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

Vinaya Vishwanathan,Patrick D’Silva

doi:10.3389/fcell.2022.847045

Vinaya Vishwanathan, Patrick D’Silva

Open Access

https://doi.org/10.3389/fcell.2022.847045

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Abstract

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.

Highlights

Congenital Sideroblastic Anemia (CSA) is a heterogeneous group of inherited erythropoietic disorders and is characterized by the presence of abnormal erythrocyte precursors or ringsideroblasts in the bone marrow
The mtHsp70 variants observed in the clinical screen of Congenital Sideroblastic Anemia are mapped to residues in both the Nucleotide Binding Domain (NBD) (S177L, V189P, G365S, and E392K) and the Substrate Binding Domain (SBD) (T516K and Q554K) (Figure 1A)
FACS analyses indicate an increase in the mitochondrial superoxide levels in the G365S and E392K mutants (Figure 4C). Together these results indicate CSAassociated mutants alter the function of mthsp70 resulting in mitochondrial dysfunction and redox imbalance, which contribute to the onset and progression of congenital sideroblastic anemia

Summary

Introduction

Congenital Sideroblastic Anemia (CSA) is a heterogeneous group of inherited erythropoietic disorders and is characterized by the presence of abnormal erythrocyte precursors or ringsideroblasts in the bone marrow. Mitochondria house the molecular machinery that is required in the various stages of heme and Fe-S cluster synthesis, and occupy a central role in iron metabolism (Ponka, 1999; Lill, 2009; Ye and Rouault, 2010). The Fe-S clusters assembled within the mitochondria serve as co-factors to several key proteins many of which are post-translational regulators of iron metabolism. It is implicit that any perturbation in mitochondrial function including impaired synthesis of heme, Fe-S cluster biogenesis, or impaired synthesis and/or import of mitochondrial proteins could contribute to the onset and progression of congenital sideroblastic

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