Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease

Abstract

Several neurological disorders have been linked to mutations in chaperonin genes and more specifically to the HSPD1 gene. 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. It functions as a macromolecular complex that provides client proteins an environment that favors proper folding in an ATP-dependent manner. It has been established that mtHsp60 plays a crucial role in the proper folding of mitochondrial proteins involved in ATP producing pathways. Recently, various single-point mutations in the mtHsp60 encoding gene have been directly linked to neuropathies and paraplegias. Individuals who harbor mtHsp60 mutations that negatively impact its folding ability display phenotypes with highly compromised muscle and neuron 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. These phenotypes are likely due to hindered energy producing pathways involved in cellular respiration resulting in ATP deprived cells. 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. 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.

Protective effects of cannabidiol on the membrane proteins of skin keratinocytes exposed to hydrogen peroxide via participation in the proteostasis network

“…Thus, a reduction in MDA-protein adduct formation may suggest a protective effect of CBD against the 60 kDa chaperonin. Such action of CBD can promote the maintenance of mitochondrial and cellular keratinocyte homeostasis [ 70 ].…”

Exosome Releasing HSPD1 Assists HNF1A in Regulating the Invasion Ability and Radiosensitivity of Esophageal Squamous Cell Carcinoma Cells via Activating EMT

“…Further studies demonstrated that depletion of HSPD1 weakened radio-resistance in ESCC cells with ectopic expression HNF1A. There were evidences that HSPD1 is involved in maintaining normal protein homeostasis and protein denaturation repair (9,25). We speculated that HSPD1 was consumed with modifying new abundant proteins which maintain cell function after ectopic expression of HNF1A.…”

“…Heat shock 60kDa protein 1 (HSPD1) was a member of the heat shock protein family, also known as HSP60. HSPD1 assisted in maintaining protein homeostasis, participated in safeguarding mitochondrial function and intracellular homeostasis, and protected cardiomyocytes from apoptosis after its overexpression (8,9). Post-translational modi cation of HSPD1 resulted in different biological functions, such as in ammation, autoimmunity, carcinogenesis, cell replication and so on (10).…”

Heat Shock Protein 60 Restricts Release of Mitochondrial dsRNA to Suppress Hepatic Inflammation and Ameliorate Non-Alcoholic Fatty Liver Disease in Mice

“…HSP60, also known as HSPD1, is a 60 kDa chaperone primarily found in the mitochondrial matrix [ 12 ]. The folding activity of HSP60 protects mitochondria from proteotoxicity under various types of stress [ 13 , 14 , 15 ].…”