zhang, Shanshan Jiang, Sailong Liu, Jing Su, Liankun Sun.

  Mitochondrial oxidative phosphorylation serves as a critical driving force in the progression of ovarian cancer. Recent studies have demonstrated that copper induces mitochondrial-dependent programmed cell death by directly binding to the thioacylated components of the tricarboxylic acid (TCA) cycle. The involvement of copper in OXPHOS complex IV, a rate-limiting step in the mitochondrial respiratory chain, suggests that the role of mitochondria in mediating copper-induced cell death can be further elucidated through the study of OXPHOS complex IV. The findings of this study indicate that the cuproptosis process in ovarian cancer, induced by Elesclomol, is associated with mitochondrial complex IV, with LRPPRC identified as a crucial factor. Following Elesclomol treatment of ovarian cancer cells, there was a notable increase in mitochondrial reactive oxygen species (ROS), a significant accumulation of the copper death marker protein DLAT, and a marked decrease in the lipoic acid synthesis-related protein FDX1. Furthermore, the expression levels of copper ion transporters ATP7B and CTR1, which are involved in the assembly and translation of complex IV, as well as the core subunit MTCO1 of complex IV, the copper chaperone protein SCO1, and the interacting protein LRPPRC, were significantly diminished. Inhibition of the IV-stabilizing protein LRPPRC in the ovarian cancer cell lines A2780 and SKOV3 through RNA interference resulted in increased sensitivity to Elesclomol. Concurrently, the expression levels of FDX1, LIAS, LIPT1, SCO1, and MTCO1 decreased significantly. These findings suggest that LRPPRC plays a role in inhibiting the expression of lipoic acid and copper chaperone proteins during Elesclomol-induced copper death in ovarian cancer. This inhibition collectively diminishes the expression and activity changes in complex IV, induces mitochondrial dysfunction, and promotes cuproptosis in ovarian cancer. This study further demonstrates that inhibiting the oxidative phosphorylation complex IV can enhance copper-induced cell death in ovarian cancer.

Keywords:  LRPPRC; complex IV; cuproptosis; mitochondria; ovarian cancer

DOI:  https://doi.org/10.3390/ijms27010451
Oncol Res. 2025 ;34(1): 22

Integrative Multi-Omics Analysis and Experiments Validation Identify COX5B as a Novel Therapeutic Target for Lung Adenocarcinoma.

Lv Ling, Minying Lu, Ling Ye, Yuanhang Chen, Sheng Lin, Jun Yang, Yu Rong, Guixiong Wu.

   Background: A significant proportion of patients still cannot benefit from existing targeted therapies and immunotherapies, making the search for new treatment strategies extremely urgent. In this study, we combined integrate public data analysis with experimental validation to identify novel prognostic biomarkers and therapeutic targets for lung adenocarcinoma (LUAD).
Methods: We analyzed RNA and protein databases to assess the expression levels of cytochrome C oxidase 5B (COX5B) in LUAD. Several computational algorithms were employed to investigate the relationship between COX5B and immune infiltration in LUAD. To further elucidate the role of COX5B in LUAD, we utilized multiple experimental approaches, including quantitative reverse transcription PCR assays, western blot, immunohistochemistry, electron microscopy, flow cytometry, and EdU proliferation assays.
Results: We revealed that COX5B was significantly elevated in LUAD and positively correlated with poor prognosis of LUAD patients. Analysis of co-expression network indicated that COX5B may take part in the intracellular adenosine triphosphate (ATP) synthesis through the oxidative phosphorylation pathway. There was a negative correlation between COX5B expression and immune infiltration in LUAD. Furthermore, we validated that COX5B levels were significantly elevated in both LUAD tissues and cell lines. Specifically, immunohistochemistry (IHC) assays revealed a 2.32-fold increase of COX5B in tumor tissues compared to that in adjacent normal tissues (p = 0.0044). Additionally, COX5B knockdown disrupted the redox homeostasis, ultimately suppressed the proliferation of LUAD cells. Subsequent investigations demonstrated that berberine effectively targeted COX5B, diminishing its protein expression and consequently inhibiting cell proliferation and tumor growth in LUAD.
Conclusions: This study established that upregulated COX5B was positive associated with poor patient prognosis in LUAD, elucidating the mechanisms by which berberine targets COX5B to inhibit tumor growth, thereby providing a novel therapeutic target and strategy for the clinical management of LUAD.

