bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2023–06–04
six papers selected by
Gavin McStay, Liverpool John Moores University
  1. Cytochrome c oxidase biogenesis - from translation to early assembly of the core subunit COX1.
  2. PET117 assembly factor stabilizes translation activator TACO1 thereby upregulates mitochondria-encoded cytochrome C oxidase 1 synthesis.
  3. An essential role for an Fe-S cluster protein in the cytochrome c oxidase complex of Toxoplasma parasites.
  4. Parkinsonism in spinocerebellar ataxia with axonal neuropathy caused by adult-onset COA7 variants: a case report.
  5. Expert panel curation of 113 primary mitochondrial disease genes for the Leigh syndrome spectrum.
  6. Structures of Tetrahymena thermophila respiratory megacomplexes on the tubular mitochondrial cristae.
  1. FEBS Lett. 2023 May 29.
    Cytochrome c oxidase biogenesis - from translation to early assembly of the core subunit COX1.
    Sven Dennerlein, Peter Rehling, Ricarda Richter-Dennerlein.
      Mitochondria are the powerhouses of the cell as they produce the majority of ATP with their oxidative phosphorylation (OXPHOS) machinery. The OXPHOS system is composed of the F1 Fo ATP synthase and four mitochondrial respiratory chain complexes, the terminal enzyme of which is the cytochrome c oxidase (complex IV) that transfers electrons to oxygen, generating water. Complex IV comprises of 14 structural subunits of dual genetic origin: while the three core subunits are mitochondrial encoded, the remaining constituents are encoded by the nuclear genome. Hence, the assembly of complex IV requires the coordination of two spatially separated gene expression machinery. Recent efforts elucidated an increasing number of proteins involved in mitochondrial gene expression, which are linked to complex IV assembly. Additionally, several COX1 biogenesis factors have been intensively biochemically investigated and an increasing number of structural snapshots shed light on the organization of macromolecular complexes such as the mitoribosome or the cytochrome c oxidase. Here, we focus on COX1 translation regulation and highlight the advanced understanding of early steps during COX1 assembly and its link to mitochondrial translation regulation.
    Keywords:  COX1; OXPHOS; complex IV; cytochrome c oxidase; mitochondria
    DOI:  https://doi.org/10.1002/1873-3468.14671
  2. Free Radic Biol Med. 2023 May 27. pii: S0891-5849(23)00446-X. [Epub ahead of print]
    PET117 assembly factor stabilizes translation activator TACO1 thereby upregulates mitochondria-encoded cytochrome C oxidase 1 synthesis.
    Qiong Sun, Le Shi, Shuaijun Li, Jialu Li, Ruifen Zhang, Xinghuai Huang, Yongping Shao, Zhihui Feng, Yunhua Peng, Zhiwei Yang, Jiankang Liu, Huadong Liu, Jiangang Long.
      Cytochrome c oxidase, also known as complex IV, facilitates the transfer of electrons from cytochrome c to molecular oxygen, resulting in the production of ATP. The assembly of complex IV is a tightly regulated and intricate process that entails the coordinated synthesis and integration of subunits encoded by the mitochondria and nucleus into a functional complex. Accurate regulation of translation is crucial for maintaining proper mitochondrial function, and defects in this process can lead to a wide range of mitochondrial disorders and diseases. However, the mechanisms governing mRNA translation by mitoribosomes in mammals remain largely unknown. In this study, we elucidate the critical role of PET117, a chaperone protein involved in complex IV assembly, in the regulation of mitochondria-encoded cytochrome c oxidase 1 (COX1) protein synthesis in human cells. Depletion of PET117 reduced mitochondrial oxygen consumption rate and impaired mitochondrial function. PET117 was found to interact with and stabilize translational activator of COX1 (TACO1) and prevent its ubiquitination. TACO1 overexpression rescued the inhibitory effects on mitochondria caused by PET117 deficiency. These findings provide evidence for a novel PET117-TACO1 axis in the regulation of mitochondrial protein expression, and revealed a previously unknown role of PET117 in human cells.
    Keywords:  COX1; Mitochondrion; PET117; Protein stability; TACO1
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.05.023
  3. PLoS Pathog. 2023 Jun 01. 19(6): e1011430
    An essential role for an Fe-S cluster protein in the cytochrome c oxidase complex of Toxoplasma parasites.
    Rachel A Leonard, Yuan Tian, Feng Tan, Giel G van Dooren, Jenni A Hayward.
      The mitochondrial electron transport chain (ETC) of apicomplexan parasites differs considerably from the ETC of the animals that these parasites infect, and is the target of numerous anti-parasitic drugs. The cytochrome c oxidase complex (Complex IV) of the apicomplexan Toxoplasma gondii ETC is more than twice the mass and contains subunits not found in human Complex IV, including a 13 kDa protein termed TgApiCox13. TgApiCox13 is homologous to a human iron-sulfur (Fe-S) cluster-containing protein called the mitochondrial inner NEET protein (HsMiNT) which is not a component of Complex IV in humans. Here, we establish that TgApiCox13 is a critical component of Complex IV in T. gondii, required for complex activity and stability. Furthermore, we demonstrate that TgApiCox13, like its human homolog, binds two Fe-S clusters. We show that the Fe-S clusters of TgApiCox13 are critical for ETC function, having an essential role in mediating Complex IV integrity. Our study provides the first functional characterisation of an Fe-S protein in Complex IV.
