Dysregulation of mitochondrial protein biosynthesis by LRRK2

Mitochondria are important components of a cell with various physiological and vital tasks, including energy production and maintenance of a cells metabolism. While the majority of the genetic information is located within a subpart of the cell called nucleus, one very special feature of mitochondria is that they possess their own genetic material. In order to build mitochondrial protein complexes, which are important for energy production, both the genetic code in the nucleus and in mitochondria must be correctly read and translated into proteins, which is called protein biosynthesis. This complex translation process is tightly regulated and highly coordinated between the nucleus and mitochondria. Furthermore, proteins encoded by the genetic material in the nucleus must be subsequently transported into mitochondria. Although a dysregulation of all these processes and their coordinated interplay can lead to various human diseases, the underlying mechanisms are incompletely understood. In this project, we are investigating the role of a human protein called leucin-rich repeat kinase 2 (LRRK2) on the process of mitochondrial protein biosynthesis. LRRK2 is leadingly involved in Parkinsons disease, a disorder of the nervous system, resulting in movement disabilities, but also in dementia and other psychiatric symptoms. Thereby, we aim to elucidate the mechanisms by which LRRK2 affects mitochondrial protein biosynthesis and its interplay with processes in the nucleus. Furthermore, we will investigate how these alterations cause cell death as a major event triggering Parkinsons disease. Of note, we analyse LRRK2-mediated disturbances throughout aging in order to understand how age as a decisive risk factor for Parkinsons disease contributes to LRRK2-caused changes.

Mitochondria are vital parts of our cells that play a major role in energy conversion. Thereby, they utilize oxygen from the air we breathe and metabolites derived from our food to produce ATP, the main form of energy used in our cells. This makes mitochondria the foundation of all oxygen-dependent life on Earth. Interestingly, mitochondria originated as separate organisms and were incorporated into our cells during evolution. Thus, they contain their own DNA, which codes for proteins essential for energy conversion. To ensure that proteins function properly, they are monitored by complex systems in a process known as protein quality control (PQC). PQC ensures accurate protein production, proper transport and placement within the cell, correct folding into functional proteins, and, if necessary, the breakdown of damaged or surplus proteins. This is particularly important for mitochondria, as their oxidative environment can damage proteins and disrupt cellular functions. Indeed, the accumulation of such damage is associated with ageing and can result in age-related diseases, including neurodegenerative disorders like Parkinson's disease. However, many aspects of mitochondrial PQC are still unknown, especially the PQC of proteins encoded by mitochondrial DNA remains enigmatic. In this project, we identified important molecular machines that monitor the production of mitochondrially-encoded proteins. Large multiprotein complexes interact with newly synthesised mitochondrially-encoded proteins early after their production and validate whether these nascent proteins can, in turn, interact with respective helper proteins, so-called assembly factors. If the interaction between all these factors is fully functional, the nascent mitochondrially-encoded proteins can proceed into the assembly of protein complexes important for energy conversion. If this interaction is not successful (e.g., because a nascent mitochondrially-encoded protein was not correctly produced), the newly synthesized protein gets degraded by a protease within the identified PQC machine. Our results provide important first insights into the molecular processes required for PQC of mitochondrially-encoded proteins. We will continue our work to decipher further molecular details of these processes and validate how these PQC mechanisms decline during ageing, potentially resulting in Parkinson's disease. With this ongoing work, we aim to lay the foundation for new therapeutic approaches against age-related cellular decline and neurodegenerative processes.