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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...

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Autores principales: Bakare, Ajibola B., Dean, Joseph, Chen, Qun, Thorat, Vedant, Huang, Yimin, LaFramboise, Thomas, Lesnefsky, Edward J., Iyer, Shilpa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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