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Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients

Mutations in MAPT gene cause multiple neurological disorders, including frontal temporal lobar degeneration and parkinsonism. Increasing evidence indicates impaired mitochondrial homeostasis and mitophagy in patients and disease models of pathogenic MAPT. Here, using MAPT patients’ fibroblasts as a...

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Autores principales: Bharat, Vinita, Hsieh, Chung-Han, Wang, Xinnan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595217/
https://www.ncbi.nlm.nih.gov/pubmed/34805172
http://dx.doi.org/10.3389/fcell.2021.765408
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author Bharat, Vinita
Hsieh, Chung-Han
Wang, Xinnan
author_facet Bharat, Vinita
Hsieh, Chung-Han
Wang, Xinnan
author_sort Bharat, Vinita
collection PubMed
description Mutations in MAPT gene cause multiple neurological disorders, including frontal temporal lobar degeneration and parkinsonism. Increasing evidence indicates impaired mitochondrial homeostasis and mitophagy in patients and disease models of pathogenic MAPT. Here, using MAPT patients’ fibroblasts as a model, we report that disease-causing MAPT mutations compromise early events of mitophagy. By employing biochemical and mitochondrial assays we discover that upon mitochondrial depolarization, the recruitment of LRRK2 and Parkin to mitochondria and degradation of the outer mitochondrial membrane protein Miro1 are disrupted. Using high resolution electron microscopy, we reveal that the contact of mitochondrial membranes with ER and cytoskeleton tracks is dissociated following mitochondrial damage. This membrane dissociation is blocked by a pathogenic MAPT mutation. Furthermore, we provide evidence showing that tau protein, which is encoded by MAPT gene, interacts with Miro1 protein, and this interaction is abolished by pathogenic MAPT mutations. Lastly, treating fibroblasts of a MAPT patient with a small molecule promotes Miro1 degradation following depolarization. Altogether, our results show molecular defects in a peripheral tissue of patients and suggest that targeting mitochondrial quality control may have a broad application for future therapeutic intervention.
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spelling pubmed-85952172021-11-18 Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients Bharat, Vinita Hsieh, Chung-Han Wang, Xinnan Front Cell Dev Biol Cell and Developmental Biology Mutations in MAPT gene cause multiple neurological disorders, including frontal temporal lobar degeneration and parkinsonism. Increasing evidence indicates impaired mitochondrial homeostasis and mitophagy in patients and disease models of pathogenic MAPT. Here, using MAPT patients’ fibroblasts as a model, we report that disease-causing MAPT mutations compromise early events of mitophagy. By employing biochemical and mitochondrial assays we discover that upon mitochondrial depolarization, the recruitment of LRRK2 and Parkin to mitochondria and degradation of the outer mitochondrial membrane protein Miro1 are disrupted. Using high resolution electron microscopy, we reveal that the contact of mitochondrial membranes with ER and cytoskeleton tracks is dissociated following mitochondrial damage. This membrane dissociation is blocked by a pathogenic MAPT mutation. Furthermore, we provide evidence showing that tau protein, which is encoded by MAPT gene, interacts with Miro1 protein, and this interaction is abolished by pathogenic MAPT mutations. Lastly, treating fibroblasts of a MAPT patient with a small molecule promotes Miro1 degradation following depolarization. Altogether, our results show molecular defects in a peripheral tissue of patients and suggest that targeting mitochondrial quality control may have a broad application for future therapeutic intervention. Frontiers Media S.A. 2021-11-03 /pmc/articles/PMC8595217/ /pubmed/34805172 http://dx.doi.org/10.3389/fcell.2021.765408 Text en Copyright © 2021 Bharat, Hsieh and Wang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Bharat, Vinita
Hsieh, Chung-Han
Wang, Xinnan
Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients
title Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients
title_full Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients
title_fullStr Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients
title_full_unstemmed Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients
title_short Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients
title_sort mitochondrial defects in fibroblasts of pathogenic mapt patients
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595217/
https://www.ncbi.nlm.nih.gov/pubmed/34805172
http://dx.doi.org/10.3389/fcell.2021.765408
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