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Axons, their growth cones, and synaptic nerve terminals are neuronal subcompartments that have high energetic needs. As such, they are enriched in mitochondria, which supply the ATP necessary to meet these demands. To date, a heterogeneous population of nuclear-encoded mitochondrial mRNAs has been identified in distal axons and growth cones. Accumulating evidence suggests that the local translation of these mRNAs is required for mitochondrial maintenance and axonal viability. Here, we review evidence that suggests a critical role for axonal translation of nuclear-encoded mitochondrial mRNAs in axonal growth and development. Additionally, we explore the role that site-specific translation at the mitochondria itself may play in this process. Finally, we briefly review the clinical implications of dysregulation of local translation of mitochondrial-related mRNAs in neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

In a previous communication, we reported the isolation of a novel cDNA clone (pA6) from a library constructed from squid axonal mRNAs. The partial cDNA clone contained a unique open reading frame that encoded 84 amino acids and was complementary to a moderately abundant mRNA approximately 550-600 nucleotides in length [Chun et al., J. Neurosci. Res. 49 (1997) 144-153]. In this report, we identify the pA6 gene product, and characterize its expression in the squid and rodent brain. Results of immunoblot analyses conducted in squid, using a polyclonal antibody raised against a synthetic peptide corresponding to the C-terminus of the putative protein, established the presence of two pA6 immunoreactive proteins of approximately 14 kDa and 26 kDa in size. In contrast, mouse brain contained only a single 26-kDa immunoreactive species. In both the squid and mouse brain, the expression of pA6 appears highly selective, being detected in certain neurons but not in non-neuronal cells, as judged by both in situ hybridization and immunocytochemistry. Findings derived from light microscopic, double-label immunohistofluorescence studies indicate that pA6 protein co-localizes with prohibitin, a mitochondrial marker protein. Consistent with these results, electron microscopy localized pA6 immunoreactivity to several membrane compartments to include the outer membrane of mitochondria, as well as to the smooth endoplasmic reticulum and tubulovesicles in dendrites, axons, and axon terminals of neurons in the rat brain. Taken together, these findings indicate that pA6 is a novel, membrane-associated protein, which is expressed in the distal structural/functional domains of neurons in both the invertebrate and vertebrate nervous systems.

Previously, we have reported that the squid giant axon contains a heterogeneous population of polyadenylated mRNAs, as well as biologically active polyribosomes. To define the composition of this unique mRNA population, cDNA libraries were constructed to RNA obtained from the axoplasm of the squid giant axon and the parental cell bodies located in the giant fiber lobe. Here, we report that the giant axon contains mRNAs encoding beta-actin and beta-tubulin. The axonal location of these mRNA species was confirmed by in situ hybridization histochemistry, and their presence in the axoplasmic polyribosome fraction was demonstrated by polymerase chain reaction methodology. Taken together, these findings establish the identity of two relatively abundant members of the axonal mRNA population and suggest that key elements of the cytoskeleton are synthesized de novo in the squid giant axon.