Project Details
Projekt
Interplay between local translation of mitochondrial proteins and proteostasis in neurons
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 541742535
Mitochondrial protein biogenesis in neurons has long been thought to occur only in the somato-dendritic compartment, yet mitochondria are actively transported into axons and dendrites. Indeed, recent reports confirm local biogenesis of mitochondrial proteins far away from the soma. However, it is unknown how mitochondrial import failure is communicated within the extended morphology of neurons and how this affects the local or global proteostasis systems. Given that both mitochondrial dysfunction and defects in proteostasis are central hallmarks of many neurodegenerative diseases, the special biology of neurons may impose challenges not present in other cell types. As an example, the time it takes to travel from the cell body to the axon terminal exceeds the half-life of many short-lived mitochondrial proteins, requiring their local translation. The Harbauer group has recently demonstrated that the local availability of the short-lived mitochondrial kinase PTEN-induced kinase 1 (PINK1) is ensured by the association of its transcript to mitochondria. How the local biogenesis of PINK1 is efficiently orchestrated by cellular signaling and how it reaches mitochondria after synthesis at Mito-ER contact sites remains to be determined. Using PINK1 as a model mitochondrial precursor, in this proposal we aim to understand the dedicated molecular mechanism that is in place to handle locally translated mitochondrial proteins in axons. We also will address the question, whether this mechanism can be used by other mitochondrial precursors and if failure of this mechanism elicits specific stress reactions, in particular on the local proteostasis due to the sequestration of specific chaperones. We will leverage the unique and complementary expertise of our two groups in mitochondrial biology and proteostasis to tackle these questions in a collaborative tandem, using newly developed fluorescent reporters, state-of-the-art cell biological, proteomic and transcriptomic analyses. The findings will advance our understanding of mitochondrial biogenesis and protein quality control in neurons, and serve as a foundation for developing new therapeutic strategies for neurodegenerative proteinopathies.
DFG Programme
Priority Programmes
