Regulation of retrograde mitochondrial transport in axons
Development and maintenance of neural circuits relies on the proper localization and function of mitochondria. While all cells rely on this organelle for energetic support, neurons are uniquely sensitive to disruptions in mitochondrial activity and localization due to their large cell volume and high metabolic demand, particularly in axons. In a forward genetic screen, we identified an actr10 mutant with a specific deficit in retrograde (cell body directed) mitochondrial motility in axons. Using live cell imaging, genetics and biochemistry we demonstrated that Actr10 is necessary for mitochondrial attachment to the dynein-dynactin retrograde motor complex for transport. Genetic complementation studies identified the dynamin-like GTPase Drp1 as a partner with Actr10 in retrograde mitochondrial transport. Despite these advances, it was still unclear how Actr10 interacts with the mitochondrial membrane as neither Actr10 or Drp1 contain membrane-associated domains. To define the mechanistic basis of dynactin-mitochondrial linkage, we performed a mass spectrometry study to identify Actr10 interactors in neurons. This yielded a list of 13 unique Actr10 interacting proteins. Using gene knockdown and gain of function approaches, we are currently testing these interactors for their function in mitochondrial transport. This work will delineate the proteins critical for mitochondrial retrograde transport which will provide valuable insights into how this organelle is properly positioned in axons.
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