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Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by cardiolipin-interacting small molecules
Barth syndrome (BTHS) is an X-linked disorder of mitochondrial phospholipid metabolism caused by pathogenic variants in TAFFAZIN, which results in abnormal cardiolipin (CL) content in the inner mitochondrial membrane. To identify unappreciated pathways of mitochondrial dysfunction in BTHS, we utiliz...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384898/ https://www.ncbi.nlm.nih.gov/pubmed/34314685 http://dx.doi.org/10.1016/j.jbc.2021.101005 |
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author | Anzmann, Arianna F. Sniezek, Olivia L. Pado, Alexandra Busa, Veronica Vaz, Frédéric M. Kreimer, Simion D. DeVine, Lauren R. Cole, Robert N. Le, Anne Kirsch, Brian J. Claypool, Steven M. Vernon, Hilary J. |
author_facet | Anzmann, Arianna F. Sniezek, Olivia L. Pado, Alexandra Busa, Veronica Vaz, Frédéric M. Kreimer, Simion D. DeVine, Lauren R. Cole, Robert N. Le, Anne Kirsch, Brian J. Claypool, Steven M. Vernon, Hilary J. |
author_sort | Anzmann, Arianna F. |
collection | PubMed |
description | Barth syndrome (BTHS) is an X-linked disorder of mitochondrial phospholipid metabolism caused by pathogenic variants in TAFFAZIN, which results in abnormal cardiolipin (CL) content in the inner mitochondrial membrane. To identify unappreciated pathways of mitochondrial dysfunction in BTHS, we utilized an unbiased proteomics strategy and identified that complex I (CI) of the mitochondrial respiratory chain and the mitochondrial quality control protease presenilin-associated rhomboid-like protein (PARL) are altered in a new HEK293–based tafazzin-deficiency model. Follow-up studies confirmed decreased steady state levels of specific CI subunits and an assembly factor in the absence of tafazzin; this decrease is in part based on decreased transcription and results in reduced CI assembly and function. PARL, a rhomboid protease associated with the inner mitochondrial membrane with a role in the mitochondrial response to stress, such as mitochondrial membrane depolarization, is increased in tafazzin-deficient cells. The increased abundance of PARL correlates with augmented processing of a downstream target, phosphoglycerate mutase 5, at baseline and in response to mitochondrial depolarization. To clarify the relationship between abnormal CL content, CI levels, and increased PARL expression that occurs when tafazzin is missing, we used blue-native PAGE and gene expression analysis to determine that these defects are remediated by SS-31 and bromoenol lactone, pharmacologic agents that bind CL or inhibit CL deacylation, respectively. These findings have the potential to enhance our understanding of the cardiac pathology of BTHS, where defective mitochondrial quality control and CI dysfunction have well-recognized roles in the pathology of diverse forms of cardiac dysfunction. |
format | Online Article Text |
id | pubmed-8384898 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-83848982021-08-30 Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by cardiolipin-interacting small molecules Anzmann, Arianna F. Sniezek, Olivia L. Pado, Alexandra Busa, Veronica Vaz, Frédéric M. Kreimer, Simion D. DeVine, Lauren R. Cole, Robert N. Le, Anne Kirsch, Brian J. Claypool, Steven M. Vernon, Hilary J. J Biol Chem Research Article Barth syndrome (BTHS) is an X-linked disorder of mitochondrial phospholipid metabolism caused by pathogenic variants in TAFFAZIN, which results in abnormal cardiolipin (CL) content in the inner mitochondrial membrane. To identify unappreciated pathways of mitochondrial dysfunction in BTHS, we utilized an unbiased proteomics strategy and identified that complex I (CI) of the mitochondrial respiratory chain and the mitochondrial quality control protease presenilin-associated rhomboid-like protein (PARL) are altered in a new HEK293–based tafazzin-deficiency model. Follow-up studies confirmed decreased steady state levels of specific CI subunits and an assembly factor in the absence of tafazzin; this decrease is in part based on decreased transcription and results in reduced CI assembly and function. PARL, a rhomboid protease associated with the inner mitochondrial membrane with a role in the mitochondrial response to stress, such as mitochondrial membrane depolarization, is increased in tafazzin-deficient cells. The increased abundance of PARL correlates with augmented processing of a downstream target, phosphoglycerate mutase 5, at baseline and in response to mitochondrial depolarization. To clarify the relationship between abnormal CL content, CI levels, and increased PARL expression that occurs when tafazzin is missing, we used blue-native PAGE and gene expression analysis to determine that these defects are remediated by SS-31 and bromoenol lactone, pharmacologic agents that bind CL or inhibit CL deacylation, respectively. These findings have the potential to enhance our understanding of the cardiac pathology of BTHS, where defective mitochondrial quality control and CI dysfunction have well-recognized roles in the pathology of diverse forms of cardiac dysfunction. American Society for Biochemistry and Molecular Biology 2021-07-24 /pmc/articles/PMC8384898/ /pubmed/34314685 http://dx.doi.org/10.1016/j.jbc.2021.101005 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Anzmann, Arianna F. Sniezek, Olivia L. Pado, Alexandra Busa, Veronica Vaz, Frédéric M. Kreimer, Simion D. DeVine, Lauren R. Cole, Robert N. Le, Anne Kirsch, Brian J. Claypool, Steven M. Vernon, Hilary J. Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by cardiolipin-interacting small molecules |
title | Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by cardiolipin-interacting small molecules |
title_full | Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by cardiolipin-interacting small molecules |
title_fullStr | Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by cardiolipin-interacting small molecules |
title_full_unstemmed | Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by cardiolipin-interacting small molecules |
title_short | Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by cardiolipin-interacting small molecules |
title_sort | diverse mitochondrial abnormalities in a new cellular model of taffazzin deficiency are remediated by cardiolipin-interacting small molecules |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384898/ https://www.ncbi.nlm.nih.gov/pubmed/34314685 http://dx.doi.org/10.1016/j.jbc.2021.101005 |
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