EXPLORING DROSOPHILA HIFα REGULATION IN NEURONAL MITOCHONDRIAL RETROGRADE SIGNALING

Inherited metabolic disorders are often mitochondrial, and tissues with high metabolic requirements, like the nervous system, are frequently affected, as reported with Alzheimer’s and Parkinson’s disease. Mitochondrial retrograde signaling is a key mechanism of cellular homeostasis and defined as the cellular response to changes in the functional state of mitochondria. This allows for changes in nuclear gene transcription and cellular signaling pathways. Hypoxia inducible factor alpha subunit (HIFα) transcription factor was found to regulate neuronal mitochondrial retrograde signaling in Drosophila. HIFα controls retrograde response genes to reprogram neurons by stopping protein translation and altering cellular metabolic states. In Drosophila larvae, estrogen related receptor (ERR) was discovered to be required for the full complement of HIF responses under hypoxic conditions. It is hypothesized that ERR is required for some/all of HIFα-dependent neuronal mitochondrial retrograde signals. The aims are 1) to investigate the functional impact of ERR in neuronal retrograde signaling under conditions of mitochondrial dysfunction and 2) to investigate if levels of ERR change in conditions of neuronal mitochondrial dysfunction. Climbing and wing inflation assays were done to assess functional impact of ERR-knockdown and immunofluorescence staining was conducted to detect changes in ERR levels under mitochondrial dysfunction conditions. ERR-knockdown driven in motor neurons significantly improves both wing inflation and climbing ability under mitochondrial dysfunction conditions and ERR levels appear to be higher in larval glutamatergic neurons with damaged mitochondria. The results support the claim that ERR may be involved in mitochondrial retrograde signaling and can possibly regulate neuronal activity.