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bioRxiv · 10.1101/2022.07.06.499030

Mitochondrial complementation occurs in rat hippocampal axons and supports the synaptic vesicle cycle.

Vevea, J. D.·Chapman, E. R.
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Abstract

Mitochondria exert powerful control over cellular physiology, contributing to ion homeostasis, energy production, and metabolite biosynthesis. Mitochondrial trafficking and function are vital to neurons, with organelle impairment or altered morphology observed in every neurodegenerative disorder studied. While this organelle and its biosynthetic products are critical for cellular function, decreased output and/or byproducts (e.g., free radicals), can be harmful, and organelle quality control (QC) mechanisms are required to maintain function and prevent a cascade of damage. Owing to its length and general lack of biosynthetic machinery, the axon is particularly sensitive to damage and there is little consensus regarding the details of mitochondrial QC mechanisms in this compartment. Here we investigate the basal, unstressed behavior of axonal mitochondria, focusing on mitochondrial trafficking and fusion to better understand potential QC mechanisms. We observed size and redox asymmetry of mitochondrial traffic in the axon, suggestive of an active QC mechanism. Importantly, we demonstrate, in detail, biochemical complementation of axonal mitochondria. Upon disruption of mitochondrial fusion, we observed an altered synaptic proteome, presynaptic calcium dyshomeostasis, decreased levels of exocytosis, and a reduction in synaptic vesicle recruitment from the reserve pool during extended stimulation. These results support an active mitochondrial trafficking and fusion related QC process that supports presynaptic physiology. O_LIAnterograde trafficked mitochondria are larger and relatively more reduced than retrograde trafficked mitochondria C_LIO_LIAnterograde mitochondria fuse with and complement resident, stationary, axonal mitochondria C_LIO_LILoss of mitofusin 2 (MFN2) mediated mitochondrial fusion leads to alterations in the synaptic vesicle cycle and decreased reserve pool mobilization C_LI

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Vevea, J. D., Chapman, E. R.. 2022-07-06. Mitochondrial complementation occurs in rat hippocampal axons and supports the synaptic vesicle cycle.. https://doi.org/10.1101/2022.07.06.499030

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