Keywords:  Lung adenocarcinoma (LUAD); berberine; cytochrome C oxidase 5B (COX5B); prognosis; proliferation

DOI:  https://doi.org/10.32604/or.2025.069889
J Agric Food Chem. 2026 Jan 07.

Combined Proteomics and Transcriptomics Analysis: Revealing the Antibacterial Mechanism of 1,3,4-Thiadiazole Metal Complexes.

Hongde Li, Jianzhuan Li, Tangbing Yang, Jiao Li, Baoan Song, Deyu Hu.

  Bacterial plant diseases severely threaten agricultural production, necessitating the development of novel and eco-friendly antimicrobial agents. In this study, two thiadiazole metal complexes were rationally designed using a molecular hybridization strategy. Compound T8 displayed outstanding antibacterial activity against Xanthomonas oryzae pv oryzae (Xoo), X. oryzae pv oryzicola (Xoc), and Xanthomonas axonopodis pv citri (Xac) in vitro and in vivo. T8 disrupted bacterial cell wall integrity and enhanced rice defense enzyme activities, effectively inhibiting Xoo proliferation. Integrated proteomic and transcriptomic analyses demonstrated that T8 promoted host mitochondrial respiration and ATP production. Functional experiments revealed that T8 activated the oxidative phosphorylation pathway by enhancing cytochrome c oxidase subunit 6b-1 (COX6b-1) activity. Molecular docking, molecular dynamics simulations, and gene expression analyses further confirmed COX6b-1 as a key mediator. These findings elucidate the molecular basis of T8-induced Xoo resistance and support the development of COX6b-1-protein bactericides.

Keywords:  antibacterial activity; control efficacy; mechanistic studies; metal complexes; molecular docking

DOI:  https://doi.org/10.1021/acs.jafc.5c14020
PLoS Genet. 2026 Jan 09. 22(1): e1011836

Local mitochondrial physiology defined by mtDNA quality guides purifying selection.

Felix Thoma, Johannes Hagen, Romina Rathberger, Francesco Padovani, David Hörl, Kurt M Schmoller, Christof Osman.

The mitochondrial genome (mtDNA) encodes essential subunits of the electron transport chain and ATP synthase. Mutations in these genes impair oxidative phosphorylation, compromise mitochondrial ATP production and cellular energy supply, and can cause mitochondrial diseases. These consequences highlight the importance of mtDNA quality control (mtDNA-QC), the process by which cells selectively maintain intact mtDNA to preserve respiratory function. Here, we developed a high-throughput flow cytometry assay for Saccharomyces cerevisiae to track mtDNA segregation in cell populations derived from heteroplasmic zygotes, in which wild-type (WT) mtDNA is fluorescently labeled and mutant mtDNA remains unlabeled. Using this approach, we observe purifying selection against mtDNA lacking subunits of complex III (COB), complex IV (COX2) or the ATP synthase (ATP6), under fermentative conditions that do not require respiratory activity. By integrating cytometric data with growth assays, qPCR-based mtDNA copy-number measurements, and simulations, we find that the decline of mtDNAΔatp6 in populations derived from heteroplasmic zygotes is largely explained by the combination of its reduced mtDNA copy number-biasing zygotes toward higher contributions of intact mtDNA-and the proliferative disadvantage of cells carrying this variant. In contrast, the loss of mtDNAΔcob and mtDNAΔcox2 cannot be explained by growth defects and copy-number asymmetries alone, indicating an additional intracellular selection against these mutant genomes when intact mtDNA is present. In heteroplasmic cells containing both intact and mutant mtDNA, fluorescent reporters revealed local reductions in ATP levels and membrane potential ([Formula: see text]) near mutant genomes, indicating spatial heterogeneity in mitochondrial physiology that reflects local mtDNA quality. Disruption of the respiratory chain by deletion of nuclear-encoded subunits (RIP1, COX4) abolished these physiological gradients and impaired mtDNA-QC, suggesting that local bioenergetic differences are required for selective recognition. Together, our findings support a model in which yeast cells assess local respiratory function as a proxy for mtDNA integrity, enabling intracellular selection for functional mitochondrial genomes.

