Due to the intrinsic instability of mtHsp60 complexes in vitro, much of what is known about mtHsp60 has come from comparing it to mutant versions of its bacterial counterpart GroEL. ATP binding, hydrolysis, and ADP release prompt conformational changes that drive the catalytic folding cycles ( Fayet et al., 1989 Ostermann et al., 1989 Saibil et al., 1993 Levy-Rimler et al., 2001 Fenton and Horwich, 2008 Illingworth et al., 2015). Chaperonins carry out protein folding cycles in an ATP-dependent manner. A small fraction of Hsp60 resides in the cytosol and also at the cell surface but the function outside of the mitochondria has not been well established ( Soltys and Radhey, 1997 Chun et al., 2010 Choi et al., 2015 Kalderon et al., 2015). The mtHsp60 encoding gene HSPD1 is a nuclear gene that is translated in the cytosol and imported into the mitochondria due to the presence of an N-terminal mitochondrial targeting sequence that is cleaved upon translocation across the mitochondrial membrane ( Cheng et al., 1989, 1990 Reading et al., 1989 Singh et al., 1990). In humans, mitochondrial Heat Shock Protein 60 (mtHsp60) is in charge of folding mitochondrial proteins along with its co-chaperonin Hsp10 ( Lubben et al., 1990 Hartman et al., 1992). Absence of chaperonins in cells results in cell death as demonstrated in bacterial, yeast, and mouse models ( Cheng et al., 1989 Fayet et al., 1989 Horwich et al., 1993 Fang and Cheng, 2002 Fan et al., 2020). Chaperonins form macromolecular protein complexes that assist the proper folding of nascent proteins to obtain the native state and to refold misfolded proteins to prevent aggregation. Protein folding is an important aspect of cellular function and viability because the accumulation of misfolded proteins leads to the formation of insoluble aggregates that ultimately cause cell death. Here, we discuss recent studies that highlight key aspects of the mtHsp60 mechanism with a focus on some of the known disease-causing point mutations, D29G and V98I, and their effect on the protein folding reaction cycle. Although the complete protein folding mechanism of mtHsp60 is not well understood, recent work suggests that several of these mutations act by destabilizing the oligomeric stability of mtHsp60. These phenotypes are likely due to hindered energy producing pathways involved in cellular respiration resulting in ATP deprived cells. Carriers of these mutations usually develop neuropathies and paraplegias at different stages of their lives mainly characterized by leg stiffness and weakness as well as degeneration of spinal cord nerves. Individuals who harbor mtHsp60 mutations that negatively impact its folding ability display phenotypes with highly compromised muscle and neuron cells. Recently, various single-point mutations in the mtHsp60 encoding gene have been directly linked to neuropathies and paraplegias. It has been established that mtHsp60 plays a crucial role in the proper folding of mitochondrial proteins involved in ATP producing pathways. ![]() It functions as a macromolecular complex that provides client proteins an environment that favors proper folding in an ATP-dependent manner. In humans, HSPD1 encodes the mitochondrial Heat Shock Protein 60 (mtHsp60) chaperonin, which carries out essential protein folding reactions that help maintain mitochondrial and cellular homeostasis. Several neurological disorders have been linked to mutations in chaperonin genes and more specifically to the HSPD1 gene. Department of Chemistry and Biochemistry, The University of Texas at El Paso, El Paso, TX, United States. ![]() Alejandro Rodriguez, Daniel Von Salzen, Bianka A.
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