Dataset Information

Mitochondrial accumulation of amyloid ? (A?) peptides requires TOMM22 as a main A? receptor in yeast.

ABSTRACT: Mitochondrial accumulation of intracellular ?-amyloid (A?) peptides is present in the brains of individuals with Alzheimer's disease (AD) as well as in related mouse models of AD. This accumulation is extremely toxic because A? disrupts the normal functions of many mitochondrial proteins, resulting in significant mitochondrial dysfunction. Therefore, understanding the mitochondrial accumulation of A? is useful for future pharmaceutical design of drugs to address mitochondrial dysfunction in AD. However, the detailed molecular mechanism of this accumulation process remains elusive. Here, using yeast mitochondria, we present direct experimental evidence suggesting that A? is specifically recognized by translocase of outer mitochondrial membrane subunit 22 (Tom22 in yeast; TOMM22 in human), a noncanonical receptor within the mitochondrial protein import machinery, and that this recognition is critical for A? accumulation in mitochondria. Furthermore, we found that residues 25-42 in the A? peptide mediate the specific interaction with TOMM22. On the basis of our findings, we propose that cytosolic A? is recognized by TOMM22; transferred to another translocase subunit, TOMM40; and transported through the TOMM channel into the mitochondria. Our results not only confirm that yeast mitochondria can be used as a model to study mitochondrial dysfunction caused by A? peptides in AD but also pave the way for future studies of the molecular mechanism of mitochondrial A? accumulation.

SUBMITTER: Hu W

PROVIDER: S-EPMC6102147 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Mitochondrial accumulation of amyloid β (Aβ) peptides requires TOMM22 as a main Aβ receptor in yeast.

Hu Wenxin W Wang Zhiming Z Zheng Hongjin H

The Journal of biological chemistry 20180620 33

Mitochondrial accumulation of intracellular β-amyloid (Aβ) peptides is present in the brains of individuals with Alzheimer's disease (AD) as well as in related mouse models of AD. This accumulation is extremely toxic because Aβ disrupts the normal functions of many mitochondrial proteins, resulting in significant mitochondrial dysfunction. Therefore, understanding the mitochondrial accumulation of Aβ is useful for future pharmaceutical design of drugs to address mitochondrial dysfunction in AD. ...[more]

PMID: 29925587

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Project description:Mitochondria are best known as the essential intracellular organelles that host the homeostasis required for cellular survival, but they also have relevance in diverse disease-related conditions, including Alzheimer's disease (AD). Amyloid β (Aβ) peptide is the key molecule in AD pathogenesis, and has been highlighted in the implication of mitochondrial abnormality during the disease progress. Neuronal exposure to Aβ impairs mitochondrial dynamics and function. Furthermore, mitochondrial Aβ accumulation has been detected in the AD brain. However, the underlying mechanism of how Aβ affects mitochondrial function remains uncertain, and it is questionable whether mitochondrial Aβ accumulation followed by mitochondrial dysfunction leads directly to neuronal toxicity. This study demonstrated that an exogenous Aβ(1-42) treatment, when applied to the hippocampal cell line of mice (specifically HT22 cells), caused a deleterious alteration in mitochondria in both morphology and function. A clathrin-mediated endocytosis blocker rescued the exogenous Aβ(1-42)-mediated mitochondrial dysfunction. Furthermore, the mitochondria-targeted accumulation of Aβ(1-42) in HT22 cells using Aβ(1-42) with a mitochondria-targeting sequence induced the identical morphological alteration of mitochondria as that observed in the APP/PS AD mouse model and exogenous Aβ(1-42)-treated HT22 cells. In addition, subsequent mitochondrial dysfunctions were demonstrated in the mitochondria-specific Aβ(1-42) accumulation model, which proved indistinguishable from the mitochondrial impairment induced by exogenous Aβ(1-42)-treated HT22 cells. Finally, cellular toxicity was directly induced by mitochondria-targeted Aβ(1-42) accumulation, which mimics the apoptosis process in exogenous Aβ(1-42)-treated HT22 cells. Taken together, these results indicate that mitochondria-targeted Aβ(1-42) accumulation is the necessary and sufficient condition for Aβ-mediated mitochondria impairments, and leads directly to cellular death rather than along with other Aβ-mediated signaling alterations.

Dataset Information

Mitochondrial accumulation of amyloid ? (A?) peptides requires TOMM22 as a main A? receptor in yeast.

Publications

Mitochondrial accumulation of amyloid β (Aβ) peptides requires TOMM22 as a main Aβ receptor in yeast.

Similar Datasets

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