Escorted by chaperones: Sti1 helps to usher precursor proteins from the ribosome to mitochondria

Hansen, Katja G.; Schlagowski, Anna M.; Herrmann, Johannes M.

doi:10.1111/febs.13821

Cited by 3 publications

(4 citation statements)

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“…Thus, targeting abnormal mitochondrial function and chaperoning of mitochondrial proteins is also a promising strategy for cancer therapeutics [38]. Hsp90 and Hsp70 play critical roles in mitochondrial protein stabilisation and folding [39] and various co-chaperones such as p23, Hsp40 and HOP are also involved [40][41][42]. In this respect, Tomm34 was originally identified as a potential mitochondrial import protein [15] and Tomm34 antibodies inhibit transport of preproteins into the mitochondria, whilst expression stimulates mitochondrial preprotein maturation and TOMM34 siRNA inhibits this process [14].…”

Section: Discussionmentioning

confidence: 99%

Tomm34 is commonly expressed in epithelial ovarian cancer and associates with tumour type and high FIGO stage

et al. 2019

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Background: Increased activity of the chaperones Hsp70 and Hsp90 is a common feature of solid tumours. Translocase of the outer mitochondrial membrane 34 (Tomm34) is a cochaperone of both Hsp70 and Hsp90 that was found to be overexpressed in colorectal, hepatocellular, lung and breast carcinomas. The expression profile of Tomm34 in ovarian cancer has not been investigated. Therefore, the aim of the current study was to investigate the expression pattern of Tomm34 in ovarian carcinomas and analyse its correlation with clinico-pathological parameters. Results: Epithelial ovarian cancers (140) were histologically classified based on their morphology and graded into two types comprising 5 histologic subgroups. Type I carcinomas comprise low grade serous (LGSC), clear cell (CCOC) and endometrioid (ENOC), type II comprises high grade serous carcinomas (HGSC) and solid, pseudoendometrioid, transitional carcinomas (SET). Tomm34 was more highly expressed in type II than type I carcinomas (p < 0.0001). Comparing tumours based on the mutation in the TP53 gene revealed similar results, where mutant tumours exhibited significantly higher levels of Tomm34 (p < 0.0001). The decreased levels of Tomm34 in type I carcinomas were particularly evident in clear cell and mucinous carcinomas. The expression of Tomm34 was also positively correlated with FIGO stage (r = 0.23; p = 0.007). Tomm34 levels also indicated poor prognosis for patients with mutant p53. Conclusions: Our data indicate that Tomm34 is commonly expressed at high levels in epithelial ovarian cancers, except for the clear cell and mucinous subtypes. The expression of Tomm34 corresponds with the dualistic model of ovarian cancer pathogenesis where high grade, type II tumours exhibit higher expression of Tomm34 in contrast to type I tumours. These data are also comparable to the previous findings that Tomm34 is a marker of progression and poor prognosis in human cancer.

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Section: Discussionmentioning

confidence: 99%

Tomm34 is commonly expressed in epithelial ovarian cancer and associates with tumour type and high FIGO stage

et al. 2019

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“…MTSs are recognized by the receptors Tom20/Tom22 and Tom70 on the mitochondrial surface, which have considerable overlap in specificity and functionality (Brix et al, 1999 ; Fan et al, 2011 ). The binding of MTSs to the TOM receptors, particularly to Tom70, is facilitated by cytosolic chaperones of the Hsp70 and Hsp90 classes as well as by co-chaperones such as Sti1 (Young et al, 2003 ; Hansen et al, 2016 ; Hoseini et al, 2016 ).…”

Section: Protein Import Into the Mitochondrial Matrixmentioning

confidence: 99%

Protein Translocation into the Intermembrane Space and Matrix of Mitochondria: Mechanisms and Driving Forces

Backes

Herrmann

2017

Front. Mol. Biosci.

