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Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes

The m.3243A>G mutation in mitochondrial tRNA-Leu(UUR) is one of the most common pathogenic mitochondrial DNA mutations in humans. The clinical manifestations are highly heterogenous and the causes for the drastic clinical variability are unknown. Approximately one third of patients suffer from ca...

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Autores principales: Ryytty, Sanna, Modi, Shalem R., Naumenko, Nikolay, Shakirzyanova, Anastasia, Rahman, Muhammad Obaidur, Vaara, Miia, Suomalainen, Anu, Tavi, Pasi, Hämäläinen, Riikka H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9406376/
https://www.ncbi.nlm.nih.gov/pubmed/36010669
http://dx.doi.org/10.3390/cells11162593
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author Ryytty, Sanna
Modi, Shalem R.
Naumenko, Nikolay
Shakirzyanova, Anastasia
Rahman, Muhammad Obaidur
Vaara, Miia
Suomalainen, Anu
Tavi, Pasi
Hämäläinen, Riikka H.
author_facet Ryytty, Sanna
Modi, Shalem R.
Naumenko, Nikolay
Shakirzyanova, Anastasia
Rahman, Muhammad Obaidur
Vaara, Miia
Suomalainen, Anu
Tavi, Pasi
Hämäläinen, Riikka H.
author_sort Ryytty, Sanna
collection PubMed
description The m.3243A>G mutation in mitochondrial tRNA-Leu(UUR) is one of the most common pathogenic mitochondrial DNA mutations in humans. The clinical manifestations are highly heterogenous and the causes for the drastic clinical variability are unknown. Approximately one third of patients suffer from cardiac disease, which often increases mortality. Why only some patients develop cardiomyopathy is unknown. Here, we studied the molecular effects of a high m.3243A>G mutation load on cardiomyocyte functionality, using cells derived from induced pluripotent stem cells (iPSC-CM) of two different m.3243A>G patients, only one of them suffering from severe cardiomyopathy. While high mutation load impaired mitochondrial respiration in both patients’ iPSC-CMs, the downstream consequences varied. mtDNA mutant cells from a patient with no clinical heart disease showed increased glucose metabolism and retained cellular ATP levels, whereas cells from the cardiac disease patient showed reduced ATP levels. In this patient, the mutations also affected intracellular calcium signaling, while this was not true in the other patient’s cells. Our results reflect the clinical variability in mitochondrial disease patients and show that iPSC-CMs retain tissue specific features seen in patients.
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spelling pubmed-94063762022-08-26 Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes Ryytty, Sanna Modi, Shalem R. Naumenko, Nikolay Shakirzyanova, Anastasia Rahman, Muhammad Obaidur Vaara, Miia Suomalainen, Anu Tavi, Pasi Hämäläinen, Riikka H. Cells Article The m.3243A>G mutation in mitochondrial tRNA-Leu(UUR) is one of the most common pathogenic mitochondrial DNA mutations in humans. The clinical manifestations are highly heterogenous and the causes for the drastic clinical variability are unknown. Approximately one third of patients suffer from cardiac disease, which often increases mortality. Why only some patients develop cardiomyopathy is unknown. Here, we studied the molecular effects of a high m.3243A>G mutation load on cardiomyocyte functionality, using cells derived from induced pluripotent stem cells (iPSC-CM) of two different m.3243A>G patients, only one of them suffering from severe cardiomyopathy. While high mutation load impaired mitochondrial respiration in both patients’ iPSC-CMs, the downstream consequences varied. mtDNA mutant cells from a patient with no clinical heart disease showed increased glucose metabolism and retained cellular ATP levels, whereas cells from the cardiac disease patient showed reduced ATP levels. In this patient, the mutations also affected intracellular calcium signaling, while this was not true in the other patient’s cells. Our results reflect the clinical variability in mitochondrial disease patients and show that iPSC-CMs retain tissue specific features seen in patients. MDPI 2022-08-19 /pmc/articles/PMC9406376/ /pubmed/36010669 http://dx.doi.org/10.3390/cells11162593 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ryytty, Sanna
Modi, Shalem R.
Naumenko, Nikolay
Shakirzyanova, Anastasia
Rahman, Muhammad Obaidur
Vaara, Miia
Suomalainen, Anu
Tavi, Pasi
Hämäläinen, Riikka H.
Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes
title Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes
title_full Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes
title_fullStr Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes
title_full_unstemmed Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes
title_short Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes
title_sort varied responses to a high m.3243a>g mutation load and respiratory chain dysfunction in patient-derived cardiomyocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9406376/
https://www.ncbi.nlm.nih.gov/pubmed/36010669
http://dx.doi.org/10.3390/cells11162593
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