scholarly journals Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 432
Author(s):  
Hope I. Needs ◽  
Margherita Protasoni ◽  
Jeremy M. Henley ◽  
Julien Prudent ◽  
Ian Collinson ◽  
...  
Keyword(s):  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Functional Protein ◽  
Mitochondrial Protein Import ◽  
Complex Assembly ◽  
Respiratory Complex ◽  
And Function

The fact that >99% of mitochondrial proteins are encoded by the nuclear genome and synthesised in the cytosol renders the process of mitochondrial protein import fundamental for normal organelle physiology. In addition to this, the nuclear genome comprises most of the proteins required for respiratory complex assembly and function. This means that without fully functional protein import, mitochondrial respiration will be defective, and the major cellular ATP source depleted. When mitochondrial protein import is impaired, a number of stress response pathways are activated in order to overcome the dysfunction and restore mitochondrial and cellular proteostasis. However, prolonged impaired mitochondrial protein import and subsequent defective respiratory chain function contributes to a number of diseases including primary mitochondrial diseases and neurodegeneration. This review focuses on how the processes of mitochondrial protein translocation and respiratory complex assembly and function are interlinked, how they are regulated, and their importance in health and disease.

scholarly journals Cryo-EM structure of the mitochondrial protein-import channel TOM complex from Saccharomyces cerevisiae

2019 ◽  
Author(s):  
Kyle Tucker ◽  
Eunyong Park
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Nuclear Genome ◽  
Molecular Organization ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Protein Import ◽  
Tom Complex ◽  
Polar Interactions

AbstractNearly all mitochondrial proteins are encoded by the nuclear genome and imported into mitochondria following synthesis on cytosolic ribosomes. These precursor proteins are translocated into mitochondria by the TOM complex, a protein-conducting channel in the mitochondrial outer membrane. Using cryo-EM, we have obtained high-resolution structures of both apo and presequence-bound core TOM complexes from Saccharomyces cerevisiae in dimeric and tetrameric forms. Dimeric TOM consists of two copies each of five proteins arranged in two-fold symmetry—Tom40, a pore-forming β-barrel with an overall negatively-charged inner surface, and four auxiliary α-helical transmembrane proteins. The structure suggests that presequences for mitochondrial targeting insert into the Tom40 channel mainly by electrostatic and polar interactions. The tetrameric complex is essentially a dimer of dimeric TOM, which may be capable of forming higher-order oligomers. Our study reveals the molecular organization of the TOM complex and provides new insights about the mechanism of protein translocation into mitochondria.

scholarly journals Novel Role of ATPase Subunit C Targeting Peptides Beyond Mitochondrial Protein Import

2010 ◽  
Vol 21 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Cristofol Vives-Bauza ◽  
Jordi Magrané ◽  
Antoni L. Andreu ◽  
Giovanni Manfredi
Keyword(s):  
Respiratory Chain ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Atp Synthesis ◽  
Mitochondrial Respiratory Chain ◽  
Genetic Redundancy ◽  
Mitochondrial Protein Import ◽  
Atpase Subunit ◽  
Subunit C ◽  
And Function

In mammals, subunit c of the F1F0-ATP synthase has three isoforms (P1, P2, and P3). These isoforms differ by their cleavable mitochondrial targeting peptides, whereas the mature peptides are identical. To investigate this apparent genetic redundancy, we knocked down each of the three subunit c isoform by RNA interference in HeLa cells. Silencing any of the subunit c isoforms individually resulted in an ATP synthesis defect, indicating that these isoforms are not functionally redundant. We found that subunit c knockdown impaired the structure and function of the mitochondrial respiratory chain. In particular, P2 silencing caused defective cytochrome oxidase assembly and function. Because the expression of exogenous P1 or P2 was able to rescue the respective silencing phenotypes, but the two isoforms were unable to cross-complement, we hypothesized that their functional specificity resided in their targeting peptides. In fact, the expression of P1 and P2 targeting peptides fused to GFP variants rescued the ATP synthesis and respiratory chain defects in the silenced cells. Our results demonstrate that the subunit c isoforms are nonredundant, because they differ functionally by their targeting peptides, which, in addition to mediating mitochondrial protein import, play a yet undiscovered role in respiratory chain maintenance.

scholarly journals Mitochondrial Protein Import

2004 ◽  
Vol 279 (44) ◽  
pp. 45701-45707 ◽  
Author(s):  
Masatoshi Esaki ◽  
Hidaka Shimizu ◽  
Tomoko Ono ◽  
Hayashi Yamamoto ◽  
Takashi Kanamori ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Intermembrane Space ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Protein Import ◽  
Tom Complex ◽  
Membrane Complex ◽  
Cytosolic Side

Protein translocation across the outer mitochondrial membrane is mediated by the translocator called the TOM (translocase of the outer mitochondrial membrane) complex. The TOM complex possesses two presequence binding sites on the cytosolic side (thecissite) and on the intermembrane space side (thetranssite). Here we analyzed the requirement of presequence elements and subunits of the TOM complex for presequence binding to thecisandtranssites of the TOM complex. The N-terminal 14 residues of the presequence of subunit 9 of F0-ATPase are required for binding to thetranssite. The interaction between the presequence and thecissite is not sufficient to anchor the precursor protein to the TOM complex. Tom7 constitutes or is close to thetranssite and has overlapping functions with the C-terminal intermembrane space domain of Tom22 in the mitochondrial protein import.

scholarly journals Mitochondrial protein import: An unexpected disulfide bond

2016 ◽  
Vol 214 (4) ◽  
pp. 363-365 ◽  
Author(s):  
Dejana Mokranjac
Keyword(s):  
Disulfide Bond ◽  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Channel Gating ◽  
Mitochondrial Proteins ◽  
Mitochondrial Protein Import ◽  
Cell Biol ◽  
Molecular Nature