DOI: https://doi.org/10.1371/journal.pgen.1011836
Expert Opin Ther Targets. 2026 Jan 05.

Therapeutic targeting LRPPRC-Mediated OXPHOS synthesis for cancer intervention.

Yuxin Liang, Lina Wang, Ziyan Yang, Wenjia Chen, Ruibin Jiang, Dachi Wang, Wenxi Wang, Wei Zhou, Xiaohong Fang.

   INTRODUCTION: Oxidative phosphorylation (OXPHOS) is essential for the progression of tumors and their resistance to therapy. Conventional inhibitors of OXPHOS that directly targeting the electron transport chain (ETC) activity often lack tumor selectivity and demonstrate limited efficacy. Inhibiting mitochondrial gene expression to block the de novo biogenesis of OXPHOS complexes - rather than inhibiting preexisting OXPHOS complexes - represents a more potent and tumor-selective strategy. This strategy highlights leucine-rich pentatricopeptide repeat-containing (LRPPRC) as a promising anticancer target.
AREAS COVERED: Extensive evidence confirms that LRPPRC is commonly overexpressed in various cancer types and is indispensable for maintaining malignant phenotypes. Mechanistically, LRPPRC binds mitochondrial mRNAs (mt-mRNAs) via its pentatricopeptide repeat (PPR) motif-rich RNA-binding domain. By stabilizing mt-mRNA and enhancing its translational efficiency, LRPPRC facilitates OXPHOS complex biogenesis and OXPHOS in tumors. We have developed the first small molecule screening platform targeting LRPPRC. Using this platform, we identified dual-function compounds that both inhibit LRPPRC's RNA-binding function and trigger its proteolytic degradation. These agents demonstrate potent suppression of OXPHOS and exhibit favorable safety profiles across multiple preclinical models.
EXPERT OPINION: Current LRPPRC inhibitors often suffer from suboptimal specificity and binding affinity. Advancing clinical translation requires co-crystal structures of LRPPRC for rational drug design and novel delivery strategies to enhance mitochondrial enrichment of inhibitors.

Keywords:  LRPPRC; OXPHOS; RNA binding protein; small molecular inhibitors; targeted therapy

DOI:  https://doi.org/10.1080/14728222.2025.2608028
Int J Mol Sci. 2025 Dec 31. pii: 428. [Epub ahead of print]27(1):

RLRL Therapeutic Feasibility and Potential Mechanism on Myopia.

Yu-Jiao Chen, In-Chul Jeon, Seung-Sik Cho, Dae-Hun Park.

  Myopia is a major global public health concern, with a particularly high and increasing prevalence in East Asia. Although significant progress has been made in regard to developing strategies to slow the progression of myopia, the precise biological mechanisms underlying the onset and progression of myopia remain unclear. Repeated low-level red light (RLRL) therapy, a novel non-invasive photobiomodulation (PBM) technique, has demonstrated promising efficacy for controlling axial elongation and refractive error progression. This review first outlines the clinical definition, epidemiology, and global health impact of myopia, followed by the etiology-based pathogenesis and corresponding intervention strategies. Special attention has been given to emerging mechanistic evidence supporting RLRL, particularly its role in activating mitochondrial cytochrome c oxidase (CCO), enhancing retinal metabolism, influencing choroidal changes in blood perfusion and thickness, and in scleral remodeling. Finally, the feasibility and potential mechanism of the RLRL therapy for slowing myopia progression have been discussed from the perspective of safety.

Keywords:  myopia; repeated low-level red light (RLRL); therapeutic mechanism

DOI:  https://doi.org/10.3390/ijms27010428
Cell. 2026 Jan 08. pii: S0092-8674(25)01423-0. [Epub ahead of print]189(1): 3-5

When heme is low, copper kills cancer.

Andreas Linkermann.

Heme carries oxygen and is critical for the control of redox reactions. In this issue of Cell, Lewis and Gruber et al. demonstrate how low concentrations of heme destabilize complex IV of the respiratory chain to release copper and kill acute myeloid leukemia cells by cuproptosis.

DOI: https://doi.org/10.1016/j.cell.2025.12.010