Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity

Abstract

SUMMARY 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. While 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.

Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

“…Why mutations in different COQ genes have such distinct effects remains unclear. Tissue-specific differences in gene expression or metabolism-regulated protein-protein interactions may play a role [87, 117]. …”

“…Delivering CoQ to specific cells in need, such as cerebellar Purkinje cells [87], is a major challenge. Exogenous CoQ is efficiently taken up by liver [174, 175], ovarian [176], and brown adipose tissues [177].…”

“…Biochemical fractionation studies localized yeast Coq3p–Coq9p to the mitochondrial matrix and, importantly, showed that they are peripherally associated with the matrix face of the inner membrane [59, 73–84]. An exception to this peripheral association is COQ8A, which has a transmembrane helix [85–87], although its yeast ortholog Coq8p may be peripherally associated [59, 81]. …”

“…Additionally, the COQ2 homolog UBIAD1 localizes to the Golgi membrane, where it supports Golgi CoQ production [28]. Whether the downstream CoQ biosynthesis proteins (COQ3–9) also localize to the Golgi is unclear, but, interestingly, Golgi dysmorphology was observed in mice that lack COQ8A [87]. …”

“…Global mass spectrometry proteomics studies demonstrated that deletion of Coq8a or Coq9 in mice causes selective and significant depletion of numerous COQ proteins [87, 116], not just that encoded by the deleted gene. Furthermore, a mitochondria-focused affinity enrichment mass spectrometry (AE-MS) study revealed a dynamic network of protein-protein interactions between COQ3–COQ9 [117].…”