Regulation of coenzyme Q biosynthesis in yeast: A new complex in the block

González-Mariscal, Isabel; García-Testón, Elena; Padilla, Sergio; Martín-Montalvo, Aléjandro; Pomares-Viciana, Teresa; Vázquez-Fonseca, Luis; Gandolfo-Domínguez, Pablo; Santos-Ocaña, Carlos

doi:10.1002/iub.1243

Cited by 36 publications

(27 citation statements)

References 51 publications

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“…78) Coq8 is a kinase that is involved in complex formation through the phosphorylation of Coq3, Coq5, and Coq7; however, it is unclear whether Coq8 phosphorylates these proteins directly or indirectly. Several lines of evidence indicate that the human CoQ biosynthetic enzymes also form a complex; 66,79) this topic has been comprehensively reviewed by Gonzalez-Mariscal et al 80) …”

Section: Three-dimensional Structures Of Proteins Involved In Coq Synmentioning

confidence: 99%

Biosynthesis of coenzyme Q in eukaryotes

Kawamukai

2016

Bioscience, Biotechnology, and Biochemistry

105

128

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Coenzyme Q (CoQ) is a component of the electron transport chain that participates in aerobic cellular respiration to produce ATP. In addition, CoQ acts as an electron acceptor in several enzymatic reactions involving oxidation-reduction. Biosynthesis of CoQ has been investigated mainly in Escherichia coli and Saccharomyces cerevisiae, and the findings have been extended to various higher organisms, including plants and humans. Analyses in yeast have contributed greatly to current understanding of human diseases related to CoQ biosynthesis. To date, human genetic disorders related to mutations in eight COQ biosynthetic genes have been reported. In addition, the crystal structures of a number of proteins involved in CoQ synthesis have been solved, including those of IspB, UbiA, UbiD, UbiX, UbiI, Alr8543 (Coq4 homolog), Coq5, ADCK3, and COQ9. Over the last decade, knowledge of CoQ biosynthesis has accumulated, and striking advances in related human genetic disorders and the crystal structure of proteins required for CoQ synthesis have been made. This review focuses on the biosynthesis of CoQ in eukaryotes, with some comparisons to the process in prokaryotes.

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Section: Three-dimensional Structures Of Proteins Involved In Coq Synmentioning

confidence: 99%

Biosynthesis of coenzyme Q in eukaryotes

Kawamukai

2016

Bioscience, Biotechnology, and Biochemistry

105

128

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“…Alteration in CoQ levels has also been associated with significant life span extensions in organisms ranging from Saccharomyces cerevisiae to mice (5)(6)(7). In S. cerevisiae (2,8,9), and potentially in higher eukaryotes (10,11), most of the COQ proteins form a biosynthetic complex on the matrix face of the inner mitochondrial membrane. Although the majority of these proteins catalyze chemical modifications to CoQ precursors, the biochemical functions for COQ4, 8, and 9 have yet to be elucidated (8,12,13).…”

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confidence: 99%

Mitochondrial COQ9 is a lipid-binding protein that associates with COQ7 to enable coenzyme Q biosynthesis

