Researchers have made a significant breakthrough in understanding how a protein assists in the removal of damaged mitochondria from the body, offering promising prospects for future treatments of Parkinson’s disease.
Mitochondria are crucial for cellular energy production and play a vital role in various functions. However, when they become damaged, they can have profound effects on cellular activity and contribute to the development of various diseases.
The process of removing and recycling broken-down mitochondria is called “mitophagy.” Two proteins, PINK1 and Parkin, play essential roles in this process by tagging malfunctioning mitochondria for elimination. In Parkinson’s disease, mutations in these proteins can lead to an accumulation of damaged mitochondria in the brain, causing motor symptoms such as tremors, stiffness, and difficulty with movement.
The recent research, published in Molecular Cell, provides answers to a long-standing mystery about how the protein Optineurin recognises the “tagged” unhealthy mitochondria identified by PINK1 and Parkin. This recognition enables the delivery of these damaged mitochondria to the body’s garbage disposal system.
Associate Professor Michael Lazarou, a Laboratory Head in WEHI’s Ubiquitin Signalling Division, emphasised that this discovery fills a crucial knowledge gap and revolutionises our understanding of this cellular pathway. He explained that until this study, the precise role of Optineurin in initiating the body’s waste disposal process was unknown.
The uniqueness of Optineurin lies in its unconventional way of linking damaged cellular materials to garbage disposal machinery. It plays a critical role in degrading mitochondria through the garbage disposal system driven by PINK1 and Parkin, particularly in the human brain.
Understanding the mechanism by which Optineurin operates provides a framework for targeting PINK1 and Parkin mitophagy in diseases and preventing the accumulation of damaged mitochondria in neurons as we age. This knowledge could significantly benefit people with Parkinson’s disease, which affects over 10 million individuals worldwide, including 80,000 Australians.
The study revealed that Optineurin removes damaged mitochondria by binding to an enzyme called TBK1. From there, TBK1 activates a specific cellular mechanism crucial for generating “garbage bags” around unhealthy mitochondria.
Dr. Thanh Nguyen, the study’s first author, highlighted that Optineurin stands out among other proteins involved in mitochondrial removal since it requires TBK1 to trigger the degradation process. This distinctive feature presents Optineurin and TBK1 as potential drug targets, marking a significant advancement in the search for new Parkinson’s disease treatments.
The ultimate goal is to enhance PINK1/Parkin mitophagy levels, especially in the brain, to more effectively remove damaged mitochondria. The researchers also hope to develop a molecule that mimics Optineurin’s actions, allowing for the removal of damaged mitochondria even without the involvement of PINK1 or Parkin.
Preventing the accumulation of damaged mitochondria in the brain, a significant precursor to Parkinson’s disease would be crucial. While the clinical application of this research is still years away and requires validation and further study, it establishes the foundation for understanding Optineurin’s functionality and the potential of targeting this pathway for future therapeutic interventions.
The study involved collaboration with Professor Sascha Martens’ lab at Max Perutz Labs, University of Vienna and received support from the National Health and Medical Research Council (NHMRC), the Australian Research Council (ARC), the Human Frontiers Science Program and Aligning Science Across Parkinson’s (ASAP) through the Michael J. Fox Foundation for Parkinson’s Research (MJFF).