Study Rationale: Mitochondrial dysfunction plays an important role in the development and progression of Parkinson’s disease (PD). In healthy cells, when mitochondria become damaged, protein called PINK1 labels the defective mitochondria so they can be removed by a process called mitophagy. In people with PD, PINK1 doesn't perform properly, leading to an accumulation of damaged mitochondria and enhanced cell death. We have discovered that PINK1 associates with mitochondrial proteins called TOM and TIM, forming a supercomplex that may be crucial for PINK1 stability and function. In this project, we will elucidate the biochemical and structural basis of PINK1-TOM-TIM supercomplex formation.
Hypothesis: We hypothesize that stressors such as mitochondrial protein misfolding trigger the formation of the PINK1-TOM-TIM supercomplex; elucidating how this takes place should facilitate the discovery of small molecules that intervene in this process, compounds that could be developed into therapeutic interventions for PD.
Study Design: We have optimized conditions that allow us to purify the intact PINK1-TOM-TIM supercomplex. Now, we aim to determine the three-dimensional structure of this complex at atomic resolution. Characterizing the complex and its components will enhance our understanding of how the complex forms and the role that it plays in mitophagy.
Impact on Diagnosis/Treatment of Parkinson’s disease: Elucidating the structural basis for the PINK1-TOM-TIM supercomplex formation in would help us develop small molecules to modulate PINK1-mediated mitophagy which has wide therapeutic implication on PD.
Next Steps for Development: Solving the structure of this complex would help us reveal some crucial structural targets for therapeutic implications.