There contain two particular mitochondrial chaperone systems

There contain two particular mitochondrial chaperone systems that boost the newly synthesized or imported proteins folding in the matrix. mtHSP70, part of presequence translocase associated import-motor (PAM) complex, and polymer HSP60/HSP10 (chaperonin60/10) as main machinery, which is evolutionary conserved to restore mitochondrial proteostasis. HAF1 and UBL5/DVE-1 complex are two main downstream effectors of UPRmt in mitochondrial matrix. HAF1 acts as an ATP-binding cassette (ABC) peptide transporter located in mitochondrial inner membrane, which is essential for UPRmt signaling cascade. A small ubiquitin-like protein UBL5 and a transcription factor DVE-1 form a complex translocated into the nucleus that regulate the transcriptional activation of HSP60. Recent findings demonstrate a separate UPR other than the ‘classical’ UPRmt, which is independent on CHOP. The separate UPR is performed in two steps in the mitochondrial IMS. First of all, the 26S proteasome degrade the ubiquitinated unfolded or misfolded proteins. Then, the overloaded proteins are obliterated through the protease HTRA2. Aggregation IMS proteins evoke estrogen receptor α (ERα) via protein kinase B (AKT) phosphorylation. ERα activation boosts the transcription of the nuclear respiratory factor 1 (NRF1) and HTRA2 to maintain mitochondrial homeostasis. Recently, we were not able to confirm certain signaling pathway of UPRmt, even more signaling molecules should be identified.
Mitochondrial protein import efficiency Recent studies indicate that the mitochondrial protein import efficiency is a potentially valuable pathway to assess mitochondrial function. As a result of mitochondrial unique structure, the protein import encounters enormous challenges. More than 99% of the total mitochondrial protein is synthesized in the N6022 which is encoded by the nuclear genome. The synthesized protein traffic to mitochondria by signal sequences as precursors. Import into mitochondria requires the translocase of the outer mitochondrial membrane (TOM) and the inner mitochondrial membrane (TIM). The outer mitochondrial membrane (TOM) acts as entrance, then the translocase of the inner mitochondria membrane (TIM) targets precursor proteins to mitochondria lumen. Proteins translocated to the mitochondrial matrix have an amphipathic helix, termed N-terminal mitochondrial targeting sequence (MTS). Firstly, the MTS binds to the cytoplasm surface of the mitochondria by the outer mitochondrial membrane channel, subsequently cross the inner membrane and enter the matrix through the TIM23 complex. Once located in the matrix, with the assistance of mitochondria chaperones system including HSP60 and mtHSP70, the MTS is cleaved in the promotion of protein refolding or assembling in the mitochondria lumen. The activating Transcription Factor associated with Stress-1 (ATFS-1), which contains both nuclear localization sequence (NLS) in the leucine zipper domain and N-terminal MTS, serves as a bridge between the mitochondria and nucleus in UPRmt signaling, and senses the import efficiency of mitochondria. Under basal condition, ATFS-1 is targeted to mitochondria and degraded by the Lon protease as an invalid regulatory mechanism. Upon mitochondrial stress, UPRmt signaling impairs mitochondrial import efficiency, part of ATFS-1 cannot be imported into mitochondria and assembles in the cytoplasm. Due to the NLS of ATFS-1, it can traffic to the nucleus to induce a protective transcriptional program to relieve the damage of mitochondrial stress. TIM-17 and TIM-23, two key elements of the TIM23 complex, are upregulated by ATFS-1, which are essential for the N-terminal MTS proteins imported to the mitochondrial matrix. As expected, ATFS-1 activated the expression of the mitochondrial chaperone and proteases genes to restore import efficiency and re-establish mitochondrial homeostasis. Recent findings have shown that any condition that disturbs import efficiency, such as deletions in mitochondrial ETC genes, mitochondrial chaperone and protease inhibition, cause ATFS-1 dependent UPRmt. These studies demonstrate that the UPRmt alters mitochondrial metabolism to protect mitochondrial homeostasis and cell survival during stress.