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Evaluating the Bioenergetics Health Index Ratio in Leigh Syndrome Fibroblasts to Understand Disease Severity
Several pediatric mitochondrial disorders, including Leigh syndrome (LS), impact mitochondrial (mt) genetics, development, and metabolism, leading to complex pathologies and energy failure. The extent to which pathogenic mtDNA variants regulate disease severity in LS is currently not well understood...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508996/ https://www.ncbi.nlm.nih.gov/pubmed/34638685 http://dx.doi.org/10.3390/ijms221910344 |
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author | Bakare, Ajibola B. Dean, Joseph Chen, Qun Thorat, Vedant Huang, Yimin LaFramboise, Thomas Lesnefsky, Edward J. Iyer, Shilpa |
author_facet | Bakare, Ajibola B. Dean, Joseph Chen, Qun Thorat, Vedant Huang, Yimin LaFramboise, Thomas Lesnefsky, Edward J. Iyer, Shilpa |
author_sort | Bakare, Ajibola B. |
collection | PubMed |
description | Several pediatric mitochondrial disorders, including Leigh syndrome (LS), impact mitochondrial (mt) genetics, development, and metabolism, leading to complex pathologies and energy failure. The extent to which pathogenic mtDNA variants regulate disease severity in LS is currently not well understood. To better understand this relationship, we computed a glycolytic bioenergetics health index (BHI) for measuring mitochondrial dysfunction in LS patient fibroblast cells harboring varying percentages of pathogenic mutant mtDNA (T8993G, T9185C) exhibiting deficiency in complex V or complex I (T10158C, T12706C). A high percentage (>90%) of pathogenic mtDNA in cells affecting complex V and a low percentage (<39%) of pathogenic mtDNA in cells affecting complex I was quantified. Levels of defective enzyme activities of the electron transport chain correlated with the percentage of pathogenic mtDNA. Subsequent bioenergetics assays showed cell lines relied on both OXPHOS and glycolysis for meeting energy requirements. Results suggest that whereas the precise mechanism of LS has not been elucidated, a multi-pronged approach taking into consideration the specific pathogenic mtDNA variant, glycolytic BHI, and the composite BHI (average ratio of oxphos to glycolysis) can aid in better understanding the factors influencing disease severity in LS. |
format | Online Article Text |
id | pubmed-8508996 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-85089962021-10-13 Evaluating the Bioenergetics Health Index Ratio in Leigh Syndrome Fibroblasts to Understand Disease Severity Bakare, Ajibola B. Dean, Joseph Chen, Qun Thorat, Vedant Huang, Yimin LaFramboise, Thomas Lesnefsky, Edward J. Iyer, Shilpa Int J Mol Sci Article Several pediatric mitochondrial disorders, including Leigh syndrome (LS), impact mitochondrial (mt) genetics, development, and metabolism, leading to complex pathologies and energy failure. The extent to which pathogenic mtDNA variants regulate disease severity in LS is currently not well understood. To better understand this relationship, we computed a glycolytic bioenergetics health index (BHI) for measuring mitochondrial dysfunction in LS patient fibroblast cells harboring varying percentages of pathogenic mutant mtDNA (T8993G, T9185C) exhibiting deficiency in complex V or complex I (T10158C, T12706C). A high percentage (>90%) of pathogenic mtDNA in cells affecting complex V and a low percentage (<39%) of pathogenic mtDNA in cells affecting complex I was quantified. Levels of defective enzyme activities of the electron transport chain correlated with the percentage of pathogenic mtDNA. Subsequent bioenergetics assays showed cell lines relied on both OXPHOS and glycolysis for meeting energy requirements. Results suggest that whereas the precise mechanism of LS has not been elucidated, a multi-pronged approach taking into consideration the specific pathogenic mtDNA variant, glycolytic BHI, and the composite BHI (average ratio of oxphos to glycolysis) can aid in better understanding the factors influencing disease severity in LS. MDPI 2021-09-26 /pmc/articles/PMC8508996/ /pubmed/34638685 http://dx.doi.org/10.3390/ijms221910344 Text en © 2021 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 Bakare, Ajibola B. Dean, Joseph Chen, Qun Thorat, Vedant Huang, Yimin LaFramboise, Thomas Lesnefsky, Edward J. Iyer, Shilpa Evaluating the Bioenergetics Health Index Ratio in Leigh Syndrome Fibroblasts to Understand Disease Severity |
title | Evaluating the Bioenergetics Health Index Ratio in Leigh Syndrome Fibroblasts to Understand Disease Severity |
title_full | Evaluating the Bioenergetics Health Index Ratio in Leigh Syndrome Fibroblasts to Understand Disease Severity |
title_fullStr | Evaluating the Bioenergetics Health Index Ratio in Leigh Syndrome Fibroblasts to Understand Disease Severity |
title_full_unstemmed | Evaluating the Bioenergetics Health Index Ratio in Leigh Syndrome Fibroblasts to Understand Disease Severity |
title_short | Evaluating the Bioenergetics Health Index Ratio in Leigh Syndrome Fibroblasts to Understand Disease Severity |
title_sort | evaluating the bioenergetics health index ratio in leigh syndrome fibroblasts to understand disease severity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508996/ https://www.ncbi.nlm.nih.gov/pubmed/34638685 http://dx.doi.org/10.3390/ijms221910344 |
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