ubiquinone-8 and Seizures

The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease.

Topics: Animals; Behavior, Animal; Cerebellar Ataxia; Cerebellum; Chlorocebus aethiops; COS Cells; Disease Models, Animal; Exercise Tolerance; Female; Genetic Predisposition to Disease; HEK293 Cells; Humans; Lipid Metabolism; Male; Maze Learning; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Models, Molecular; Motor Activity; Muscle Strength; Muscle, Skeletal; Phenotype; Protein Binding; Protein Conformation; Proteomics; Recognition, Psychology; Rotarod Performance Test; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Seizures; Structure-Activity Relationship; Time Factors; Transfection; Ubiquinone

Coenzyme Q(10) (CoQ(10)) plays a pivotal role in oxidative phosphorylation (OXPHOS) in that it distributes electrons between the various dehydrogenases and the cytochrome segments of the respiratory chain. Primary coenzyme Q(10) deficiency represents a clinically heterogeneous condition suggestive of genetic heterogeneity, and several disease genes have been previously identified. The CABC1 gene, also called COQ8 or ADCK3, is the human homolog of the yeast ABC1/COQ8 gene, one of the numerous genes involved in the ubiquinone biosynthesis pathway. The exact function of the Abc1/Coq8 protein is as yet unknown, but this protein is classified as a putative protein kinase. We report here CABC1 gene mutations in four ubiquinone-deficient patients in three distinct families. These patients presented a similar progressive neurological disorder with cerebellar atrophy and seizures. In all cases, enzymological studies pointed to ubiquinone deficiency. CoQ(10) deficiency was confirmed by decreased content of ubiquinone in muscle. Various missense mutations (R213W, G272V, G272D, and E551K) modifying highly conserved amino acids of the protein and a 1 bp frameshift insertion c.[1812_1813insG] were identified. The missense mutations were introduced into the yeast ABC1/COQ8 gene and expressed in a Saccharomyces cerevisiae strain in which the ABC1/COQ8 gene was deleted. All the missense mutations resulted in a respiratory phenotype with no or decreased growth on glycerol medium and a severe reduction in ubiquinone synthesis, demonstrating that these mutations alter the protein function.

Topics: Adolescent; Adult; Amino Acid Sequence; Benzoquinones; Brain; Cerebellar Ataxia; Female; Haplotypes; Humans; Magnetic Resonance Imaging; Male; Molecular Sequence Data; Muscle, Skeletal; Mutation, Missense; Pedigree; Seizures; Ubiquinone