Parkinson’s disease (PD) is a chronic neurodegenerative disease of the brain and affects approximately one million people in the USA. PD patients lose motor control, balance and coordination following loss of dopamine-releasing neurons in the substantia nigra region of the brain. Current PD therapies attempt to alleviate symptoms by augmenting dopaminergic signaling, but there presently is no cure for PD.
The majority of PD cases (85–90%) are sporadic, but 10–15% result from inherited mutations. Three genes associated with inherited forms of the disease, parkin, pink1 and DJ-1, are involved in mitochondrial function, supporting the idea that oxidative damage and/or defective mitochondria may cause the loss of dopaminergic neurons seen in PD.
In this study, the authors identified the previously uncharacterized gene clueless (clu). Flies that are mutant for clu are short-lived, uncoordinated, and male and female sterile. They exhibit structurally abnormal mitochondria in muscle and germ cells, and mislocalized and clustered mitochondria in germ cells. These phenotypes are very similar to those observed in parkin mutants, a Drosophila model for PD. Additionally, clu and parkin interact genetically, thus suggesting that they similarly affect mitochondrial function and movement. The authors hypothesize that both clu and parkin influence the subcellular localization of mitochondria in response to the physiological state of the cell. Mutant clu and the absence of dynamic positioning may therefore lead to impaired mitochondrial function, increased reactive oxygen production, and eventual cell apoptosis owing to mitochondrial damage.
This work identifies a new mechanism linking mitochondrial subcellular localization to mitochondrial function, repair and reactive oxygen output. Since Clu orthologs have highly conserved functions, clu-mediated mitochondrial regulation may have implications for neuronal health and PD in humans. Mutation or misregulation of the human Clu ortholog, KIAA0664, may underlie some heritable and sporadic cases of PD. Further studies of clu are likely to advance our understanding of how mitochondrial dynamics contributes to oxidative damage control. This work also supports the previous notion that altered mitochondrial function may be important in the onset of some cases of PD, and suggests new approaches for therapeutic intervention of disease progression.
