bims-cytox1 2026-04-26 papers

J Biol Chem. 2026 Apr 17. pii: S0021-9258(26)00347-9. [Epub ahead of print] 111475

Molecular analysis of a new patient COX15 mutation provides insight into the etiology of fatal infantile cardioencephalopathy.

Jayda A Carroll-Deaton, Iryna Bohovych, Faith T Emetu, Jonathan V Dietz, Elise D Rivett, Elinor Stanley, Eric L Hegg, Jennifer L Fox, Oleh Khalimonchuk.

Mitochondrial disease can result from mutations in the enzymes responsible for biosynthesis of heme a and hemylation of respiratory complex IV of the electron transport chain, also known as cytochrome c oxidase (CcO). One of these enzymes, which is essential for assembly and function of CcO and thus function of the electron transport chain, is heme a synthase, COX15. A previously unknown fatal missense mutation of COX15, c.232G>A (p.Gly78Arg), was recently described in a case report by Galvão de Oliveira et al. Here, we show that the p.Gly78Arg-mimicking substitution in the homologous Cox15 protein in Saccharomyces cerevisiae (Gly95Arg) causes Cox15 protein instability and recapitulates the CcO defect observed in the patient. We demonstrate that the CcO defect observed with this Cox15 variant stems from insufficient heme a synthesis, and consequently, insufficient CcO hemylation and decreased levels of CcO. Our results provide insights into the etiology of the disease caused by this variant, suggesting that Cox15 protein instability and consequent attenuation of heme a synthase function is the main molecular factor behind the resulting multisystemic mitochondrial disorder in humans.

Keywords: COX15; Cytochrome c oxidase; Heme; Heme A Synthase; Mitochondria; Yeast model

DOI: https://doi.org/10.1016/j.jbc.2026.111475

Front Neurol. 2026 ;17 1793054

Study on Leigh syndrome caused by SURF1 gene mutations and its mechanisms.

Chunmei Wang, Longlong Lin, Yuanfeng Zhang, Simei Wang, Xiaona Luo, Xuqin Chen.

Leigh syndrome (LS) is a prevalent mitochondrial encephalomyopathy in childhood, triggered by mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). The protein encoded by the SURF1 gene localizes to the inner mitochondrial membrane and is involved in the biosynthesis of the cytochrome c oxidase (COX) complex. We enrolled 5 children harboring SURF1 gene variants whose clinical manifestations were highly consistent with LS. The clinical characteristics and potential pathogenic mechanisms of the disease were elucidated by systematic analysis of their clinical data. Among the 5 patients, 4 were female and 1 was male, with ages ranging from 13 months to 2 years and 7 months. Next-generation sequencing (NGS) results revealed 6 variant sites in the SURF1 gene among the 5 patients, of which 2 were known variants and 4 were unreported novel variants, namely c.314-317delTGCC (p.L105Qfs*7), c.588+1_588+3delGTA (splicing), c.655G>T (p.Glu219), and c.515+3G>C. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed on the peripheral blood of 4 patients, and the results demonstrated that the messenger RNA (mRNA) expression level of the SURF1 gene was significantly lower than that in their parents. Using 10 healthy children as controls, we analyzed the ratios of mitochondria-related NADH-ubiquinone oxidoreductase core subunit 1 (ND1), Cytochrome c oxidase subunit I (COX1), Cytochrome c oxidase subunit II (COX2), NADH-ubiquinone oxidoreductase chain 4 (ND4), Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a nuclear reference gene. Mitochondrial DNA content was determined by measuring the ND1/GAPDH ratio using RT-qPCR, and further verified with COX1, COX2, and ND4. These ratios were all significantly decreased, indicating reduced mitochondrial DNA (mtDNA) copy number/mtDNA depletion. Iterative Threading ASSEmbly Refinement (I-TASSER)-based three-dimensional (3D) structural analysis indicated that all 6 variant sites induced alterations in the spatial structure of the SURF1 protein. The SURF1 protein is a hydrophilic protein, protein hydrophobicity and stability analyses showed that the 4 unreported novel variants could reduce the hydrophilicity, increase the hydrophobicity, and decrease the structural stability of the protein. The Saccharomyces cerevisiae Homolog of Yeast 1 (Shy1) domain serves as the key structural basis for SURF1 to exert its mitochondrial functions. We found that all 6 variant sites in the SURF1 gene were located within the Shy1 domain.

