Abstract
Since their discovery, heat shock proteins (HSPs) have been identified in all domains of life, which demonstrates their importance and conserved functional role in maintaining protein homeostasis. Mitochondria possess several members of the major HSP sub-families that perform essential tasks for keeping the organelle in a fully functional and healthy state. In humans, the mitochondrial HSP70 chaperone system comprises a central molecular chaperone, mtHSP70 or mortalin (HSPA9), which is actively involved in stabilizing and importing nuclear gene products and in refolding mitochondrial precursor proteins, and three co-chaperones (HSP70-escort protein 1—HEP1, tumorous imaginal disc protein 1—TID-1, and Gro-P like protein E—GRPE), which regulate and accelerate its protein folding functions. In this review, we summarize the roles of mitochondrial molecular chaperones with particular focus on the human mtHsp70 and its co-chaperones, whose deregulated expression, mutations, and post-translational modifications are often considered to be the main cause of neurological disorders, genetic diseases, and malignant growth.
Highlights
The mitochondrial protein quality control (PQC) system is a network-like organization of chaperones and proteases whose major role is to preserve the functional and active states of mitochondrial proteins under diverse, and sometimes pathogenic, conditions
Mitochondria can trigger apoptosis to preserve the integrity of the tissue or organism, while on the organellar level, a selective form of mitophagy ensures the disposal of non-functional parts
The mitochondrial HSP70 chaperone system consisting of mortalin and its co-chaperones HEP1, TID-1, and GRPE, forms one of the key components of PQC in mitochondria
Summary
The mitochondrial protein quality control (PQC) system is a network-like organization of chaperones and proteases whose major role is to preserve the functional and active states of mitochondrial proteins under diverse, and sometimes pathogenic, conditions. Mitochondria loss leads to a dramatic drop in oxidative phosphorylation and ATP levels, causing a further imbalance in homeostasis, leading to cell death [4] To avoid this fate, cells possess so-called heat shock proteins (HSPs), whose expression increases in response to such stresses, and which serve as the foundation of resistance to hostile conditions [3]. The accumulation of misfolded proteins and proteins irreversibly modified by posttranslational modifications (e.g., protein glycation, methionine oxidation, deamination of asparaginyl and glutaminyl residues) that induce conformational changes and impaired protein functions has been observed in ageing [5] Such alterations cannot be reversed by molecular chaperones, these may only accompany their substrates and by a stable association with their hydrophobic surfaces prevent their aggregation shifting the normal functions of HSPs from protein maintenance to fighting the growing number of damaged or non-functional enzymes [5,7]. Genetic mutations in genes encoding HSPs were shown as causative agents of several hereditary autosomal dominant or recessive disorders (e.g., hereditary spastic paraplegia SPG13, MitCHAP-60, EVEN-PLUS syndrome, and congenital sideroblastic anemia SIDBA4) suggesting that defects in mitochondrial chaperones exert a profound impact on overall mitochondrial biogenesis, integrity, and function
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