Unlocking the presequence import pathway

Schulz, Christian; Schendzielorz, Alexander Benjamin; Rehling, Peter

doi:10.1016/j.tcb.2014.12.001

Cited by 154 publications

(171 citation statements)

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“…The TIM23 complex mediates protein transport into the matrix and lateral release into the inner membrane. TIM23 subunits dynamically interact with the PAM module for transport into the matrix (3)(4)(5)(6)(7)(8)(9). Furthermore, the TIM23 complex interacts with the TOM complex during preprotein transfer.…”

Section: Discussionmentioning

confidence: 99%

“…More than 99% of the mitochondrial proteins are synthesized as precursors on cytosolic ribosomes. Mitochondria contain a sophisticated system of protein translocases to import precursor proteins (3)(4)(5)(6)(7)(8)(9). The translocase of the outer membrane (TOM 3 complex) forms the general entry gate for most precursor proteins.…”

mentioning

confidence: 99%

“…Two inner membrane-bound protein complexes mediate protein import. The presequence translocase (also termed TIM23 complex) transports precursor proteins with a cleavable presequence into the inner membrane and the matrix, whereas the carrier translocase (also termed TIM22 complex) inserts proteins with multiple transmembrane segments into the inner membrane (3)(4)(5)(6)(7)(8)(9). The membrane potential across the inner membrane provides the driving force for both protein import pathways and is generated by the activity of the respiratory chain.…”

mentioning

confidence: 99%

“…For transport into the mitochondrial matrix, the TIM23 complex dynamically associates with the presequence translocase-associated motor (PAM). The ATP consuming activity of the mitochondrial Hsp70 within the PAM module completes preprotein transport into the matrix (3)(4)(5)(6)(7)(8)(9). Finally, the presequence is removed by the mitochondrial processing peptidase.…”

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confidence: 99%

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Phosphatidylcholine Affects Inner Membrane Protein Translocases of Mitochondria

Schuler¹,

Bartolomeo

Mårtensson

et al. 2016

Journal of Biological Chemistry

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Two protein translocases transport precursor proteins into or across the inner mitochondrial membrane. The presequence translocase (TIM23 complex) sorts precursor proteins with a cleavable presequence either into the matrix or into the inner membrane. The carrier translocase (TIM22 complex) inserts multispanning proteins into the inner membrane. Both protein import pathways depend on the presence of a membrane potential, which is generated by the activity of the respiratory chain. The non-bilayer-forming phospholipids cardiolipin and phosphatidylethanolamine are required for the activity of the respiratory chain and therefore to maintain the membrane potential for protein import. Depletion of cardiolipin further affects the stability of the TIM23 complex. The role of bilayer-forming phospholipids like phosphatidylcholine (PC) in protein transport into the inner membrane and the matrix is unknown. Here, we report that import of presequence-containing precursors and carrier proteins is impaired in PC-deficient mitochondria. Surprisingly, depletion of PC does not affect stability and activity of respiratory supercomplexes, and the membrane potential is maintained. Instead, the dynamic TIM23 complex is destabilized when the PC levels are reduced, whereas the TIM22 complex remains intact. Our analysis further revealed that initial precursor binding to the TIM23 complex is impaired in PC-deficient mitochondria. We conclude that reduced PC levels differentially affect the TIM22 and TIM23 complexes in mitochondrial protein transport.Mitochondria fulfill essential functions for the survival of the cell like energy conversion to produce ATP, synthesis of amino acids, lipids, and heme, as well as the generation of iron-sulfur clusters. They contain about 1000 proteins in yeast and 1500 proteins in humans (1, 2). More than 99% of the mitochondrial proteins are synthesized as precursors on cytosolic ribosomes. Mitochondria contain a sophisticated system of protein translocases to import precursor proteins (3-9). The translocase of the outer membrane (TOM 3 complex) forms the general entry gate for most precursor proteins. After passage of the TOM channel, distinct protein translocases sort the preproteins into the different subcompartments: the outer and inner membrane as well as the two aqueous compartments, the matrix and intermembrane space.The majority of mitochondrial proteins are sorted into the inner membrane and the matrix. Two inner membrane-bound protein complexes mediate protein import. The presequence translocase (also termed TIM23 complex) transports precursor proteins with a cleavable presequence into the inner membrane and the matrix, whereas the carrier translocase (also termed TIM22 complex) inserts proteins with multiple transmembrane segments into the inner membrane (3-9). The membrane potential across the inner membrane provides the driving force for both protein import pathways and is generated by the activity of the respiratory chain. Presequence-containing preproteins are directly transferred from the ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Phosphatidylcholine Affects Inner Membrane Protein Translocases of Mitochondria