Keywords: Chinese children; Leigh syndrome; Shy1 domain; mitochondrial DNA depletion; splice-site variant

DOI: https://doi.org/10.3389/fneur.2026.1793054

Nat Commun. 2026 Apr 21.

Mitochondrial respirasome-like supercomplexes support metabolic flexibility in yeast.

Mazzen H Eldeeb, Zoe Cosner, Andreas Carlström, Jeffri-Noelle Mays, Gabriella F Rodriguez, Jens Berndtsson, Martin Ott, Flavia Fontanesi.

The mitochondrial respiratory chain (MRC) complexes, crucial for aerobic energy transduction in eukaryotes, form conserved higher-order structures called supercomplexes (SCs). The elucidation of SC physiological relevance is critical for our understanding of mitochondrial function and bioenergetics but has been hindered by the limited availability of experimental models isolating SC formation as the sole variable. In baker's yeast, SCs comprise III2IV1 and III2IV2 configurations, which enhance respiratory rates by facilitating cytochrome c diffusion along the SC surface. However, the roles of distinct SC conformations and MRC plasticity remain unclear. To address these questions, we engineered a yeast strain expressing a covalently-linked III2IV2 SC, structurally like the wild-type. Expression of this tethered SC supports robust respiratory activity but selectively impacts cytosolic NADH-driven respiration, due to distinct interactions with the NADH dehydrogenase Nde1. We propose that in yeast mitochondria, substrate-specific respirasome-like SCs contribute to the optimization of electron fluxes and support metabolic flexibility.

DOI: https://doi.org/10.1038/s41467-026-72228-8

Nat Microbiol. 2026 Apr 20.

MoCox6 is a regulator of mitophagy and a druggable target in Magnaporthe oryzae.

Ming-Hua Wu, Ya-Nan Lv, Hui Li, Hui Qian, Yun-Yun Wei, Yun-Ran Zhang, Shuang Liang, Xue-Ming Zhu, Jian-Ping Lu, Maurizio Del Poeta, Zong-Hua Wang, Yong-Hwan Lee, Naweed I Naqvi, Richard A Wilson, Daniel J Klionsky, Fu-Cheng Lin, Xiao-Hong Liu.

Mitophagy is a selective autophagic process that maintains cellular homeostasis by degrading damaged mitochondria and is a promising antifungal target. However, few inner mitochondrial membrane (IMM) regulators of mitophagy are known. Here we identify cytochrome c oxidase subunit 6 (MoCox6) as an IMM regulator in Magnaporthe oryzae that binds MoAtg5 and MoAtg14 following outer mitochondrial membrane rupture to mediate mitophagy. MoSirt5 regulates this process by desuccinylating MoCox6 at K144. Structural analysis revealed that residue D95 at the MoSirt5-MoCox6 interface mediates the dual role of MoCox6 in mitophagy and mitochondrial metabolic competence. Deletion of the COX6 gene significantly reduced vegetative growth and virulence in both M. oryzae and Alternaria alternata. Through high-throughput screening, we identified a small-molecule compound, Pan-RAS-IN-1, which targets MoCox6 to inhibit mitophagy, thereby suppressing M. oryzae virulence. Pan-RAS-IN-1 exhibits broad-spectrum antifungal activity, and its application to rice plants significantly suppressed rice blast incidence.

