Work from this lab and others has established that mitochondrial motility is governed by a motor/adaptor complex that couples both kinesin and dynein motors to the mitochondrial surface. Much, however, remains unknown about how regulation of that complex determines when and where a mitochondrion will stop, or why some mitochondria are long-term stationary, while others only pause briefly before continuing to move. Anchoring proteins are known that can hold mitochondria in place, but the interplay of anchoring proteins and mitochondrial motors is poorly understood. This proposal seeks to understand mechanisms that regulate the assembly of the motor/adaptor complex and signaling pathways that can turn off those motors. The proposal also seeks to understand when mitochondria are merely passively stationary and when they are being actively held in place by an anchor. The exceptional shapes of neurons makes mitochondrial motility and its regulation particularly important so that the branches of axons and dendrites can be properly supplied with mitochondria and certain locations with high energetic demand, such as synapses, can have increased density of mitochondria. This proposal therefore places special emphasis on how mitochondrial dynamics are regulated in axons and on signals that may localize mitochondria to synapses. To better understand mitochondrial regulation, the proposal introduces two novel approaches. One approach is the misdirection of the mitochondrial motor/adaptor complex to peroxisomes so that assembly and regulation of the complex can be studied and mutated away from the endogenous mitochondrial proteins. The other new approach is to use a heterodimerizing agent to attach a constitutively active kinesin motor to mitochondria and thereby test whether mitochondria are being actively held in place by an anchor. In addition, this proposal introduces two new factors that govern the motility of mitochondria, a protein that anchors mitochondria to the actin cytoskeleton, and a kinase that regulates the localization of mitochondria at synapses.
In Aim 1 we propose to study how a GTPase domain of Miro regulates the ability of the complex to assemble and what physiological significance there is to the GTPase activity.
In Aim 2 we investigate competing models for how elevated Ca2+and the PINK1/Parkin pathway cause mitochondria to stop and ask whether or not they immobilize mitochondria with anchoring proteins.
In Aim 3 we investigate the mechanism by which Aurora kinase B inhibits mitochondrial movement and thereby promotes the localization of mitochondria to synapses.
This proposal seeks to understand signaling mechanisms that can control the stop and go of mitochondria and the anchors that can hold mitochondria in place. Mitochondria are highly dynamic organelles and their ability to move is particularly crucial for supplying energy throughout the axons and dendrites of nerve cells. Among the mechanisms to be studied are a kinase that may instruct mitochondria to become resident at synapses and a signaling pathway that is mutated in forms of Parkinson's disease.
|Misgeld, Thomas; Schwarz, Thomas L (2017) Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture. Neuron 96:651-666|
|Gornstein, Erica L; Schwarz, Thomas L (2017) Neurotoxic mechanisms of paclitaxel are local to the distal axon and independent of transport defects. Exp Neurol 288:153-166|
|Cartoni, Romain; Pekkurnaz, Gulcin; Wang, Chen et al. (2017) A high mitochondrial transport rate characterizes CNS neurons with high axonal regeneration capacity. PLoS One 12:e0184672|
|Su, Cathy; Schwarz, Thomas L (2017) O-GlcNAc Transferase Is Essential for Sensory Neuron Survival and Maintenance. J Neurosci 37:2125-2136|
|Shlevkov, Evgeny; Kramer, Tal; Schapansky, Jason et al. (2016) Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility. Proc Natl Acad Sci U S A 113:E6097-E6106|
|Cartoni, Romain; Norsworthy, Michael W; Bei, Fengfeng et al. (2016) The Mammalian-Specific Protein Armcx1 Regulates Mitochondrial Transport during Axon Regeneration. Neuron 92:1294-1307|
|Chung, Jarom Yan-Ming; Steen, Judith Arunodhaya; Schwarz, Thomas Lewis (2016) Phosphorylation-Induced Motor Shedding Is Required at Mitosis for Proper Distribution and Passive Inheritance of Mitochondria. Cell Rep 16:2142-2155|
|Ashrafi, Ghazaleh; Schwarz, Thomas L (2015) PINK1- and PARK2-mediated local mitophagy in distal neuronal axons. Autophagy 11:187-9|
|Gornstein, Erica; Schwarz, Thomas L (2014) The paradox of paclitaxel neurotoxicity: Mechanisms and unanswered questions. Neuropharmacology 76 Pt A:175-83|
|Ashrafi, Ghazaleh; Schlehe, Julia S; LaVoie, Matthew J et al. (2014) Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol 206:655-70|
Showing the most recent 10 out of 17 publications