Neurotransmitter release makes the brain one of the most energy-demanding organs in the human body and because of this, mitochondrial function (e.g. efficient ATP production) is intimately connected to neuronal viability. The neuron's high demand for ATP is not its only hurdle: neurons are extremely long cells in which over 90% of a neuron's volume resides in its axons. What is more, synapses consume the most energy, yet are far from the cell body where the most protein synthesis occurs. Therefore, not only must neurons produce enough mitochondria, but they must also ensure that healthy mitochondria are distributed throughout the cell. It is well-established that mitochondria move in neurons; however, why mitochondria move and the extent to which they move remains controversial. Given the great length of axons, and that mitochondrial proteins have half-lives ranging from several hours to several months, the question arises as to whether mitochondrial proteins are predominantly made in the soma, or whether, and to what extent, mitochondrial proteins are also synthesized in the periphery. Here I propose an approach to label mitochondria in the neuronal soma and track this labeled pool to determine if and to what extent it provides new mitochondria to the neuronal periphery. I also consider the alternative hypothesis, that neurons replenish distal axons with new mitochondrial proteins by local translation of mitochondrial mRNA's. Lastly, I investigate whether these two mechanisms account for peripheral mitochondrial turnover in vivo. These basic questions about how mitochondrial proteins are replenished in distal axons remain open and answering them will provide insight into how neurons maintain a healthy supply of mitochondria.
Defects in mitochondrial health are associated with many neurodegenerative diseases, such as Parkinson's disease and ALS. Neurons are often extremely long cells (extending up to meters in length), and therefore face the particular challenge of ensuring that healthy mitochondria are distributed throughout the whole cell. The goal of this project is to understand the mechanisms by which neurons supply and maintain healthy peripheral mitochondria.
