Abstract
The process of mitochondrial fission-fusion has been implicated in diverse neuronal roles including neuronal survival, axon degeneration, and axon regeneration. However, whether increased fission or fusion is beneficial for neuronal health and/or axonal growth is not entirely clear, and is likely situational and cell type-dependent. In searching for mitochondrial fission-fusion regulating proteins for improving axonal growth within the visual system, we uncover that mitochondrial fission process 1,18 kDa (MTP18/MTFP1), a pro-fission protein within the CNS, is critical to maintaining mitochondrial size and volume under normal and injury conditions, in retinal ganglion cells (RGCs). We demonstrate that MTP18’s expression is regulated by transcription factors involved in axonal growth, Kruppel-like factor (KLF) transcription factors-7 and -9, and that knockdown of MTP18 promotes axon growth. This investigation exposes MTP18’s previously unexplored role in regulating mitochondrial fission, implicates MTP18 as a downstream component of axon regenerative signaling, and ultimately lays the groundwork for investigations on the therapeutic efficacy of MTP18 expression suppression during CNS axon degenerative events.
Highlights
Studies have implicated mitochondria as integral components in axon regeneration[7,8,9], with some evidence suggesting a role of mitochondrial fission-fusion in orchestrating these events
Unlike Fis[1] and dynamin related protein-1 (Drp-1) which participate in canonical GTP-dependent outer mitochondrial membrane (OMM) fission, MTP18 localizes within the mitochondria and is thought to coordinate a novel process of inner mitochondrial membrane (IMM) fission with OMM fission[23]
To investigate whether mitochondrial dynamics are involved in CNS axonal growth, we ask whether mitochondrial fission-fusion genes are being regulated by a set of growth suppressive or regenerative transcription factors, the KLFs
Summary
Studies have implicated mitochondria as integral components in axon regeneration[7,8,9], with some evidence suggesting a role of mitochondrial fission-fusion in orchestrating these events. We expand on these observations by presenting evidence for a mechanism in which axonal growth promoting and suppressing factors, KLF7 and -9, respectively, regulate mitochondrial fission and fusion via the expression of a nuclear-encoded mitochondrial gene, MTP18. We find that MTP18 is expressed within the CNS and is detectable at both the RNA and protein level within retinas and RGCs. As a result, here we aim to identify and possibly expand MTP18’s pro-fission role within CNS neurons, and present data implicating this novel protein as a prominent regulator of both mitochondrial size and axonal growth during CNS development and injury conditions
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