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Loss of Function of mtHsp70 Chaperone Variants Leads to Mitochondrial Dysfunction in Congenital Sideroblastic Anemia

Congenital Sideroblastic Anemias (CSA) is a group of rare genetic disorders characterized by the abnormal accumulation of iron in erythrocyte precursors. A common hallmark underlying these pathological conditions is mitochondrial dysfunction due to altered protein homeostasis, heme biosynthesis, and...

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Autores principales: Vishwanathan, Vinaya, D’Silva, Patrick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888832/
https://www.ncbi.nlm.nih.gov/pubmed/35252210
http://dx.doi.org/10.3389/fcell.2022.847045
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author Vishwanathan, Vinaya
D’Silva, Patrick
author_facet Vishwanathan, Vinaya
D’Silva, Patrick
author_sort Vishwanathan, Vinaya
collection PubMed
description Congenital Sideroblastic Anemias (CSA) is a group of rare genetic disorders characterized by the abnormal accumulation of iron in erythrocyte precursors. A common hallmark underlying these pathological conditions is mitochondrial dysfunction due to altered protein homeostasis, heme biosynthesis, and oxidative phosphorylation. A clinical study on congenital sideroblastic anemia has identified mutations in mitochondrial Hsp70 (mtHsp70/Mortalin). Mitochondrial Hsp70 plays a critical role in maintaining mitochondrial function by regulating several pathways, including protein import and folding, and iron-sulfur cluster synthesis. Owing to the structural and functional homology between human and yeast mtHsp70, we have utilized the yeast system to delineate the role of mtHsp70 variants in the etiology of CSA’s. Analogous mutations in yeast mtHsp70 exhibited temperature-sensitive growth phenotypes under non-respiratory and respiratory conditions. In vivo analyses indicate a perturbation in mitochondrial mass and functionality accompanied by an alteration in the organelle network and cellular redox levels. Preliminary in vitro biochemical studies of mtHsp70 mutants suggest impaired import function, altered ATPase activity and substrate interaction. Together, our findings suggest the loss of chaperone activity to be a pivotal factor in the pathophysiology of congenital sideroblastic anemia.
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spelling pubmed-88888322022-03-03 Loss of Function of mtHsp70 Chaperone Variants Leads to Mitochondrial Dysfunction in Congenital Sideroblastic Anemia Vishwanathan, Vinaya D’Silva, Patrick Front Cell Dev Biol Cell and Developmental Biology Congenital Sideroblastic Anemias (CSA) is a group of rare genetic disorders characterized by the abnormal accumulation of iron in erythrocyte precursors. A common hallmark underlying these pathological conditions is mitochondrial dysfunction due to altered protein homeostasis, heme biosynthesis, and oxidative phosphorylation. A clinical study on congenital sideroblastic anemia has identified mutations in mitochondrial Hsp70 (mtHsp70/Mortalin). Mitochondrial Hsp70 plays a critical role in maintaining mitochondrial function by regulating several pathways, including protein import and folding, and iron-sulfur cluster synthesis. Owing to the structural and functional homology between human and yeast mtHsp70, we have utilized the yeast system to delineate the role of mtHsp70 variants in the etiology of CSA’s. Analogous mutations in yeast mtHsp70 exhibited temperature-sensitive growth phenotypes under non-respiratory and respiratory conditions. In vivo analyses indicate a perturbation in mitochondrial mass and functionality accompanied by an alteration in the organelle network and cellular redox levels. Preliminary in vitro biochemical studies of mtHsp70 mutants suggest impaired import function, altered ATPase activity and substrate interaction. Together, our findings suggest the loss of chaperone activity to be a pivotal factor in the pathophysiology of congenital sideroblastic anemia. Frontiers Media S.A. 2022-02-16 /pmc/articles/PMC8888832/ /pubmed/35252210 http://dx.doi.org/10.3389/fcell.2022.847045 Text en Copyright © 2022 Vishwanathan and D’Silva. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Vishwanathan, Vinaya
D’Silva, Patrick
Loss of Function of mtHsp70 Chaperone Variants Leads to Mitochondrial Dysfunction in Congenital Sideroblastic Anemia
title Loss of Function of mtHsp70 Chaperone Variants Leads to Mitochondrial Dysfunction in Congenital Sideroblastic Anemia
title_full Loss of Function of mtHsp70 Chaperone Variants Leads to Mitochondrial Dysfunction in Congenital Sideroblastic Anemia
title_fullStr Loss of Function of mtHsp70 Chaperone Variants Leads to Mitochondrial Dysfunction in Congenital Sideroblastic Anemia
title_full_unstemmed Loss of Function of mtHsp70 Chaperone Variants Leads to Mitochondrial Dysfunction in Congenital Sideroblastic Anemia
title_short Loss of Function of mtHsp70 Chaperone Variants Leads to Mitochondrial Dysfunction in Congenital Sideroblastic Anemia
title_sort loss of function of mthsp70 chaperone variants leads to mitochondrial dysfunction in congenital sideroblastic anemia
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888832/
https://www.ncbi.nlm.nih.gov/pubmed/35252210
http://dx.doi.org/10.3389/fcell.2022.847045
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