Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. Neuronal mitochondrial dysfunction causes reduced viability, defects in neuronal function, decreased redox potential, and reduced numbers of presynaptic mitochondria and active zones. We find that neuronal mitochondrial dysfunction stimulates a retrograde signaling response that controls the expression of several hundred nuclear genes. We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson’s disease. Thus, mitochondrial retrograde signaling regulates neuronal activity and can be manipulated to enhance neuronal function, despite mitochondrial impairment.
Patients with PDD have a deficiency in mitochondrial complex I activity and reduced mitochondrial DNA levels in the prefrontal cortex without a change in mitochondrial protein quantity. Therefore, mitochondrial complex I deficiency and reduced mitochondrial DNA in the prefrontal cortex may be a hallmark of dementia in patients with PD.
Mitochondrial dysfunction activates the mitochondrial retrograde signaling pathway, resulting in large scale changes in gene expression. Mitochondrial retrograde signaling in neurons is poorly understood and whether retrograde signaling contributes to cellular dysfunction or is protective is unknown. We show that inhibition of Ras-ERK-ETS signaling partially reverses the retrograde transcriptional response to alleviate neuronal mitochondrial dysfunction. We have developed a novel genetic screen to identify genes that modify mitochondrial dysfunction in Drosophila. Knock-down of one of the genes identified in this screen, the Ras-ERK-ETS pathway transcription factor Aop, alleviates the damaging effects of mitochondrial dysfunction in the nervous system. Inhibition of Ras-ERK-ETS signaling also restores function in Drosophila models of human diseases associated with mitochondrial dysfunction. Importantly, Ras-ERK-ETS pathway inhibition partially reverses the mitochondrial retrograde transcriptional response. Therefore, mitochondrial retrograde signaling likely contributes to neuronal dysfunction through mis-regulation of gene expression.
Mitochondrial dysfunction has been suggested to contribute to neurodegenerative diseases, including Alzheimer and Parkinson disease. Cells respond to changes in the functional state of mitochondria via retrograde signaling pathways from the mitochondria to the nucleus, but little is known about retrograde signaling in the nervous system. We have recently shown that inhibition of retrograde signaling reduces the impact of neuronal mitochondrial dysfunction. We performed a study designed to characterize the mitochondrial retrograde signaling pathway in the Drosophila nervous system. Using several different models we found that neuronal specific mitochondrial dysfunction results in defects in synapse development and neuronal function. Moreover, we identified the Drosophila hypoxia inducible factor α (HIFα) ortholog Sima as a key neuronal transcriptional regulator. Knock-down of sima restores function in several Drosophila models of mitochondrial dysfunction, including models of human disease. Here we discuss these findings and speculate on the potential benefits of inhibition of retrograde signaling. We also describe how our results relate to other studies of mitochondrial retrograde signaling and the potential therapeutic applications of these discoveries.
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