Abstract
BackgroundThe establishment and maintenance of functional neural connections relies on appropriate distribution and localization of mitochondria in neurites, as these organelles provide essential energy and metabolites. In particular, mitochondria are transported to axons and support local energy production to maintain energy-demanding neuronal processes including axon branching, growth, and regeneration. Additionally, local protein synthesis is required for structural and functional changes in axons, with nuclear-encoded mitochondrial mRNAs having been found localized in axons. However, it remains unclear whether these mRNAs are locally translated and whether the potential translated mitochondrial proteins are involved in the regulation of mitochondrial functions in axons. Here, we aim to further understand the purpose of such compartmentalization by focusing on the role of mitochondrial initiation factor 3 (mtIF3), whose nuclear-encoded transcripts have been shown to be present in axonal growth cones.ResultsWe demonstrate that brain-derived neurotrophic factor (BDNF) induces local translation of mtIF3 mRNA in axonal growth cones. Subsequently, mtIF3 protein is translocated into axonal mitochondria and promotes mitochondrial translation as assessed by our newly developed bimolecular fluorescence complementation sensor for the assembly of mitochondrial ribosomes. We further show that BDNF-induced axonal growth requires mtIF3-dependent mitochondrial translation in distal axons.ConclusionWe describe a previously unknown function of mitochondrial initiation factor 3 (mtIF3) in axonal protein synthesis and development. These findings provide insight into the way neurons adaptively control mitochondrial physiology and axonal development via local mtIF3 translation.
Highlights
The establishment and maintenance of functional neural connections relies on appropriate distribution and localization of mitochondria in neurites, as these organelles provide essential energy and metabolites
brain-derived neurotrophic factor (BDNF) induces local protein synthesis of mitochondrial initiation factor 3 (mtIF3) in axon growth cone We first confirmed that mtIF3 mRNAs were present in both cell bodies and axons of primary hippocampal neurons (Fig. 1a), consistent with a previous report [11]
To examine whether locally translated mtIF3 proteins translocate into mitochondria, we generated a transgene that expresses fluorescent mtIF3 proteins fused to photoconvertible Dendra2 along with mtIF3 untranslated regions (UTRs) (5′UTRmtIF3-mtIF3-Dendra2-3′UTRmtIF3)
Summary
The establishment and maintenance of functional neural connections relies on appropriate distribution and localization of mitochondria in neurites, as these organelles provide essential energy and metabolites. Local protein synthesis is required for structural and functional changes in axons, with nuclear-encoded mitochondrial mRNAs having been found localized in axons. Previous studies have revealed that transcripts of the nuclear-encoded mitochondrial genes can be locally translated in distal axons [10,11,12,13,14]. It is still elusive whether any local synthesis of the nuclear-encoded mitochondrial proteins governs mitochondrial function in axon growth cone
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