Abstract
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.
Highlights
The use of ATP as a universal currency of energy transfer makes this molecule essential for life
Loss of mitochondrial function activates the mitochondrial retrograde signaling pathway resulting in large scale changes in nuclear gene transcription
We identify Ras-ERK-E-twenty six (ETS) signaling as a novel mitochondrial retrograde signaling pathway in the Drosophila nervous system
Summary
The use of ATP as a universal currency of energy transfer makes this molecule essential for life. ATP is generated either by glycolysis in the cytosol, or through the action of the tricarboxylic acid (TCA) cycle and β-oxidation of fatty acids coupled to oxidative phosphorylation (OXPHOS) in mitochondria. The mitochondrial electron transport chain (ETC) couples the transfer of electrons to the pumping of protons into the inter-membrane space [1]. This creates a membrane potential (ΔC), which is used by the mitochondrial ATP synthase to convert ADP to ATP [2]. Under normal aerobic conditions mitochondria use OXPHOS to generate the majority of cellular ATP. Mitochondria metabolize fatty acids, synthesize amino acids, buffer cellular calcium ions (Ca2+), produce the majority of cellular reactive oxygen species, synthesise iron-sulphur clusters and mediate programmed cell death
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