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Chronic exposure to sub‐lethal beta‐amyloid (Aβ) inhibits the import of nuclear‐encoded proteins to mitochondria in differentiated PC12 cells*
Author(s) -
Sirk Daniel,
Zhu Ziping,
Wadia Jehangir S.,
Shulyakova Natalya,
Phan Nam,
Fong Jamie,
Mills Linda R.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04907.x
Subject(s) - mitochondrion , biology , reactive oxygen species , microbiology and biotechnology , cytoplasm , neurotoxicity , amyloid beta , transfection , biochemistry , medicine , peptide , toxicity , gene
Studies on amyloid beta (Aβ|), the peptide thought to play a crucial role in the pathogenesis of Alzheimer’s disease, have implicated mitochondria in Aβ‐mediated neurotoxicity. We used differentiated PC12 cells stably transfected with an inducible green fluorescent protein (GFP) fusion protein containing an N′‐terminal mitochondrial targeting sequence (mtGFP), to examine the effects of sub‐lethal Aβ on the import of nuclear‐encoded proteins to mitochondria. Exposure to sub‐lethal Aβ 25–35 (10 μmol/L) for 48 h inhibited mtGFP import to mitochondria; average rates decreased by 20 ± 4%. Concomitant with the decline in mtGFP, cytoplasmic mtGFP increased significantly while mtGFP expression and intramitochondrial mtGFP turnover were unchanged. Sub‐lethal Aβ 1–42 inhibited mtGFP import and increased cytoplasmic mtGFP but only after 96 h. The import of two endogenous nuclear‐encoded mitochondrial proteins, mortalin/mtHsp70 and Tom20 also declined. Prior to the decline in import, mitochondrial membrane potential (mmp), and reactive oxygen species levels were unchanged in Aβ‐treated cells versus reverse phase controls. Sustained periods of decreased import were associated with decreased mmp, increased reactive oxygen species, increased vulnerability to oxygen‐glucose deprivation and altered mitochondrial morphology. These findings suggest that an Aβ‐mediated inhibition of mitochondrial protein import, and the consequent mitochondrial impairment, may contribute to Alzheimer’s disease.