Dual interaction of scaffold protein Tim44 of mitochondrial import motor with channel-forming translocase subunit Tim23

Ting, See-Yeun; Yan, N.; Schilke, Brenda; Craig, Elizabeth A.

doi:10.7554/elife.23609

Cited by 41 publications

(37 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In mitochondria, the protein functions as a molecular tether of the Hsp70 motor (PAM) complex to the TIM23 translocase ( Kronidou et al. 1994 ; Ting et al. 2017 ).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

A Single Tim Translocase in the Mitosomes of Giardia intestinalis Illustrates Convergence of Protein Import Machines in Anaerobic Eukaryotes

Pyrihová

Motyčková

Voleman

et al. 2018

Genome Biology and Evolution

View full text Add to dashboard Cite

Mitochondria have evolved diverse forms across eukaryotic diversity in adaptation to anoxia. Mitosomes are the simplest and the least well-studied type of anaerobic mitochondria. Transport of proteins via TIM complexes, composed of three proteins of the Tim17 protein family (Tim17/22/23), is one of the key unifying aspects of mitochondria and mitochondria-derived organelles. However, multiple experimental and bioinformatic attempts have so far failed to identify the nature of TIM in mitosomes of the anaerobic metamonad protist, Giardia intestinalis, one of the few experimental models for mitosome biology. Here, we present the identification of a single G. intestinalis Tim17 protein (GiTim17), made possible only by the implementation of a metamonad-specific hidden Markov model. While very divergent in primary sequence and in predicted membrane topology, experimental data suggest that GiTim17 is an inner membrane mitosomal protein, forming a disulphide-linked dimer. We suggest that the peculiar GiTim17 sequence reflects adaptation to the unusual, detergent resistant, inner mitosomal membrane. Specific pull-down experiments indicate interaction of GiTim17 with mitosomal Tim44, the tethering component of the import motor complex. Analysis of TIM complexes across eukaryote diversity suggests that a “single Tim” translocase is a convergent adaptation of mitosomes in anaerobic protists, with Tim22 and Tim17 (but not Tim23), providing the protein backbone.

show abstract

“…In mitochondria, the protein functions as a molecular tether of the Hsp70 motor (PAM) complex to the TIM23 translocase ( Kronidou et al. 1994 ; Ting et al. 2017 ).…”

Section: Resultsmentioning

confidence: 99%

“…However, we were not able to confirm the direct interaction between GiTim17 and GiTim44 in Y2H assays (data not shown). Whether the negative result reflects the absence of another interacting component or the experimental limitations of Y2H, requires future in vitro characterization of both proteins ( Ting et al. 2017 ).…”

Section: Resultsmentioning

confidence: 99%

A Single Tim Translocase in the Mitosomes of Giardia intestinalis Illustrates Convergence of Protein Import Machines in Anaerobic Eukaryotes

Pyrihová

Motyčková

Voleman

et al. 2018

Genome Biology and Evolution

View full text Add to dashboard Cite

show abstract

“…Tim23 and Tim17 are two structurally related multi-spanning inner membrane proteins that form the protein-conducting channel of the inner membrane (Truscott et al, 2001 ; Meier et al, 2005 ; Zarsky and Dolezal, 2016 ). Tim17, which shows the highest degree of sequence conservation of all TOM and TIM subunits, coordinates the membrane potential-dependent opening of the channel with the binding of the import motor on the matrix site via the membrane-associated subunit Tim44 (Meier et al, 2005 ; Martinez-Caballero et al, 2007 ; Ramesh et al, 2016 ; Demishtein-Zohary et al, 2017 ; Matta et al, 2017 ; Ting et al, 2017 ). Tim44 serves as binding site for the mitochondrial Hsp70 (mtHsp70) of the matrix which binds tightly to incoming polypeptides upon hydrolysis of its bound ATP to ADP in a reaction regulated by Pam18/Tim14 and Pam16/Tim16, a J protein and a J-like protein, respectively, that are associated with the TIM23 complex.…”

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.

View full text Add to dashboard Cite

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.

show abstract

“…Mitochondrial biogenesis requires the import and trafficking of proteins synthesized in the cytosol into the intramitochondrial compartments. Proteins destined to the mitochondrial matrix are targeted to the inner membrane Tim17/23 translocon by their pre-sequences [ 36 ]. This is carried out using a mitochondrial targeting sequence (MTS), which is located at the N-terminal position of the protein to be imported.…”

Section: Introductionmentioning

confidence: 99%

Impact of Mitophagy and Mitochondrial Unfolded Protein Response as New Adaptive Mechanisms Underlying Old Pathologies: Sarcopenia and Non-Alcoholic Fatty Liver Disease

Urbina-Varela

Castillo

Videla

et al. 2020

IJMS

View full text Add to dashboard Cite

Mitochondria are the first-line defense of the cell in the presence of stressing processes that can induce mitochondrial dysfunction. Under these conditions, the activation of two axes is accomplished, namely, (i) the mitochondrial unfolded protein response (UPRmt) to promote cell recovery and survival of the mitochondrial network; (ii) the mitophagy process to eliminate altered or dysfunctional mitochondria. For these purposes, the former response induces the expression of chaperones, proteases, antioxidant components and protein import and assembly factors, whereas the latter is signaled through the activation of the PINK1/Parkin and BNIP3/NIX pathways. These adaptive mechanisms may be compromised during aging, leading to the development of several pathologies including sarcopenia, defined as the loss of skeletal muscle mass and performance; and non-alcoholic fatty liver disease (NAFLD). These age-associated diseases are characterized by the progressive loss of organ function due to the accumulation of reactive oxygen species (ROS)-induced damage to biomolecules, since the ability to counteract the continuous and large generation of ROS becomes increasingly inefficient with aging, resulting in mitochondrial dysfunction as a central pathogenic mechanism. Nevertheless, the role of the integrated stress response (ISR) involving UPRmt and mitophagy in the development and progression of these illnesses is still a matter of debate, considering that some studies indicate that the prolonged exposure to low levels of stress may trigger these mechanisms to maintain mitohormesis, whereas others sustain that chronic activation of them could lead to cell death. In this review, we discuss the available research that contributes to unveil the role of the mitochondrial UPR in the development of sarcopenia, in an attempt to describe changes prior to the manifestation of severe symptoms; and in NAFLD, in order to prevent or reverse fat accumulation and its progression by means of suitable protocols to be addressed in future studies.

show abstract

Dual interaction of scaffold protein Tim44 of mitochondrial import motor with channel-forming translocase subunit Tim23

Cited by 41 publications

References 57 publications

A Single Tim Translocase in the Mitosomes of Giardia intestinalis Illustrates Convergence of Protein Import Machines in Anaerobic Eukaryotes

A Single Tim Translocase in the Mitosomes of Giardia intestinalis Illustrates Convergence of Protein Import Machines in Anaerobic Eukaryotes

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

Impact of Mitophagy and Mitochondrial Unfolded Protein Response as New Adaptive Mechanisms Underlying Old Pathologies: Sarcopenia and Non-Alcoholic Fatty Liver Disease

Contact Info

Product

Resources

About