Cargando…
Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease
Dysfunction of mitochondria causes defects in oxidative phosphorylation system (OXPHOS) and increased production of reactive oxygen species (ROS) triggering the activation of the cell death pathway that underlies the pathogenesis of aging and various diseases. The process of autophagy to degrade dam...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356288/ https://www.ncbi.nlm.nih.gov/pubmed/30658448 http://dx.doi.org/10.3390/cells8010065 |
_version_ | 1783391498521280512 |
---|---|
author | Lin, Dar-Shong Huang, Yu-Wen Ho, Che-Sheng Hung, Pi-Lien Hsu, Mei-Hsin Wang, Tuan-Jen Wu, Tsu-Yen Lee, Tsung-Han Huang, Zo-Darr Chang, Po-Chun Chiang, Ming-Fu |
author_facet | Lin, Dar-Shong Huang, Yu-Wen Ho, Che-Sheng Hung, Pi-Lien Hsu, Mei-Hsin Wang, Tuan-Jen Wu, Tsu-Yen Lee, Tsung-Han Huang, Zo-Darr Chang, Po-Chun Chiang, Ming-Fu |
author_sort | Lin, Dar-Shong |
collection | PubMed |
description | Dysfunction of mitochondria causes defects in oxidative phosphorylation system (OXPHOS) and increased production of reactive oxygen species (ROS) triggering the activation of the cell death pathway that underlies the pathogenesis of aging and various diseases. The process of autophagy to degrade damaged cytoplasmic components as well as dysfunctional mitochondria is essential for ensuring cell survival. We analyzed the role of autophagy inpatient-specific induced pluripotent stem (iPS) cells generated from fibroblasts of patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with well-characterized mitochondrial DNA mutations and distinct OXPHOS defects. MELAS iPS cells recapitulated the pathogenesis of MELAS syndrome, and showed an increase of autophagy in comparison with its isogenic normal counterpart, whereas mitophagy is very scarce at the basal condition. Our results indicated that the existence of pathogenic mtDNA alone in mitochondrial disease was not sufficient to elicit the degradation of dysfunctional mitochondria. Nonetheless, oxidative insults induced bulk macroautophagy with the accumulation of autophagosomes and autolysosomes upon marked elevation of ROS, overload of intracellular calcium, and robust depolarization of mitochondrial membrane potential, while mitochondria respiratory function was impaired and widespread mitophagy compromised cell viability. Collectively, our studies provide insights into the dysfunction of autophagy and activation of mitophagy contributing to the pathological mechanism of mitochondrial disease. |
format | Online Article Text |
id | pubmed-6356288 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-63562882019-02-06 Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease Lin, Dar-Shong Huang, Yu-Wen Ho, Che-Sheng Hung, Pi-Lien Hsu, Mei-Hsin Wang, Tuan-Jen Wu, Tsu-Yen Lee, Tsung-Han Huang, Zo-Darr Chang, Po-Chun Chiang, Ming-Fu Cells Article Dysfunction of mitochondria causes defects in oxidative phosphorylation system (OXPHOS) and increased production of reactive oxygen species (ROS) triggering the activation of the cell death pathway that underlies the pathogenesis of aging and various diseases. The process of autophagy to degrade damaged cytoplasmic components as well as dysfunctional mitochondria is essential for ensuring cell survival. We analyzed the role of autophagy inpatient-specific induced pluripotent stem (iPS) cells generated from fibroblasts of patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with well-characterized mitochondrial DNA mutations and distinct OXPHOS defects. MELAS iPS cells recapitulated the pathogenesis of MELAS syndrome, and showed an increase of autophagy in comparison with its isogenic normal counterpart, whereas mitophagy is very scarce at the basal condition. Our results indicated that the existence of pathogenic mtDNA alone in mitochondrial disease was not sufficient to elicit the degradation of dysfunctional mitochondria. Nonetheless, oxidative insults induced bulk macroautophagy with the accumulation of autophagosomes and autolysosomes upon marked elevation of ROS, overload of intracellular calcium, and robust depolarization of mitochondrial membrane potential, while mitochondria respiratory function was impaired and widespread mitophagy compromised cell viability. Collectively, our studies provide insights into the dysfunction of autophagy and activation of mitophagy contributing to the pathological mechanism of mitochondrial disease. MDPI 2019-01-17 /pmc/articles/PMC6356288/ /pubmed/30658448 http://dx.doi.org/10.3390/cells8010065 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lin, Dar-Shong Huang, Yu-Wen Ho, Che-Sheng Hung, Pi-Lien Hsu, Mei-Hsin Wang, Tuan-Jen Wu, Tsu-Yen Lee, Tsung-Han Huang, Zo-Darr Chang, Po-Chun Chiang, Ming-Fu Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease |
title | Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease |
title_full | Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease |
title_fullStr | Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease |
title_full_unstemmed | Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease |
title_short | Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease |
title_sort | oxidative insults and mitochondrial dna mutation promote enhanced autophagy and mitophagy compromising cell viability in pluripotent cell model of mitochondrial disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356288/ https://www.ncbi.nlm.nih.gov/pubmed/30658448 http://dx.doi.org/10.3390/cells8010065 |
work_keys_str_mv | AT lindarshong oxidativeinsultsandmitochondrialdnamutationpromoteenhancedautophagyandmitophagycompromisingcellviabilityinpluripotentcellmodelofmitochondrialdisease AT huangyuwen oxidativeinsultsandmitochondrialdnamutationpromoteenhancedautophagyandmitophagycompromisingcellviabilityinpluripotentcellmodelofmitochondrialdisease AT hochesheng oxidativeinsultsandmitochondrialdnamutationpromoteenhancedautophagyandmitophagycompromisingcellviabilityinpluripotentcellmodelofmitochondrialdisease AT hungpilien oxidativeinsultsandmitochondrialdnamutationpromoteenhancedautophagyandmitophagycompromisingcellviabilityinpluripotentcellmodelofmitochondrialdisease AT hsumeihsin oxidativeinsultsandmitochondrialdnamutationpromoteenhancedautophagyandmitophagycompromisingcellviabilityinpluripotentcellmodelofmitochondrialdisease AT wangtuanjen oxidativeinsultsandmitochondrialdnamutationpromoteenhancedautophagyandmitophagycompromisingcellviabilityinpluripotentcellmodelofmitochondrialdisease AT wutsuyen oxidativeinsultsandmitochondrialdnamutationpromoteenhancedautophagyandmitophagycompromisingcellviabilityinpluripotentcellmodelofmitochondrialdisease AT leetsunghan oxidativeinsultsandmitochondrialdnamutationpromoteenhancedautophagyandmitophagycompromisingcellviabilityinpluripotentcellmodelofmitochondrialdisease AT huangzodarr oxidativeinsultsandmitochondrialdnamutationpromoteenhancedautophagyandmitophagycompromisingcellviabilityinpluripotentcellmodelofmitochondrialdisease AT changpochun oxidativeinsultsandmitochondrialdnamutationpromoteenhancedautophagyandmitophagycompromisingcellviabilityinpluripotentcellmodelofmitochondrialdisease AT chiangmingfu oxidativeinsultsandmitochondrialdnamutationpromoteenhancedautophagyandmitophagycompromisingcellviabilityinpluripotentcellmodelofmitochondrialdisease |