    DOI:  https://doi.org/10.1371/journal.ppat.1011430
  4. BMC Neurol. 2023 Jun 01. 23(1): 211
    Parkinsonism in spinocerebellar ataxia with axonal neuropathy caused by adult-onset COA7 variants: a case report.
    Shogo Ouchi, Kazuhiro Ishii, Kenjiro Kosaki, Hisato Suzuki, Mamiko Yamada, Toshiki Takenouchi, Akira Tamaoka.
       BACKGROUND: Individuals with variants of cytochrome c oxidase assembly factor 7 (COA7), a mitochondrial functional-related gene, exhibit symptoms of spinocerebellar ataxia with axonal neuropathy before the age of 20. However, COA7 variants with parkinsonism or adult-onset type cases have not been described.
    CASE PRESENTATION: We report the case of a patient who developed cerebellar symptoms and slowly progressive sensory and motor neuropathy in the extremities, similar to Charcot-Marie-Tooth disease, at age 30, followed by parkinsonism at age 58. Exome analysis revealed COA7 missense mutation in homozygotes (NM_023077.2:c.17A > G, NP_075565.2: p.Asp6Gly). Dopamine transporter single-photon emission computed tomography using a 123I-Ioflupane revealed clear hypo-accumulation in the bilateral striatum. However, 123I-metaiodobenzylguanidine myocardial scintigraphy showed normal sympathetic nerve function. Levodopa administration improved parkinsonism in this patient.
    CONCLUSIONS: COA7 gene variants may have caused parkinsonism in this case because mitochondrial function-related genes, such as parkin and PINK1, are known causative genes in some familial Parkinson's diseases.
    Keywords:  COA7; Charcot-Marie-Tooth disease; Parkinsonism; Spinocerebellar ataxia
    DOI:  https://doi.org/10.1186/s12883-023-03202-w
  5. Ann Neurol. 2023 May 31.
    Expert panel curation of 113 primary mitochondrial disease genes for the Leigh syndrome spectrum.
    NICHD ClinGen U24 Mitochondrial Disease Gene Curation Expert Panel
       OBJECTIVE: Primary mitochondrial diseases (PMDs) are heterogeneous disorders caused by inherited mitochondrial dysfunction. Classically defined neuropathologically as subacute necrotizing encephalomyelopathy, Leigh syndrome spectrum (LSS) is the most frequent manifestation of PMD in children, but may also present in adults. A major challenge for accurate diagnosis of LSS in the genomic medicine era is establishing gene-disease relationships (GDRs) for this syndrome with >100 monogenic causes across both nuclear and mitochondrial genomes.
    METHODS: The Clinical Genome Resource (ClinGen) Mitochondrial Disease Gene Curation Expert Panel (GCEP), comprising 40 international PMD experts, met monthly for 4 years to review GDRs for LSS. The GCEP standardized gene curation for LSS by refining the phenotypic definition, modifying the ClinGen Gene-Disease Clinical Validity Curation Framework to improve interpretation for LSS, and establishing a scoring rubric for LSS.
    RESULTS: The GDR with LSS across the nuclear and mitochondrial genomes was classified as definitive for 31/114 gene-disease relationships curated (27%); moderate for 38 (33%); limited for 43 (38%); and 2 as disputed (2%). Ninety genes were associated with autosomal recessive inheritance, 16 were maternally inherited, 5 autosomal dominant, and 3 X-linked.
    INTERPRETATION: GDRs for LSS were established for genes across both nuclear and mitochondrial genomes. Establishing these GDRs will allow accurate variant interpretation, expedite genetic diagnosis of LSS, and facilitate precision medicine, multi-system organ surveillance, recurrence risk counselling, reproductive choice, natural history studies and eligibility for interventional clinical trials. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ana.26716
  6. Nat Commun. 2023 May 29. 14(1): 2542
    Structures of Tetrahymena thermophila respiratory megacomplexes on the tubular mitochondrial cristae.
    Fangzhu Han, Yiqi Hu, Mengchen Wu, Zhaoxiang He, Hongtao Tian, Long Zhou.
      Tetrahymena thermophila, a classic ciliate model organism, has been shown to possess tubular mitochondrial cristae and highly divergent electron transport chain involving four transmembrane protein complexes (I-IV). Here we report cryo-EM structures of its ~8 MDa megacomplex IV2 + (I + III2 + II)2, as well as a ~ 10.6 MDa megacomplex (IV2 + I + III2 + II)2 at lower resolution. In megacomplex IV2 + (I + III2 + II)2, each CIV2 protomer associates one copy of supercomplex I + III2 and one copy of CII, forming a half ring-shaped architecture that adapts to the membrane curvature of mitochondrial cristae. Megacomplex (IV2 + I + III2 + II)2 defines the relative position between neighbouring half rings and maintains the proximity between CIV2 and CIII2 cytochrome c binding sites. Our findings expand the current understanding of divergence in eukaryotic electron transport chain organization and how it is related to mitochondrial morphology.
    DOI:  https://doi.org/10.1038/s41467-023-38158-5
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