Co-transport of the nuclear-encoded Cox7c mRNA with mitochondria along axons occurs through a coding-region-dependent mechanism

Abstract

Nuclear encoded mitochondrial protein mRNAs have been found to be localized and locally translated within neuronal processes. However, the transport mechanism of those mRNAs to distal locations is not fully understood. Here, we describe axonal co-transport of Cox7c with mitochondria. Fractionation analysis and smFISH assay revealed that endogenous mRNA encoding Cox7c is preferentially associated with mitochondria from a neuronal cell line and within primary motor neuron axons, while other mRNAs, which do not encode mitochondrial protein are much less associated. Live cell imaging of MS2-tagged Cox7c mRNA further confirmed the preferential colocalization and co-transport of Cox7c mRNA with mitochondria in motor neuron axons. Intriguingly, the coding region, rather than the 3' UTR, was the key domain for the cotransport. Our results reveal that Cox7c mRNA can be transported with mitochondria along significant distances and its coding region is a major recognition feature. This is consistent with the idea that mitochondria can play a vital role in spatial regulation of the axonal transcriptome at distant neuronal sites.

Axonal ER tubules regulate local translation via P180/RRBP1-mediated ribosome interactions

“…8 Previous studies have shown a role for lysosomes and mitochondria in axonal mRNA localization and translation through RNA granule hitchhiking. [35][36][37][38] The ER forms contacts with many different organelles, including mitochondria and lysosomes, but also with RNA granules. 39,40 We observe that ER tubule disruption reduces local translation, which is caused by impaired ribosome distribution.…”

Looking for answers far away from the soma—the (un)known axonal functions of TDP-43, and their contribution to early NMJ disruption in ALS

“…Moreover, a recent report also demonstrated that the knock-down of TDP-43 disrupts axonal transcriptome and impairs local translation [ 21 ]. Recently, Liao and colleagues have suggested that RNP granules interact with Annexin A11 to hitchhike lysosomes and traffic long distances in axons [ 44 ], while others have indicated that nuclear-encoded mitochondrial mRNA transports into axons on top of mitochondria [ 99 , 100 ]. Cioni et al, have reported that RNP granules and ribosomes associate with late endosomes that anchor axonal mitochondria and serve as a platform for local synthesis of essential mitochondrial proteins [ 101 ].…”

Metabolic Regulation of Mitochondrial Protein Biogenesis from a Neuronal Perspective

“…An emerging concept is the tethering of mRNPs directly onto organelles allowing for mRNA transport along axons and also on-demand local translation in distal parts of the neurons. It has already been demonstrated that mRNPs can hitchhike on mitochondria, early endosomes, late endosomes and lysosomes [ 84 , 85 , 95 , 96 , 97 ]. Since these organelles are being transported back and forth along neurons, hitchhiking represents an ideal, energy efficient way to distribute mRNAs in axons.…”

“…A similar translation dependent mechanism may be tethering the Cox7c (cytochrome c oxidase subunit 7C) transcript to mitochondria. Cox7c mRNA encoding an essential component of the mitochondrial respiratory chain has been demonstrated to be associated and co-transported with mitochondria along axons [ 95 ] ( Figure 2 A). Another recent study has found several mRNAs localized to early endosomes [ 102 ].…”