ABSTRACT
The prevalence of intellectual disability is around 3%; however, the etiology of the disease remains unclear in most cases. We identified a series of patients with X-linked intellectual disability presenting mutations in the Rad6a (Ube2a) gene, which encodes for an E2 ubiquitin-conjugating enzyme. Drosophila deficient for dRad6 display defective synaptic function as a consequence of mitochondrial failure. Similarly, mouse mRad6a (Ube2a) knockout and patient-derived hRad6a (Ube2a) mutant cells show defective mitochondria. Using in vitro and in vivo ubiquitination assays, we show that RAD6A acts as an E2 ubiquitin-conjugating enzyme that, in combination with an E3 ubiquitin ligase such as Parkin, ubiquitinates mitochondrial proteins to facilitate the clearance of dysfunctional mitochondria in cells. Hence, we identify RAD6A as a regulator of Parkin-dependent mitophagy and establish a critical role for RAD6A in maintaining neuronal function.
Subject(s)
Mental Retardation, X-Linked/genetics , Mitophagy , Ubiquitin-Conjugating Enzymes/genetics , Ubiquitin-Protein Ligases/metabolism , Adolescent , Adult , Animals , Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology , Case-Control Studies , Cell Line , Child , Drosophila , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Exome , Genetic Association Studies , Humans , Kinetics , Male , Membrane Potential, Mitochondrial , Mice , Mice, Knockout , Mitochondria, Muscle/drug effects , Mitochondria, Muscle/physiology , Mutation, Missense , Neuromuscular Junction/metabolism , Pedigree , Sequence Analysis, DNA , Ubiquitin-Conjugating Enzymes/metabolism , Ubiquitination , Uncoupling Agents/pharmacologyABSTRACT
Human UBIAD1 localizes to mitochondria and converts vitamin K(1) to vitamin K(2). Vitamin K(2) is best known as a cofactor in blood coagulation, but in bacteria it is a membrane-bound electron carrier. Whether vitamin K(2) exerts a similar carrier function in eukaryotic cells is unknown. We identified Drosophila UBIAD1/Heix as a modifier of pink1, a gene mutated in Parkinson's disease that affects mitochondrial function. We found that vitamin K(2) was necessary and sufficient to transfer electrons in Drosophila mitochondria. Heix mutants showed severe mitochondrial defects that were rescued by vitamin K(2), and, similar to ubiquinone, vitamin K(2) transferred electrons in Drosophila mitochondria, resulting in more efficient adenosine triphosphate (ATP) production. Thus, mitochondrial dysfunction was rescued by vitamin K(2) that serves as a mitochondrial electron carrier, helping to maintain normal ATP production.
