Authors
Liam P Coyne, Arnav Rana, Xiaowen Wang, Joseph Mauro, Sanaea Bhagwagar, Yumiko Umino, Eduardo C Solessio, Frank Middleton, Xin Jie Chen
Published in
Life science alliance. Volume 10. Issue 1. Epub Nov 10, 2026.
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.
PMID:
43009280
Bibliographic data and abstract were imported from PubMed on 11 Nov 2026.
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