Local translation at mitochondria in neurons

• Applicant: Professorin Dr. Angelika Harbauer
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Molecular and Cellular Neurology and Neuropathology ; Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 453679203

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. The time it takes to travel from the cell body to the axon terminal however exceeds the half-life of many short-lived mitochondrial proteins. As a Post-Doctoral fellow Dr. Harbauer unraveled a neuron-specific mechanism that allows for local synthesis of a particularily short lived mitochondrial protein, PINK1. Transport of the Pink1 mRNA on the mitochondrial surface keeps a steady supply of freshly synthesized PINK1 precursor available. This allows neuronal mitochondria to activate the PINK1/Parkin pathway of mitophagy also far away from the cell body. Transport is mediated by an RNA anchoring complex on the mitochondrial surface formed by the mitochondrial outer membrane protein SYNJ2BP and the RNA binding protein Synaptojanin 2 (SYNJ2). Several lines of evidence connect the RNA anchoring complex to translation and potential contact sites between organelles. SYNJ2BP has been implicated in a novel ER-mitochondria contact site enriched in ribosomes, whereas SYNJ2 also has a role on early endosomes. Likewise, both SYNJ2BP and the translation product of the transported mRNA, PINK1, have multiple interactions with proteins translation factors. One of these interactors, translation initiation factor eIF4G, is potentially linked to familiar forms of Parkinson’s disease (PD), as are mutations in PINK1. It is therefore conceivable, that these interactions play an important role in the integration of mitochondrial fitness with local protein biogenesis at organellar contact sites.We therefore propose to investigate how loss of SYNJ2BP affects local protein biogenesis at mitochondria in neurons. We will therefore investigate the neuron-specific interactome of SYNJ2BP to get the complete picture of SYNJ2BP interacting translation factors. We will then use reporter constructs as well as activity dependent ribosomal stainings and ribosomal foot printing to analyze the role of SYNJ2BP for local translation in vitro and in vivo. In parallel, we will utilize superresolution and electron microscopy to investigate organellar contact sites in SYNJ2BP knock our animals and their role in local translation. Finally, we will use these findings to investigate the effect of local translation stimulation on survival of neurons derived from PD patients.Given the large size of neurons, the local maintenance of mitochondrial health is a key challenge for the cell that contributes to the vulnerability of neurons to mitochondrial insults. By elucidating the locally active mechanisms that allow mitochondrial protein translation locally we aim to uncover novel approaches to improve mitochondrial biogenesis in neurons.

• DFG Programme: Research Grants
• International Connection: USA
• Co-Investigator: Dr. Georg Borner
• Cooperation Partner: Professorin Dr. L. Stirling Churchman