Most mitochondrial proteins are imported through the TIM23 translocation channel, the structure and molecular nature of which are still unclear. In this issue, Ramesh et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201602074) show that the TIM23 subunit Tim17 contains a disulfide bond that is crucial for protein translocation and channel gating.

scholarly journals Tim23–Tim50 pair coordinates functions of translocators and motor proteins in mitochondrial protein import

2009 ◽  
Vol 184 (1) ◽  
pp. 129-141 ◽  
Author(s):  
Yasushi Tamura ◽  
Yoshihiro Harada ◽  
Takuya Shiota ◽  
Koji Yamano ◽  
Kazuaki Watanabe ◽  
...  
Keyword(s):  
Motor Proteins ◽  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Intermembrane Space ◽  
Mitochondrial Protein Import ◽  
Inner Membrane ◽  
The Matrix ◽  
General Protein ◽  
Mitochondrial Hsp70

Mitochondrial protein traffic requires coordinated operation of protein translocator complexes in the mitochondrial membrane. The TIM23 complex translocates and inserts proteins into the mitochondrial inner membrane. Here we analyze the intermembrane space (IMS) domains of Tim23 and Tim50, which are essential subunits of the TIM23 complex, in these functions. We find that interactions of Tim23 and Tim50 in the IMS facilitate transfer of precursor proteins from the TOM40 complex, a general protein translocator in the outer membrane, to the TIM23 complex. Tim23–Tim50 interactions also facilitate a late step of protein translocation across the inner membrane by promoting motor functions of mitochondrial Hsp70 in the matrix. Therefore, the Tim23–Tim50 pair coordinates the actions of the TOM40 and TIM23 complexes together with motor proteins for mitochondrial protein import.

Structural basis of mitochondrial protein import by the TIM complex

2021 ◽  
Author(s):  
Sue Im Sim ◽  
Yuanyuan Chen ◽  
Eunyong Park
Keyword(s):  
Protein Import ◽  
Protein Translocation ◽  
Structural Information ◽  
Mitochondrial Protein ◽  
Structural Basis ◽  
Mitochondrial Protein Import ◽  
Conducting Channel ◽  
The Core ◽  
The Matrix ◽  
Membrane Envelope

Mitochondria import nearly all their ~1,000-2,000 constituent proteins from the cytosol across their double membrane envelope. Genetic and biochemical studies have shown that the conserved protein translocase, termed the TIM complex (also known as TIM23 complex), mediates import of presequence-containing proteins into the mitochondrial matrix and inner membrane. Among ~10 different subunits of the complex, the essential multi-pass membrane protein Tim23, together with the evolutionarily related protein Tim17, has long been postulated to form a protein-conducting channel. However, the mechanism of TIM-mediated protein import remains uncertain due to a lack of structural information on the complex. Here, we have determined the cryo-EM structure of the core TIM complex (Tim17-Tim23-Tim44) from Saccharomyces cerevisiae. We show that, contrary to the prevailing model, Tim23 and Tim17 do not form a water-filled channel, but instead have separate, lipid-exposed concave cavities that face in opposite directions. Remarkably, our data suggest that the cavity of Tim17 itself forms the protein translocation path whereas Tim23 plays a structural role. We also show how the Tim17-Tim23 heterodimer associates with the scaffold protein Tim44 and J-domain proteins to mediate Hsp70-driven polypeptide transport into the matrix. Our work provides the structural foundation to understand the mechanism of TIM-mediated protein import and sorting, a central pathway in mitochondrial biogenesis.

scholarly journals Structure and function of Tim14 and Tim16, the J and J-like components of the mitochondrial protein import motor

2006 ◽  
Vol 25 (19) ◽  
pp. 4675-4685 ◽  
Author(s):  
Dejana Mokranjac ◽  
Gleb Bourenkov ◽  
Kai Hell ◽  
Walter Neupert ◽  
Michael Groll
Keyword(s):  
Protein Import ◽  
Mitochondrial Protein ◽  
Structure And Function ◽  
Mitochondrial Protein Import ◽  
And Function

Mitochondrial diseases caused by dysfunctional mitochondrial protein import

2018 ◽  
Vol 46 (5) ◽  
pp. 1225-1238 ◽  
Author(s):  
Thomas Daniel Jackson ◽  
Catherine Sarah Palmer ◽  
Diana Stojanovski
Keyword(s):  
Mitochondrial Disease ◽  
Genetic Disease ◽  
Molecular Basis ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Mitochondrial Diseases ◽  
Mitochondrial Proteins ◽  
Eukaryotic Cells ◽  
Mitochondrial Protein Import ◽  
Mitochondrial Proteome

Mitochondria are essential organelles which perform complex and varied functions within eukaryotic cells. Maintenance of mitochondrial health and functionality is thus a key cellular priority and relies on the organelle's extensive proteome. The mitochondrial proteome is largely encoded by nuclear genes, and mitochondrial proteins must be sorted to the correct mitochondrial sub-compartment post-translationally. This essential process is carried out by multimeric and dynamic translocation and sorting machineries, which can be found in all four mitochondrial compartments. Interestingly, advances in the diagnosis of genetic disease have revealed that mutations in various components of the human import machinery can cause mitochondrial disease, a heterogenous and often severe collection of disorders associated with energy generation defects and a multisystem presentation often affecting the cardiovascular and nervous systems. Here, we review our current understanding of mitochondrial protein import systems in human cells and the molecular basis of mitochondrial diseases caused by defects in these pathways.

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