Role of lysosomal function in PINK1 protein biogenesis 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 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 576693647

The projections of our nerve cells, called neurites, can reach astonishing lengths of up to one meter. Mitochondria are transported into these projections to ensure the local supply of ATP. However, mitochondrial damage leads to the production of reactive oxygen species and must be rapidly eliminated by the cell. This occurs through the uptake of damaged mitochondria into an autophagosome via a process called mitophagy. The autophagosome ultimately fuses with a lysosome, where the final degradation of the mitochondrion takes place. Mutations in proteins responsible for recognizing and degrading damaged mitochondria are causally involved in hereditary cases of Parkinson’s disease. One of these proteins is PINK1, which plays a key role in identifying damaged mitochondria. To ensure that neuronal mitochondria always have a supply of the short-lived PINK1 protein, the mRNA encoding PINK1 is transported together with mitochondria into neurites, where it is locally produced. We have demonstrated that PINK1 production specifically occurs at contact sites between mitochondria and lysosomes. Preliminary data suggest that lysosomal damage also impairs PINK1 production. In this proposal, we aim to investigate the role of lysosomes in PINK1 biogenesis. We will compare various pharmacological and genetic disruptions and examine their effects on lysosomal pH, lysosome-associated signaling pathways, and ultimately on PINK1 biogenesis and the detection of damaged mitochondria. Finally, we will study the contact sites between lysosomes and mitochondria, both by modulating already known contact proteins and through a proteomic characterization of these sites. Through this work, we hope to better understand the link between lysosomal and mitochondrial dysfunction in order to develop new theories regarding the onset or treatment of Parkinson’s disease.

• DFG Programme: Research Grants