Zoe Blumenthal

Introduction: Mitochondria are double membrane-bound organelles found in all eukaryotic organisms with an independent genome from the cell’s DNA. Mitochondria serve an important function in the cell to produce ATP energy and regulate cellular metabolism. When responding to stress, the mitochondria utilize complementary pathways to determine cellular fate^1,2,3. Researchers have set out to investigate the mechanism by which mitochondrial dysfunction leads to selective dendritic loss in Drosophila melanogaster Class IV dendritic arbor neurons to investigate the role mitochondrial stress responses could play in neurodegenerative disease⁴. The most recent studies indicate that eIF2alpha is the mediator of neuronal pathology in D. melanogaster and C. elegans models^1,4. While human studies are the next step in establishing the role of signaling pathways of dysfunctional mitochondria in human neurodegenerative diseases, like Parkinson’s, the similarity in the dopamine neurons between Drosophila and human models indicate that the research has the potential of being clinically applicable to human models. Methods: While one team utilized C. elegans models, most researchers utilize the mitochondrial genome of Drosophila melanogaster to investigate the stress response of mitochondria. Teams utilized a variety of strategies to induce mitochondrial stress. For example: exposure to rotenone, myxothiazol treatment, and plasmid induction of transgenic flies with mutations in their mitochondria. The studies utilized imaging methods such as immunostaining for gene expression and antibodies against eIF2alpha.  Results: In the Drosophila melanogaster model based studies, results indicated that ATP depletion was not the direct cause of dendritic loss in class IV neurons, but that P-eIF2alpha-mediated translational repression as a result of mitochondrial dysfunction contributes to dendritic loss in the class IV neurons⁴. The studies also implicated that upon initial time of mitochondrial inhibition, induction of ATF4 is upregulated, a protective effect for the mitochondria, but upon further inhibition of mitochondrial function the ATF4 expression becomes suppressed leading to a pro-apoptotic effect on the cell⁵.  Conclusions: Studies have found that mitochondrial retrograde signaling plays a pivotal role in neuronal health and that manipulation of these signaling pathways can have potential therapeutic benefit in mitochondrial and neuronal degenerative diseases. Cross talk between neuroprotective ATF4 pathways and apoptotic p53 pathways is imperative in determining the cell fate after mitochondrial dysfunction. The pathways that mediate the mitochondrial stress signals, not the subsequent reduction of ATP production, is what contributes to the neuronal loss and dendritic pathogenesis, with the eIF2alpha pathway being indicated as having an important role in the maintenance of mitochondrial function and protein homeostasis.

1. Baker B, Nargund A, Sun T, Haynes C. Protective Coupling of Mitochondrial Function and Protein Synthesis via the eIF2α Kinase GCN-2. PLoS Genetics. 2012;8(6):e1002760. doi:10.1371/journal.pgen.1002760.
2. Cagin U, Duncan O, Gatt A, Dionne M, Sweeney S, Bateman J. Mitochondrial retrograde signaling regulates neuronal function. Proceedings of the National Academy of Sciences. 2015;112(44):E6000-E6009. doi:10.1073/pnas.1505036112.
3. Oruganty-Das A, Ng T, Udagawa T, Goh E, Richter J. Translational Control of Mitochondrial Energy Production Mediates Neuron Morphogenesis. Cell Metabolism. 2012;16(6):789-800. doi:10.1016/j.cmet.2012.11.002.
4. Tsuyama T, Tsubouchi A, Usui T, Imamura H, Uemura T. Mitochondrial dysfunction induces dendritic loss via eIF2α phosphorylation. The Journal of Cell Biology. 2017;216(3):815-834. doi:10.1083/jcb.201604065.
5. Evstafieva A, Garaeva A, Khutornenko A et al. A sustained deficiency of mitochondrial respiratory complex III induces an apoptotic cell death through the p53-mediated inhibition of pro-survival activities of the activating transcription factor 4. Cell Death and Disease. 2014;5(11):e1511. doi:10.1038/cddis.2014.469.