Abstract

The mitochondrion is a complex organelle, conserved throughout evolutionary history. Although the mitochondrion contains its own genome, most of the proteins required for function are encoded within the nucleus and need to be imported into mitochondria. As a result, many of these import components are essential for viability, making their study via canonical knockdown methods extremely difficult. To this end, small molecules have been identified that block these proteins temporally. Here I describe the work done to characterize 2 inhibitors of mitochondrial function identified in the laboratory. Through the work done with zebrafish, we show that these drugs affect particular aspects of embryonic development, providing validation for the MitoBloCK compounds as tools for targeted in vivo study, as well as providing information as to the importance and role of mitochondria during embryonic development. Over the past decade neurodegenerative diseases such as Parkinson's disease and Huntington's disease have been found to contain pathological links to mitochondrial dysfunction. Additionally, many known mitochondrial myopathies such as Leigh's syndrome and MERRF have neurodegenerative components. Here we utilize the MitoBloCK compounds to study mitochondrial function and dynamics in motor neuron development. Through small molecule treatment with MitoBloCK-6, an identified inhibitor of mitochondrial import protein ALR, I show that inhibition of ALR results in a significant decrease in the growth and branching of developing zebrafish motor neurons. Additionally, treatment with MitoBloCK-6 drastically reduces the distance and velocity of mitochondrial trafficking within axonal projections. Together, this work illustrates a new method for studying mitochondrial biology in vivo, and highlights the important role mitochondria play in development as a whole, as well as specifically within neuronal environment.