TRAK-mediated neuronal mitochondrial trafficking mechanisms: regulation and impact on neuronal function

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Information in our brains is processed by a network of specialized cells, neurons. Neurons are asymmetric. Each has a cell body from which processes known as axons and dendrites emerge. Axons transmit information to other neurons by forming connections (synapses) onto cell bodies or dendrites. Dendrites are extensive processes that receive information from axons. Synaptic transmission, information transfer from axon terminal to dendrites, requires particular proteins and energy in the form of the molecule, ATP. Further the transfer of information from dendrites to cell bodies also requires special proteins and energy. New proteins are mostly synthesized in cell bodies so they have to be trafficked to their correct location. This is transport. It is important for movement of newly synthesized proteins and trafficking of organelles such as mitochondria, the ATP supply of cells. The components of transport are kinesins (motor proteins) which travel along the microtubular network ferrying their cargoes, proteins and organelles. The kinesins do not bind directly to their cargoes but employ adaptor proteins. At any one time, ~ 30% of neuronal mitochondria are mobile moving towards (anterograde) and away from (retrograde) synapses. Mitochondria need to be able to translocate rapidly to areas of high energy demand (synapses) and once there, need to be anchored or "parked". Until recently, we did not know the identity of any of the players that are involved in moving mitochondria. Significant advances have now been made. The Stephenson group identified a family of proteins, the TRAKs, which are the major adaptors involved in their anterograde transport. She used advanced imaging methods to visualize moving mitochondria in axons in cultured neuronal cells and showed that TRAKs are important for mitochondrial movement. TRAKs are present in dendrites too where they are likely to be involved in mitochondrial motility. Having discovered the function of this important family of proteins, we now want to determine the importance of this for proper neuronal function (synaptic transmission and dendritic information processing) in the brain. We plan to investigate this using acute brain slices obtained from adult rodent brain where neuronal network activity is retained together with state-of the art techniques such as electrophysiological recordings from single cells and two photon imaging. We also want to understand further how TRAK-mediated mitochondrial transport is regulated. We have found that an enzyme, N-acetylglucosamine transferase (OGT), is another component of the TRAK/kinesin mitochondrial trafficking complex. OGT is a nutrient sensor. This means that its activity is regulated by metabolic demands. It modifies proteins by addition of a sugar, N-acetylglucosamine. Since mitochondria supply energy it is not unreasonable to hypothesize that the activity of this enzyme may regulate the formation of the kinesin/TRAK/mitochondrial complex to enable mitochondria to traffic to respond to local energy requirements. These are important questions since many neurodegenerative diseases, for example Alzheimer's disease, motor neuron disease and Huntington's disease, for which there are currently no effective treatments have deficits with respect to mitochondrial distribution and function. Deficits in mitochondrial trafficking i.e. appropriate availability of energy sources may be early events compromising neuronal function eventually contributing or even being causal to these diseases. Understanding these basic trafficking mechanisms may contribute towards development of innovative therapies for their treatment.