Hsp60andHsp70Chaperones: Guardians of Mitochondrial Proteostasis

Abstract

Most protein molecules are dynamic and marginally stable and therefore constantly at risk for acquiring misfolded conformations. Constant surveillance is required to preserve proteostasis. Maintenance of the mitochondrial proteome relies on a diverse set of molecular chaperones and proteases, which together form an interconnected network. An imbalance in mitochondrial proteostasis will result in the accumulation of damaged polypeptides, potentially leading to collapse of mitochondrial integrity. The Hsp60 and Hsp70 chaperone systems play a central role in the folding of matrix‐localised proteins. In this article, we summarise major aspects of the molecular function of these nano‐machines and their interplay with other matrix chaperones and proteases. Key Concepts Hsp60 and Hsp70 chaperone systems play a crucial role in the maintenance of mitochondrial proteostasis. Hsp60 and Hsp70 carry out various functions via interaction with a large number of extra‐mitochondrial complexes. In addition to its critical role in protein import into the mitochondria, Hsp70 plays an important role in protein folding, disaggregation and degradation in the mitochondrial matrix. Hsp60 is an essential protein that plays a central role in protein‐folding within the mitochondrial matrix. The Hsp60 reaction cycle differs from that of GroEL in its incorporation of a single‐ring intermediate in the reaction cycle.

Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease

“…MtHsp60 can alternate between single and double heptameric ring conformations upon nucleotide binding and following hydrolysis ( Viitanen et al, 1992 , 1998 ; Nielsen and Cowan, 1998 ; Nielsen et al, 1999 ; Levy-Rimler et al, 2001 ; Nisemblat et al, 2014 , 2015 ; Vilasi et al, 2014 , 2018 ; Enriquez et al, 2017 ; Jebara et al, 2017 ; Bhatt et al, 2018 ; Wang et al, 2019 ; Gomez-Llorente et al, 2020 ). Furthermore, the structure of the ATP bound conformation has recently been solved, both by crystallography and electron microscopy.…”

“…However, contrary to the GroEL mechanism, recent structural studies have determined that mtHsp60 in its catalytically active form exists as a single ring (heptamer) or a double ring (tetradecamer). These single ring intermediates have not been well documented in the GroEL folding cycle and require additional studies ( Viitanen et al, 1992 , 1998 ; Nielsen and Cowan, 1998 ; Nielsen et al, 1999 ; Levy-Rimler et al, 2001 ; Sun et al, 2003 ; Chen et al, 2006 ; Liu et al, 2009 ; Illingworth et al, 2011 ; Nisemblat et al, 2014 , 2015 ; Vilasi et al, 2014 ; Enriquez et al, 2017 ; Jebara et al, 2017 ; Bhatt et al, 2018 ; Yan et al, 2018 ). Nucleotide binding and release control the association or dissociation of the heptameric rings along their equatorial domains as protein folding takes place inside the mtHsp60 cavity.…”

Probing the mechanism of inhibition of amyloid-β(1–42)–induced neurotoxicity by the chaperonin GroEL

“…Human Hsp60 and its bacterial homolog GroEL share 51% sequence identity and comprise two cylindrical, stacked heptameric rings, each enclosing a large cavity that binds protein substrates (19,20). Hsp60 alone or in combination with Hsp70 and possibly Hsp90 protects against intracellular β-amyloid stress (21,22), suggesting a role for Hsp60 in the development of Alzheimer's disease.…”

Unravelling the neuroprotective mechanisms of carotenes in differentiated human neural cells: Biochemical and proteomic approaches

“…The HSPA9 or Mortalin is a mitochondrial chaperone protein that functions as a neuronal sensor and plays a vital role as a quality regulator of proteins translocated into the mitochondria ( Ferré, Thouard, Bétourné, Belenguer, Miquel, Peyrin, & Szelechowski, 2020 ). The association of HSPA9 with imported precursor proteins found in the import channel into the mitochondria implied that HSPA9 is accountable for the unfolding of proteins during their transportation ( Jebara, Weiss, & Azem, 2017 ). This process is crucial as the import channel is narrow (approximately between 20A and 26A) for the movement of folded proteins into the mitochondria ( Schwartz & Matouschek, 1999 ).…”