Schuler¹,

Bartolomeo

Mårtensson

et al. 2016

Journal of Biological Chemistry

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“…It is now evident that most of our understanding of the mitochondrial protein import process has been derived from studies in the yeast system and there has been considerable advance in the understanding of how nuclear-encoded precursor proteins are translocated across and into the membranes of mitochondria (Schulz et al, 2015;Sokol et al, 2014). Human mitochondria translocation machineries were being thought to be similar to that of yeast (Bauer et al., 1999).…”

Section: Human Mitochondrial Protein Transport -An Enigmamentioning

confidence: 99%

Post Genomics Identification of Blood Stage Invasins of Plasmodium Falciparum

Chauhan¹

2017

Proceedings of the Indian National Science Academy

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Human mitochondria require ~1500 proteins for its constitutive functions. However, the mitochondrial genome is gene deficient and most of the mitochondrial proteome is nuclear encoded and transported into the organelle. Import of majority of mitochondrial proteome is mediated by presequence pathway and requires functional interplay between a subset of molecular chaperones, along with accessory factors. Although detailed analysis has been carried out in yeast system, our understanding of human mitochondrial proteome maintenance has been severely limited by the absence of significant structural and functional information on the organization TIM23 complex in humans. Recent studies have revealed the presence of multiple presequence translocases in human mitochondria that show considerable diversity in their substrate and physiological specificity. The core organization and inter-molecular interactions between these machineries seems to be evolutionary conserved. These translocases have principally diversified due to divergence of Hsp70 co-chaperones and channel component Tim17. Another important feature associated with human mitochondrial translocases, which in most cases are absent in lower eukaryotes, is its multifunctionality. Other than housekeeping protein import, human mitochondrial translocases have gained secondary functions such asinvolvment in ROS sensing and regulation of redox balance, modulation of cellular sensitivity to xenobiotic drugs, maintenance of mitochondrial DNA, assembly of respiratory complexes' and import of non-canonical mitochondrial substrates. The origin of multifunctionality is indicative towards the possibility of functional connections between mitochondrial protein import and regulation of cellular pathways; hence, opening up new avenues of future research. Keywords IntroductionMitochondria are endosymbiotic cellular organelle enclosed in double membrane and form an integral part of eukaryotic cells. The word mitochondrion comes from the Greek ìßôïò, mitos, i.e. "thread", and ÷ïíäñßïí, chondrion, i.e. "granule". The term "mitochondria" was coined by Carl Benda in 1898 (cited in Margulis, 1970). Benjamin F. Kingsbury (1912) first related these organelles with cell respiration (cited in Sagan, 1967), followed by Otto Heinrich Warburg (Ernster and Schatz, 1981; Gray et al., 1999). In addition to supplying cellular energy, mitochondria are involved in other tasks such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth (Gray et al., 1999). Mitochondria have been implicated in several human diseases, including mitochondrial disorders and cardiac dysfunction, and may play a role in the aging process (Fulda et al., 2010; Gulbins et al., 2003; Hayashi et al., 2009; Kroemer, 2006; Lesnefsky et al., 2001; McBride et al., 2006).Mitochondrial genomes are very small and show a great deal of variation as a result of divergent evolution (Ernster and Schatz, 1981; Henze and Martin, 2003; Peng et al., 2005). The human mitochondrial geno...

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Mitochondrial proteases in human diseases

Gala

Vögtle

2021

FEBS Letters

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Mitochondria contain more than 1000 different proteins, including several proteolytic enzymes. These mitochondrial proteases form a complex system that performs limited and terminal proteolysis to build the mitochondrial proteome, maintain and control its functions or degrade mitochondrial proteins and peptides. During protein biogenesis presequence proteases cleave and degrade mitochondrial targeting signals to obtain mature functional proteins. Processing by proteases also exerts a regulatory role in modulation of mitochondrial functions and quality control enzymes degrade misfolded, aged or superfluous proteins. Depending on their different functions and substrates, defects in mitochondrial proteases can affect the majority of the mitochondrial proteome or only a single protein. Consequently, mutations in mitochondrial proteases have been linked to several human diseases. This review gives an overview of the components and functions of the mitochondrial proteolytic machinery and highlights the pathological consequences of dysfunctional mitochondrial protein processing and turnover.

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Unlocking the presequence import pathway

Cited by 154 publications

References 123 publications

Phosphatidylcholine Affects Inner Membrane Protein Translocases of Mitochondria

Phosphatidylcholine Affects Inner Membrane Protein Translocases of Mitochondria

Post Genomics Identification of Blood Stage Invasins of Plasmodium Falciparum

Mitochondrial proteases in human diseases

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