The regulation of mitochondrial dynamics by local protein translation in neurons
Description: Mitochondria perform numerous cellular functions and form a highly dynamic network which rapidly modulates its structure through fission and fusion to meet cellular needs. Disturbances in mitochondrial dynamics have severe bioenergetic consequences in all cells but primarily manifest in neurological disorders. In neurons, mitochondria face particular challenges: thousands of mitochondria have to be distributed throughout the neuronal arbores to account for the high energetic demand of neurons. At the same time, neurons are not renewed over a humans' lifetime, meaning that oxidative damage and mtDNA mutations escaping quality control accumulate over decades. However, little is known about how mitochondrial dynamics ensure lifelong adaptation and rejuvenation of the mitochondrial network. Peripheral fission initiates the selective degradation of dysfunctional mitochondria through mitophagy. Preliminary data from my host lab challenge the traditional view that mitochondria are transported back to the soma for mitophagy, but suggest a local, PINK1-independent degradation mechanism in synapses. Given that local protein synthesis is an important process that enables the polarized functions of neurons, I hypothesize that it also plays a role in mediating mitochondrial dynamics. However, barriers in spatial and temporal imaging resolution have made it difficult to study local protein synthesis in neurons. In this project I will investigate if local protein synthesis is responsible for the local regulation of fission, fusion and mitophagy and how it supports the maintenance of mitochondrial homeostasis in neurons. First, I will study the distribution of the mRNA encoding for mitophagy- and mitochondrial dynamics-related proteins in human iPSC-derived neurons. I will establish single molecule inexpensive fluorescence in situ hybridization combined with super-resolution microscopy to visualize the distribution of multiple RNA species simultaneously with high spatial resolution. After identification of locally translated proteins, I will develop a novel live-cell super-resolution imaging pipeline to characterize the dynamics of local mRNA translation in different neuronal compartments. For this, I will use a SunTag system to fluorescently label nascent polypeptides during mRNA translation and mitochondrial fluorescent probes suited for long-term super resolution imaging. Finally, I will compare local protein translation and mitochondrial dynamics between healthy and aged neurons. For this I will use oxidative stressors to induce cellular senescence in iPSC-derived neurons and image fission events and local translation of proteins using the above-described methods. Ultimately, I will validate our findings in vivo in aged mice in collaboration with Patricia Boya (University of Fribourg). I expect that our results will provide a new perspective on the molecular mechanisms involved in preserving mitochondrial homeostasis in healthy and aged neurons.
Funder: Human Frontier Science Program
Amount:
Funding type: award
Start date: 2026-01-01
End date: 2028-12-31
Investigator: Raluca Groza
Institution: Swiss Federal Institute of Technology in Zurich (ETH Zurich/ETH Zürich)
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 0
Funder award ID: LT0033/2025-L
OpenAlex ID: G3661241989