Local translation couples synaptic activity to mitochondrial adaptation in dendrites
- 1The Wertheim UF Scripps Institute
Abstract
Neurons rely on localized protein synthesis to rapidly adapt synaptic function to activity, yet how dendritic translation regulates mitochondrial remodeling during synaptic plasticity remains poorly understood. Here, we show that neuronal activity engages a spatially restricted translational program that couples local protein synthesis to mitochondrial function through the non-canonical translation initiation factor eIF4G2. Using proximity labeling to profile the dendritic RNA interactome, translatome, and proteome, we identify a cohort of nuclear-encoded mitochondrial mRNAs that are selectively recruited for translation following depolarization and mGluR activation. This program drives activity-dependent increases in mitochondrial membrane potential, mitochondrial abundance, and oxygen consumption. Loss of eIF4G2 abolishes these responses, whereas dendrite-specific, but not soma-restricted, rescue restores mitochondrial remodeling, demonstrating that eIF4G2 functions locally at postsynaptic sites. Mechanistically, eIF4G2 binds the 5 prime or minute untranslated regions of activity-responsive mitochondrial transcripts and promotes translation of both upstream open reading frames (uORFs) and downstream coding sequences. Using a dendritically targeted split-GFP reporter, we further show that neuronal activity induces local uORF translation to generate previously unannotated micropeptides. Together, our findings identify eIF4G2-dependent local translation as a mechanism that establishes mitochondrial competence during synaptic activity by coordinating the production of mitochondrial proteins and uORF-encoded micropeptides.
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BibTeX
@misc{jones2026local,
title = {{Local translation couples synaptic activity to mitochondrial adaptation in dendrites}},
author = {M. T. Jones and N. Noble and R. B. Darnell and E. Hacisuleyman},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752159},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752159v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Local translation couples synaptic activity to mitochondrial adaptation in dendrites
AU - M. T. Jones
AU - N. Noble
AU - R. B. Darnell
AU - E. Hacisuleyman
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752159
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752159v1
AB - Neurons rely on localized protein synthesis to rapidly adapt synaptic function to activity, yet how dendritic translation regulates mitochondrial remodeling during synaptic plasticity remains poorly understood. Here, we show that neuronal activity engages a spatially restricted translational program that couples local protein synthesis to mitochondrial function through the non-canonical translation initiation factor eIF4G2. Using proximity labeling to profile the dendritic RNA interactome, translatome, and proteome, we identify a cohort of nuclear-encoded mitochondrial mRNAs that are selectively recruited for translation following depolarization and mGluR activation. This program drives activity-dependent increases in mitochondrial membrane potential, mitochondrial abundance, and oxygen consumption. Loss of eIF4G2 abolishes these responses, whereas dendrite-specific, but not soma-restricted, rescue restores mitochondrial remodeling, demonstrating that eIF4G2 functions locally at postsynaptic sites. Mechanistically, eIF4G2 binds the 5 prime or minute untranslated regions of activity-responsive mitochondrial transcripts and promotes translation of both upstream open reading frames (uORFs) and downstream coding sequences. Using a dendritically targeted split-GFP reporter, we further show that neuronal activity induces local uORF translation to generate previously unannotated micropeptides. Together, our findings identify eIF4G2-dependent local translation as a mechanism that establishes mitochondrial competence during synaptic activity by coordinating the production of mitochondrial proteins and uORF-encoded micropeptides.
ER -