DOI: https://doi.org/10.1038/s41564-026-02329-z

Biochim Biophys Acta Rev Cancer. 2026 Apr 17. pii: S0304-419X(26)00065-X. [Epub ahead of print] 189593

Mitochondrial respiration supports cancer growth independent of OXPHOS.

Christos Chinopoulos.

Oxidative phosphorylation is a coordinated process yielding ATP, yet its constituent modules can operate autonomously and support oxygen-dependent, non-OXPHOS reactions that serve cellular proliferation, including neoplasia. Furthermore, even with oxygen present and ETC active, ATP synthesis requires surpassing defined thresholds; thus, respiration is not equivalent to phosphorylation. This review surveys mitochondrial pathways that use the ETC with oxygen as the terminal electron acceptor yet decouple respiration from ATP synthesis. These pathways support tumor progression by sustaining mechanistically distinct respiration-supported currencies, states, and signals, including oxidized coenzyme Q, matrix NAD+, mitochondrial membrane potential, transhydrogenase-derived NADPH, the downstream oxidizing capacity of the CIII-cytochrome c-CIV segment, and ROS as context-dependent outputs. These determinants shape de novo purine and pyrimidine biosynthesis, one‑carbon metabolism, shuttling of reducing equivalents, heme and FeS biogenesis, and proline, choline, and sulfide metabolism, revealing targetable nodes in the respiratory redox network. Therapeutic progress is expected from interventions that collapse the underlying infrastructure - particularly at the coenzyme Q-junction and the CIII-cytochrome c-CIV segment - rather than from strategies aimed solely at ATP deprivation.

Keywords: Metabolic rewiring; Nucleotide biosynthesis; Oncometabolism; One‑carbon metabolism; Redox homeostasis; Respiratory chain; Tumor metabolism; Ubiquinone; electron transport chain

DOI: https://doi.org/10.1016/j.bbcan.2026.189593

Phys Med Biol. 2026 Apr 21.

Recent Near-Infrared Approaches to Cytochrome-c-Oxidase Monitoring: A Systematic Review of Instruments and Algorithms.

Robert James Ward, Mamadou Diop, Ilias Tachtsidis, Felipe Orihuela-Espina.

Broadband Near-Infrared Spectroscopy (bNIRS) has emerged as a promising technique for non-invasive monitoring of the redox state of cytochrome-c-oxidase (CCO), a key enzyme in cellular energy production. While early work focused on linear approaches based on the modified Beer-Lambert Law (MBLL), recent decades have seen substantial diversification in both instrumentation and computational strategies. To capture this evolution, we conducted a systematic review following PRISMA guidelines across PubMed, Web of Science, ScienceDirect (limited to the journal NeuroImage), and IEEE Xplore, identifying 35 studies that reported novel hardware or algorithmic approaches to CCO reconstruction. Hardware developments ranged from broadband lamps and supercontinuum lasers to LED and CMOS-based miniaturised systems, reflecting a trade-off between spectral coverage, portability, and sensitivity. Algorithmic innovations encompassed refinements of MBLL, diffusion theory, stochastic Monte Carlo modelling, and emerging machine learning methods, each addressing challenges of scattering, spectral overlap, and low signal-to-noise. Despite progress, the field remains limited by variability in instrumentation, standardised validation protocols, and the inherent weakness of the CCO signal relative to haemoglobin. We conclude that advancing bNIRS toward robust, clinically relevant metabolic monitoring will require integration of wearable system design, high-performance computational modelling, and shared benchmarking datasets. This review provides a structured synthesis of hardware and algorithmic advances, highlighting the underlying physics that govern light-tissue interaction and reconstruction, and identifying key directions for future research at the intersection of optical modelling, biomedical engineering, and translational neuroscience.

Keywords: Algorithms; Broadband Near-Infrared Spectroscopy; Cytochrome-c-Oxidase; Hardware; Review; hyperspectral Near-infrared Spectroscopy

DOI: https://doi.org/10.1088/1361-6560/ae62f3