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Mitochondria contain two aqueous subcompartments, the matrix and the intermembrane space (IMS). The matrix is enclosed by both the inner and outer mitochondrial membranes, whilst the IMS is sandwiched between the two. Proteins of the matrix are synthesized in the cytosol as preproteins, which contain amino-terminal matrix targeting sequences that mediate their translocation through translocases embedded in the outer and inner membrane. For these proteins, the translocation reaction is driven by the import motor which is part of the inner membrane translocase. The import motor employs matrix Hsp70 molecules and ATP hydrolysis to ratchet proteins into the mitochondrial matrix. Most IMS proteins lack presequences and instead utilize the IMS receptor Mia40, which facilitates their translocation across the outer membrane in a reaction that is coupled to the formation of disulfide bonds within the protein. This process requires neither ATP nor the mitochondrial membrane potential. Mia40 fulfills two roles: First, it acts as a holdase, which is crucial in the import of IMS proteins and second, it functions as a foldase, introducing disulfide bonds into newly imported proteins, which induces and stabilizes their natively folded state. For several Mia40 substrates, oxidative folding is an essential prerequisite for their assembly into oligomeric complexes. Interestingly, recent studies have shown that the two functions of Mia40 can be experimentally separated from each other by the use of specific mutants, hence providing a powerful new way to dissect the different physiological roles of Mia40. In this review we summarize the current knowledge relating to the mitochondrial matrix-targeting and the IMS-targeting/Mia40 pathway. Moreover, we discuss the mechanistic properties by which the mitochondrial import motor on the one hand and Mia40 on the other, drive the translocation of their substrates into the organelle. We propose that the lateral diffusion of Mia40 in the inner membrane and the oxidation-mediated folding of incoming polypeptides supports IMS import.

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“…These ribosomes reside in the vicinity of the OMM or near contact sites between the mitochondria and the endoplasmic reticulum (ER) [ 22 , 23 ]. During protein transport from cytosol to mitochondria, chaperones and co-chaperones play a critical role to prevent the misfolding or damage of mitochondrial precursor proteins [ 24 ]. Co-chaperones, including Yeast dnaJ 1 (Ydj1; the homolog of human heat-shock protein 40 (HSP40)), first target unfolded precursor proteins, which are subsequently transferred to Hsp70 and then to Hsp90 [ 25 , 26 ].…”

Section: The Origin Of Mitochondrial Proteinsmentioning

confidence: 99%

“…HSP40 is a cytosolic chaperone, which helps target precursor proteins from the cytosol to the OMM and facilitates protein import, folding, and degradation [ 24 , 27 ]. Various types of HSP40 may impart different effects on cancer cells [ 184 ]; for example, two subtypes of DNAJ (the HSP40 family) are implicated in breast cancer development, as the DNAJA subtype induces apoptosis, while the DNAJB subtype inhibits apoptosis [ 185 ].…”

Section: Mpqc Goes Awry In Cancermentioning

confidence: 99%

Failure to Guard: Mitochondrial Protein Quality Control in Cancer

Friedlander

Shen

Zeng

et al. 2021

IJMS

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Mitochondria are energetic and dynamic organelles with a crucial role in bioenergetics, metabolism, and signaling. Mitochondrial proteins, encoded by both nuclear and mitochondrial DNA, must be properly regulated to ensure proteostasis. Mitochondrial protein quality control (MPQC) serves as a critical surveillance system, employing different pathways and regulators as cellular guardians to ensure mitochondrial protein quality and quantity. In this review, we describe key pathways and players in MPQC, such as mitochondrial protein translocation-associated degradation, mitochondrial stress responses, chaperones, and proteases, and how they work together to safeguard mitochondrial health and integrity. Deregulated MPQC leads to proteotoxicity and dysfunctional mitochondria, which contributes to numerous human diseases, including cancer. We discuss how alterations in MPQC components are linked to tumorigenesis, whether they act as drivers, suppressors, or both. Finally, we summarize recent advances that seek to target these alterations for the development of anti-cancer drugs.

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Escorted by chaperones: Sti1 helps to usher precursor proteins from the ribosome to mitochondria

Cited by 3 publications

References 16 publications

Tomm34 is commonly expressed in epithelial ovarian cancer and associates with tumour type and high FIGO stage

Tomm34 is commonly expressed in epithelial ovarian cancer and associates with tumour type and high FIGO stage

Protein Translocation into the Intermembrane Space and Matrix of Mitochondria: Mechanisms and Driving Forces

Failure to Guard: Mitochondrial Protein Quality Control in Cancer

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