Franck Polleux, PhD
Professor
Department of Neuroscience
Columbia University
(January 24, 2017)
Novel Mechanisms Regulating Calcium Homeostasis in Neurons Through Control of Mitochondria Function and Mitochondria-ER Interface
Neurons are a unique type of cell in the body. They have distinct features, the axon and dendrites that allow communication with other neurons. Dr. Polleux and his lab are researching factors involved in the development of these distinct features. He discussed the protein LKB1, which he has shown is necessary for the regulation of an important part of neuronal growth – capturing mitochondria. Mitochondria are structures that generate power for cells. He also discussed the importance of mitochondrial size in the axon and dendrites. Mitochondria are longer in the dendrites than in the axon, and this feature has proven to be important for how the cells communicate with other neurons.
Our laboratory is focusing on the cellular and molecular mechanisms underlying the development of the mammalian brain. Neurons are among the most highly polarized cells in our body. Neurons are truly unique cells with regard to their size and morphological complexity. They are highly compartmentalized elaborating a single long axon (transmitting information to other neurons) and multiple dendrites (that receive thousands of synaptic inputs made by the axons of other neurons). We have identified several new signaling pathways regulating the development of neuronal morphology including axonal and dendritic growth, guidance and branching. My seminar focused on recent advances from our lab in understanding the function of a specific signaling pathway centered around kinase LKB1. LKB1 regulates terminal axon branching through regulation of a novel cell biological step: the capture of mitochondria at presynaptic boutons (Courchet, Lewis et al. Cell 2013). We found that during development, synapses made along the axon (called presynaptic boutons) capture a single mitochondria which seems largely dispensable for ATP production, but plays a critical role in regulating cytoplasmic calcium dynamics during neurotransmitter release (Kwon et al. PLoS Biology 2016).
I also presented preliminary evidence demonstrating the drastic difference in morphology between axonal and dendritic mitochondria in cortical pyramidal neurons. In the dendrites of these large neurons, mitochondria are long (~5-15 microns in length) and form an extended network covering >80% of the dendritic tree. In contrast, axonal mitochondria are small (~1 micron in length) and are mostly localized at presynaptic boutons covering only 5-10% of the total axonal length. This suggested that mitochondrial fission must be dominant in axons, whereas fusion must be dominant in the dendrites of the same neurons. This degree of fission/fusion compartmentalization was never explored before and we identified the mitochondrial fission factor (a Drp1 ‘receptor’ called Mff) that regulates mitochondria size in the axon specifically. Upon knocking down Mff, axonal mitochondria become very long, as observed in dendrites, but they are still trafficked normally and captured presynaptically. We demonstrate that compared to control, these long mitochondria offered a larger volume for calcium uptake and therefore lowered the concentration of cytoplasmic calcium presynaptically during evoked release, significantly lowering presynaptic release probability. Our results demonstrate that in axons, mitochondria size is regulated by a high level of Mff-dependent fission, which plays a critical role in determining their calcium uptake capacity, thereby regulating presynaptic release properties.