UCLA researchers have developed two novel small molecule probes, MB-10 and DECA, that attenuate PINK1 and Parkin trafficking in mitochondrial in human cells that provide a new approach to elucidate the mechanisms of mitophagy.
BACKGROUND:
Mitophagy is an important pathway that selectively degrades dysfunctional mitochondria to keep the cell healthy. Neurodegenerative disorders, such as Parkinson’s disease, have been linked to the accumulation of dysfunctional mitochondrial with the loss of functional PTEN-induced kinase I (PINK1) and Parkin, which are genes that play an important role in mitophagy. In healthy mitochondria, PINK1 is imported through the outer membrane and spans the inner mitochondrial membrane, whereas in unhealthy mitochondria, PINK1 cannot be imported into the mitochondria, and accumulations of PINK1 on the outer membrane recruits Parkin to initiate the mitophagy. Loss of function in either of these genes results in accumulation of dysfunctional mitochondria and eventually lead to neuronal death. Although mitophagy pathways are becoming well-characterized, little is known about the molecular mechanisms for PINK1 trafficking in mitochondria and its subsequent recruitment of Parkin. The existing methods to study this pathway focus downstream of PINK1 on Parkin recruitment, and commonly utilize mitochondrial uncouplers. New methods are needed to further characterize the mitophagy pathway.
INNOVATION:
UCLA researchers have developed two novel small molecule probes, MB-10 and DECA, that attenuate PINK1 and Parkin trafficking in mitochondrial in human cells that provide new approach to elucidate the mechanism of mitophagy. MB-10 altered trafficking upon mitochondrial insult such that PINK1 import and subsequent degradation in healthy mitochondria were impaired. On the other hand, DECA treatment promoted the accumulation of PINK1 on the mitochondrial outer membrane, causing subsequent Parkin recruitment and degradation of mitochondrial proteins via mitophagy. DECA does not uncouple or impair mitochondria severely, compared to uncouplers and respiratory inhibitors. These small molecule probes will facilitate studying the induction of PINK1-dependent mitophagy in cells and animal models.
POTENTIAL APPLICATIONS:
• Mitochondrial research tools
ADVANTAGES:
• Targeted inhibitor of the PINK1/Parkin pathway
• Stable and effective small molecule probes
DEVELOPMENT-TO-DATE:
This invention has been developed and tested in vitro.