Lohman¹,

Forouhar

Beebe

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

111

144

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Coenzyme Q (CoQ) is an isoprenylated quinone that is essential for cellular respiration and is synthesized in mitochondria by the combined action of at least nine proteins (COQ1-9). Although most COQ proteins are known to catalyze modifications to CoQ precursors, the biochemical role of COQ9 remains unclear. Here, we report that a disease-related COQ9 mutation leads to extensive disruption of the CoQ protein biosynthetic complex in a mouse model, and that COQ9 specifically interacts with COQ7 through a series of conserved residues. Toward understanding how COQ9 can perform these functions, we solved the crystal structure of Homo sapiens COQ9 at 2.4 Å. Unexpectedly, our structure reveals that COQ9 has structural homology to the TFR family of bacterial transcriptional regulators, but that it adopts an atypical TFR dimer orientation and is not predicted to bind DNA. Our structure also reveals a lipid-binding site, and mass spectrometry-based analyses of purified COQ9 demonstrate that it associates with multiple lipid species, including CoQ itself. The conserved COQ9 residues necessary for its interaction with COQ7 comprise a surface patch around the lipid-binding site, suggesting that COQ9 might serve to present its bound lipid to COQ7. Collectively, our data define COQ9 as the first, to our knowledge, mammalian TFR structural homolog and suggest that its lipid-binding capacity and association with COQ7 are key features for enabling CoQ biosynthesis.biquinone, also known as coenzyme Q (CoQ), is a lipophilic, redox-active small molecule that is present in nearly every cellular membrane. CoQ is a critical component of the mitochondrial electron transport chain where it shuttles electrons from complexes I and II to complex III. In addition to its vital role in cellular respiration, CoQ is instrumental in cellular antioxidation, extracellular electron transport, and membrane rigidity (1).The de novo biosynthesis of CoQ in eukaryotes takes place in the mitochondrial matrix via the collective action of at least 10 proteins (COQ1-10; Fig. S1) (2). Mutations in these proteins can cause primary CoQ deficiency-a condition associated with cerebellar ataxia, kidney disease, isolated myopathy, and severe childhood-onset multisystemic disorders (3, 4). Alteration in CoQ levels has also been associated with significant life span extensions in organisms ranging from Saccharomyces cerevisiae to mice (5-7). In S. cerevisiae (2, 8, 9), and potentially in higher eukaryotes (10, 11), most of the COQ proteins form a biosynthetic complex on the matrix face of the inner mitochondrial membrane. Although the majority of these proteins catalyze chemical modifications to CoQ precursors, the biochemical functions for COQ4, 8, and 9 have yet to be elucidated (8, 12, 13). Recently, García-Corzo et al. developed a mouse harboring a truncated version of Coq9 (Coq9 R239X)-modeled after a similar mutation observed in a human patient-that causes an encephalomyopathy associated with CoQ deficiency (11,14). A hallmark feature of these mice is a decreas...

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“…The mild biochemical defects in mitochondrial respiratory chain activities, CoQ 10 level and oxidative phosphorylation observed in AOA1 fibroblasts may reflect more severe abnormalities in other tissues, as tissue specificity is frequently observed in mitochondrial disorders including the autosomal recessive cerebellar ataxia caused by ADCK3 mutations, the most common primary CoQ 10 deficiency (43). ADCK3 is an atypical protein kinase that regulated CoQ biosynthesis and is the homolog of coq8 in yeast (44). Previous studies of ADCK3-mutant fibroblasts demonstrated mild CoQ 10 deficiency and mitochondrial respiratory chain defects strikingly similar to those observed in APTXmutant cells, and have slightly increased ROS production and proteins and lipid oxidation when stressed with glucose-free medium (45).…”

Section: Discussionmentioning

confidence: 99%

Lack of aprataxin impairs mitochondrial functions via downregulation of the APE1/NRF1/NRF2 pathway

García-Díaz¹,

Barca

Balreira³

et al. 2015

Hum. Mol. Genet.

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Ataxia oculomotor apraxia type 1 (AOA1) is an autosomal recessive disease caused by mutations in APTX, which encodes the DNA strand-break repair protein aprataxin (APTX). CoQ 10 deficiency has been identified in fibroblasts and muscle of AOA1 patients carrying the common W279X mutation, and aprataxin has been localized to mitochondria in neuroblastoma cells, where it enhances preservation of mitochondrial function. In this study, we show that aprataxin deficiency impairs mitochondrial function, independent of its role in mitochondrial DNA repair. The bioenergetics defect in AOA1-mutant fibroblasts and APTX-depleted Hela cells is caused by decreased expression of SDHA and genes encoding CoQ biosynthetic enzymes, in association with reductions of APE1, NRF1 and NRF2. The biochemical and molecular abnormalities in APTXdepleted cells are recapitulated by knockdown of APE1 in Hela cells and are rescued by overexpression of NRF1/2. Importantly, pharmacological upregulation of NRF1 alone by 5-aminoimidazone-4-carboxamide ribonucleotide does not rescue the phenotype, which, in contrast, is reversed by the upregulation of NRF2 by rosiglitazone. Accordingly, we propose that the lack of aprataxin causes reduction of the pathway APE1/NRF1/NRF2 and their target genes. Our findings demonstrate a critical role of APTX in transcription regulation of mitochondrial function and the pathogenesis of AOA1 via a novel pathomechanistic pathway, which may be relevant to other neurodegenerative diseases.

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Regulation of coenzyme Q biosynthesis in yeast: A new complex in the block

Cited by 36 publications

References 51 publications

Biosynthesis of coenzyme Q in eukaryotes

Biosynthesis of coenzyme Q in eukaryotes

Mitochondrial COQ9 is a lipid-binding protein that associates with COQ7 to enable coenzyme Q biosynthesis

Lack of aprataxin impairs mitochondrial functions via downregulation of the APE1/NRF1/NRF2 pathway

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