Suppressing the SREBP-mediated lipogenic pathway rescues pink1 deficiency in Drosophila and influences mitochondrial morphology

Sterol-regulatory element binding proteins (SREBP) are master transcriptional factors controlling lipogenesis. In Drosophila, the SREBP-mediated lipogenic pathway is essential for development. Homozygous SREBP mutants are lipid deficient and larval lethal, whereas excessive lipids in flies are often associated with neurodegeneration. Since SREBP has previously been identified as a risk factor for Parkinson's disease, we further investigated the role of SREBP-mediated lipogenesis in a pink1 deficient Drosophila parkinsonism model. We found that expressing either dominant negative SREBP or knocking down its downstream target rescues pink1 mutant phenotypes including thorax indentation and impaired locomotion. Investigation of the indirect flight muscles reveals that suppression of the lipogenic pathway restores defective muscle morphology and mitochondrial defects, and reduces ectopic ROS associated with the pink1 null allele. Interestingly, we found altered mitochondrial morphologies when the lipogenic pathway was manipulated under physiological condition, suggesting the SREBP-mediated lipogenic pathway plays a role in regulating mitochondrial shapes. Our findings highlight the tight connection between lipid metabolism and mitochondria in both disease and physiological setting.