Mgr2 regulates mitochondrial preprotein import by associating with channel-forming Tim23 subunit

Matta, Srujan Kumar; Kumar, Abhishek; D’Silva, Patrick

doi:10.1091/mbc.e19-12-0677

Cited by 17 publications

(11 citation statements)

References 77 publications

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“…For translocation of MIM proteins containing the hydrophobic sorting sequence, Pam17 dissociates from TIM23 when the hydrophobic region of the precursor protein reaches the TIM23 channel. At this point, Mgr2 recruits Tim21 to the TIM23 translocase, and the channel opens laterally for translocation of the protein to the MIM [92]. many HAD phosphatases also possesses a similar substrate-binding groove with the signature sequence hhhhDxDx(T/V)(L/I)h (h, hydrophobic residue) [77].…”

Section: Role Of Tim50 In Mitochondrial Protein Importmentioning

confidence: 99%

Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase

Chaudhuri

Tripathi

Gonzalez

2021

IJMS

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Mitochondria are essential in eukaryotes. Besides producing 80% of total cellular ATP, mitochondria are involved in various cellular functions such as apoptosis, inflammation, innate immunity, stress tolerance, and Ca2+ homeostasis. Mitochondria are also the site for many critical metabolic pathways and are integrated into the signaling network to maintain cellular homeostasis under stress. Mitochondria require hundreds of proteins to perform all these functions. Since the mitochondrial genome only encodes a handful of proteins, most mitochondrial proteins are imported from the cytosol via receptor/translocase complexes on the mitochondrial outer and inner membranes known as TOMs and TIMs. Many of the subunits of these protein complexes are essential for cell survival in model yeast and other unicellular eukaryotes. Defects in the mitochondrial import machineries are also associated with various metabolic, developmental, and neurodegenerative disorders in multicellular organisms. In addition to their canonical functions, these protein translocases also help maintain mitochondrial structure and dynamics, lipid metabolism, and stress response. This review focuses on the role of Tim50, the receptor component of one of the TIM complexes, in different cellular functions, with an emphasis on the Tim50 homologue in parasitic protozoan Trypanosoma brucei.

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Section: Role Of Tim50 In Mitochondrial Protein Importmentioning

confidence: 99%

Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase

Chaudhuri

Tripathi

Gonzalez

2021

IJMS

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“…Using a chimaeric version of Tim17–Pam18, they could show that Pam18 association the TIM23 complex (TIM23MOTOR) inhibited the lateral release of hydrophobic protein sequences, suggesting that Pam18 blocks the lateral gate of Tim23 [ 60 ]. A second conformation of the TIM23 complex containing Tim21 (TIM23SORT) is instead used for the partitioning of hydrophobic sequences into the inner membrane [ 61 ] aided by the gatekeeping protein Mgr2 [ 59 , 62 ]. Following lateral release, the matrix targeting presequence is cleaved by the matrix processing peptidase (MPP), while a second cleavage by the Imp1 or Imp2 proteases in the IMS releases the final mature protein domain in the IMS [ 56 ].…”

Section: Alternative Ims Import Pathwaysmentioning

confidence: 99%

The mitochondrial intermembrane space: the most constricted mitochondrial sub-compartment with the largest variety of protein import pathways

2021

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The mitochondrial intermembrane space (IMS) is the most constricted sub-mitochondrial compartment, housing only about 5% of the mitochondrial proteome, and yet is endowed with the largest variability of protein import mechanisms. In this review, we summarize our current knowledge of the major IMS import pathway based on the oxidative protein folding pathway and discuss the stunning variability of other IMS protein import pathways. As IMS-localized proteins only have to cross the outer mitochondrial membrane, they do not require energy sources like ATP hydrolysis in the mitochondrial matrix or the inner membrane electrochemical potential which are critical for import into the matrix or insertion into the inner membrane. We also explore several atypical IMS import pathways that are still not very well understood and are guided by poorly defined or completely unknown targeting peptides. Importantly, many of the IMS proteins are linked to several human diseases, and it is therefore crucial to understand how they reach their normal site of function in the IMS. In the final part of this review, we discuss current understanding of how such IMS protein underpin a large spectrum of human disorders.

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“…Tim21 also promotes bridging of TIM23 with the respiratory chain complexes III and IV. Mgr2 interacts with both Tim23 and Tim21 via its transmembrane domain and helps recruit the respiratory chain complexes in the near vicinity of TIM23 channel, thereby participating in lateral targeting of preproteins into the IMM [Matta et al., 2020]. In addition, Tim17 plays a vital role in the sorting of membrane precursor proteins [Chacinska et al., 2009; Endo and Yamano, 2009; Wagner et al., 2009; Mokranjac and Neupert, 2010; van der Laan et al., 2010; Marom et al., 2011].…”

Section: Protein Import Pathways Into Mitochondriamentioning

confidence: 99%

Mitochondrial protein import as a quality control sensor

Maity

Chakrabarti

2021

Biology of the Cell

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Mitochondria are organelles involved in various functions related to cellular metabolism and homoeostasis. Though mitochondria contain own genome, their nuclear counterparts encode most of the different mitochondrial proteins. These are synthesised as precursors in the cytosol and have to be delivered into the mitochondria. These organelles hence have elaborate machineries for the import of precursor proteins from cytosol. The protein import machineries present in both mitochondrial membrane and aqueous compartments show great variability in pre‐protein recognition, translocation and sorting across or into it. Mitochondrial protein import machineries also interact transiently with other protein complexes of the respiratory chain or those involved in the maintenance of membrane architecture. Hence mitochondrial protein translocation is an indispensable part of the regulatory network that maintains protein biogenesis, bioenergetics, membrane dynamics and quality control of the organelle. Various stress conditions and diseases that are associated with mitochondrial import defects lead to changes in cellular transcriptomic and proteomic profiles. Dysfunction in mitochondrial protein import also causes over‐accumulation of precursor proteins and their aggregation in the cytosol. Multiple pathways may be activated for buffering these harmful consequences. Here, we present a comprehensive picture of import machinery and its role in cellular quality control in response to defective mitochondrial import. We also discuss the pathological consequences of dysfunctional mitochondrial protein import in neurodegeneration and cancer.

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Mgr2 regulates mitochondrial preprotein import by associating with channel-forming Tim23 subunit

Cited by 17 publications

References 77 publications

Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase

Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase

The mitochondrial intermembrane space: the most constricted mitochondrial sub-compartment with the largest variety of protein import pathways

Mitochondrial protein import as a quality control sensor

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