Mitochondrial protein import clogging as a mechanism of disease
- SUNY Upstate Medical University, United States
- University of Freiburg, Germany
- University of Bonn, Germany
Abstract
Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core import machinery. Whether and how the biophysical properties of substrate preproteins affect overall import efficiency is underexplored. Here, we show that protein traffic into mitochondria can be disrupted by amino acid substitutions in a single substrate preprotein. Pathogenic missense mutations in ADP/ATP translocase 1 (ANT1), and its yeast homolog Aac2, cause the protein to accumulate along the protein import pathway, thereby obstructing general protein translocation into mitochondria. This impairs mitochondrial respiration, cytosolic proteostasis and cell viability independent of ANT1's nucleotide transport activity. The mutations act synergistically, as double mutant Aac2/ANT1 cause severe clogging primarily at the Translocase of the Outer Membrane (TOM) complex. This confers extreme toxicity in yeast. In mice, expression of a super-clogger ANT1 variant led to neurodegeneration and an age-dependent dominant myopathy that phenocopy ANT1-induced human disease, suggesting clogging as a mechanism of disease. More broadly, this work implies the existence of uncharacterized amino acid requirements for mitochondrial carrier proteins to avoid clogging and subsequent disease.
Data availability
The small datasets generated in the study are included in the supplemental tables. The RNA-seq data has been deposited to NCBI Gene Expression Omnibus/Sequence Read Archive with the accession number GSE227295.
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Mitochondrial protein import clogging as a mechanism of diseaseNCBI Gene Expression Omnibus, GSE227295.
Article and author information
Author details
Funding
National Institute on Aging (R01AG063499)
- Xin Jie Chen
National Institute on Aging (R01AG061204)
- Xin Jie Chen
National Institute on Aging (F30AG060702)
- Liam P Coyne
Deutsche Forschungsgemeinschaft (project ID 269925409)
- Thomas Becker
Deutsche Forschungsgemeinschaft (BE 4679 2/2)
- Thomas Becker
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (D1600318) of the State University of New York Upstate Medical University. The protocol was approved by the Committee on the Ethics of Animal Experiments of SUNY Upstate Medical University (Permit Number: #268).
Copyright
© 2023, Coyne et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mitochondrial protein import clogging as a mechanism of disease
eLife 12:e84330.
https://doi.org/10.7554/eLife.84330
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