Mitochondrial protein import stress augments α-synuclein aggregation and neural damage.
Overview
- Department of Biochemistry and Molecular Biology, State University of New York Upstate Medical University, Syracuse, NY, USA
- Center for Vision Research, Department of Ophthalmology, State University of New York Upstate Medical University, Syracuse, NY, USA
- Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, NY, USA
Abstract
Genetic and environmental factors are known to converge on mitochondria to cause Parkinson’s disease. The underlying mechanism is incompletely understood. In addition to bioenergetic defects, nonbioenergetic pathways have been largely unexplored. Validating the nonbioenergetic mitochondrial stressors as independent pathogenic factors is challenging because most mouse models of mitochondrial stress are confounded by bioenergetic defects. Here, we show that expression of Ant1P.A114P,A123D, previously shown to cause mitochondrial protein import clogging in cultured human cells, does not affect the overall bioenergetic capacity, yet it induces proteostatic stress responses in the cytosol that suggests accumulation of unimported precursor proteins. In a Parkinson’s disease model expressing α-synuclein (A53T), Ant1P.A114P,A123D increased the size of α-synuclein aggregates, increased aggregation of mitochondrial preproteins, heightened neuroinflammation, and worsened motor coordination defects. Importantly, we found no evidence of bioenergetic defects in either α-synuclein (A53T) or α-synuclein (A53T) + Ant1P.A114P,A123D mice. These data suggest that Ant1P.A114P,A123D likely induces mitochondrial protein import stress, and contributes to neural damage through cytosolic proteostatic stress and altered aggregation dynamics of neuropathogenic proteins independent of bioenergetics.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
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Data
Datasets cited
- geo:GSE236975, at NCBI GEO; found in “Data Availability”
Data Availability
The RNA-seq and proteomic datasets generated as part of this study are presented as supplemental tables. The data have also been deposited to NCBI Gene Expression Omnibus/
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 12 November 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 15 MeSH terms, 3 funders, 80 references.
Cite
This paper
Coyne, L. P., Rana, A., Wang, X., Mauro, J., Bhagwagar, S., Umino, Y., Solessio, E. C., Middleton, F., & Chen, X. J. (2026). Mitochondrial protein import stress augments α-synuclein aggregation and neural damage. Life science alliance, 10(1), e202603770. https://
BibTeX
@article{coyne2026mitoch
author = {Coyne, Liam P and Rana, Arnav and Wang, Xiaowen and Mauro, Joseph and Bhagwagar, Sanaea and Umino, Yumiko and Solessio, Eduardo C and Middleton, Frank and Chen, Xin Jie},
title = {{Mitochondrial protein import stress augments α-synuclein aggregation and neural damage}},
journal = {Life science alliance},
year = {2026},
month = nov,
volume = {10},
number = {1},
pages = {e202603770},
publisher = {Life Science Alliance LLC},
issn = {2575-1077},
doi = {10.26508/
url = {https://
pmid = {43009280},
pmcid = {PMC13752406}
}
RIS
TY - JOUR
AU - Coyne, Liam P
AU - Rana, Arnav
AU - Wang, Xiaowen
AU - Mauro, Joseph
AU - Bhagwagar, Sanaea
AU - Umino, Yumiko
AU - Solessio, Eduardo C
AU - Middleton, Frank
AU - Chen, Xin Jie
TI - Mitochondrial protein import stress augments α-synuclein aggregation and neural damage
T2 - Life science alliance
J2 - Life Sci Alliance
PY - 2026
DA - 2026/
VL - 10
IS - 1
SP - e202603770
SN - 2575-1077
PB - Life Science Alliance LLC
DO - 10.26508/
UR - https://
LA - en
ER -
CSL-JSON
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