The MICOS complex, a structural element of mitochondria with versatile functions

2020 ◽  
Vol 401 (6-7) ◽  
pp. 765-778
Author(s):  
Siavash Khosravi ◽  
Max E. Harner
Keyword(s):  
Mitochondrial Membrane ◽  
Protein Import ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Inner Mitochondrial Membrane ◽  
Structural Element ◽  
Charcot Marie Tooth Disease ◽  
Form And Function ◽  
Steroidogenic Cells ◽  
And Function

AbstractMitochondria perform a plethora of functions in various cells of different tissues. Their architecture differs remarkably, for instance in neurons versus steroidogenic cells. Furthermore, aberrant mitochondrial architecture results in mitochondrial dysfunction. This indicates strongly that mitochondrial architecture and function are intimately linked. Therefore, a deep knowledge about the determinants of mitochondrial architecture and their function on a molecular level is of utmost importance. In the past decades, various proteins and protein complexes essential for formation of mitochondrial architecture have been identified. Here we will review the current knowledge of the MICOS complex, one of the major structural elements of mitochondria. MICOS is a multi-subunit complex present in the inner mitochondrial membrane. Multiple interaction partners in the inner and outer mitochondrial membrane point to participation in a multitude of important processes, such as generation of mitochondrial architecture, lipid metabolism, and protein import into mitochondria. Since the MICOS complex is highly conserved in form and function throughout evolution, we will highlight the importance of MICOS for mammals. We will emphasize in particular the current knowledge of the association of MICOS with severe human diseases, including Charcot–Marie–Tooth disease type 2, Alzheimer's disease, Parkinson's disease, Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

scholarly journals The mycotoxin phomoxanthone A disturbs the form and function of the inner mitochondrial membrane

2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Philip Böhler ◽  
Fabian Stuhldreier ◽  
Ruchika Anand ◽  
Arun Kumar Kondadi ◽  
David Schlütermann ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Form And Function ◽  
And Function

Structure and function of Pet100p, a molecular chaperone required for the assembly of cytochrome c oxidase in Saccharomyces cerevisiae

2001 ◽  
Vol 29 (4) ◽  
pp. 436-441 ◽  
Author(s):  
D. Forsha ◽  
C. Church ◽  
P. Wazny ◽  
R. O. Poyton
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Molecular Chaperone ◽  
Mitochondrial Membrane ◽  
Protein Complexes ◽  
Structure And Function ◽  
Eukaryotic Cells ◽  
Mitochondrial Membranes ◽  
Inner Mitochondrial Membrane ◽  
And Function

The assembly of cytochrome c oxidase in the inner mitochondrial membranes of eukaryotic cells requires the protein products of a large number of nuclear genes. In yeast, some of these act globally and affect the assembly of several respiratory-chain protein complexes, whereas others act in a cytochrome c oxidase-specific fashion. Many of these yeast proteins have human counterparts, which when mutated lead to energy-related diseases. One of these proteins, Pet100p, is a novel molecular chaperone that functions to incorporate a subcomplex containing cytochrome c oxidase subunits VII, VIIa and VIII into holo-(cytochrome c oxidase). Here we report the topological disposition of Pet100p in the inner mitochondrial membrane and show that its C-terminal domain is essential for its function as a cytochrome c oxidase-specific ‘assembly facilitator’.

scholarly journals Transmembrane BAX Inhibitor-1 Motif Containing Protein 5 (TMBIM5) Sustains Mitochondrial Structure, Shape, and Function by Impacting the Mitochondrial Protein Synthesis Machinery

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2147
Author(s):  
Bruno Seitaj ◽  
Felicia Maull ◽  
Li Zhang ◽  
Verena Wüllner ◽  
Christina Wolf ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Synthesis ◽  
Mitochondrial Membrane ◽  
Mitochondrial Protein ◽  
Mitochondrial Protein Synthesis ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Structure ◽  
Protein Synthesis Machinery ◽  
Atp Generation ◽  
And Function

The Transmembrane Bax Inhibitor-1 motif (TMBIM)-containing protein family is evolutionarily conserved and has been implicated in cell death susceptibility. The only member with a mitochondrial localization is TMBIM5 (also known as GHITM or MICS1), which affects cristae organization and associates with the Parkinson’s disease-associated protein CHCHD2 in the inner mitochondrial membrane. We here used CRISPR-Cas9-mediated knockout HAP1 cells to shed further light on the function of TMBIM5 in physiology and cell death susceptibility. We found that compared to wild type, TMBIM5-knockout cells were smaller and had a slower proliferation rate. In these cells, mitochondria were more fragmented with a vacuolar cristae structure. In addition, the mitochondrial membrane potential was reduced and respiration was attenuated, leading to a reduced mitochondrial ATP generation. TMBIM5 did not associate with Mic10 and Mic60, which are proteins of the mitochondrial contact site and cristae organizing system (MICOS), nor did TMBIM5 knockout affect their expression levels. TMBIM5-knockout cells were more sensitive to apoptosis elicited by staurosporine and BH3 mimetic inhibitors of Bcl-2 and Bcl-XL. An unbiased proteomic comparison identified a dramatic downregulation of proteins involved in the mitochondrial protein synthesis machinery in TMBIM5-knockout cells. We conclude that TMBIM5 is important to maintain the mitochondrial structure and function possibly through the control of mitochondrial biogenesis.

Abstract 15070: Micu1 Regulates Mitochondrial Cristae Structure and Function Independent of the Mitochondrial Calcium Uniporter Channel

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Dhanendra Tomar ◽  
Manfred Thomas ◽  
Joanne Garbincius ◽  
Devin Kolmetzky ◽  
Oniel Salik ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Coiled Coil ◽  
Structure And Function ◽  
Membrane Dynamics ◽  
Size Exclusion ◽  
Null Mouse ◽  
Intermembrane Space ◽  
Inner Mitochondrial Membrane ◽  
Cytochrome C Release ◽  
And Function

Background: MICU1 is an EF-hand domain containing Ca 2+ -sensor regulating the mitochondrial Ca 2+ uniporter channel and mitochondrial Ca 2+ uptake. MICU1-null mouse and fly models display perinatal lethality with disorganized mitochondrial architecture. Interestingly, these phenotypes are distinct from other mtCU loss-of-function models ( MCU, MICU2, EMRE, MCUR1 ) and thus are likely not explained solely by changes in matrix Ca 2+ content. Using size-exclusion proteomics and co-immunofluorescence, we found that MICU1 localizes to mitochondrial complexes lacking MCU. These observations suggest that MICU1 may have additional cellular functions independent of the MCU. Methods: Biotin-based proximity labeling and proteomics, protein biochemistry, live-cell Ca 2+ imaging, electron microscopy, confocal and super-resolution imaging were utilized to identify and validate MICU1 novel functions. Results: The expression of a MICU1-BioID2 fusion protein in MCU +/+ and MCU -/- cells allowed the identification of the total vs. MCU-independent MICU1 interactome. LC-MS analysis of purified biotinylated proteins identified the mitochondrial contact site and cristae organizing system (MICOS) components Mitofilin (MIC60) and Coiled-coil-helix-coiled-coil helix domain containing 2 (CHCHD2) as MCU independent novel MICU1 interactors. We demonstrate that MICU1 is essential for proper organization of the MICOS complex and that MICU1 ablation results in altered cristae organization, mitochondrial ultrastructure, mitochondrial membrane dynamics, membrane potential, and cell death signaling. We hypothesize that MICU1 is a MICOS Ca 2+ - sensor since perturbing MICU1 is sufficient to modulate cytochrome c release independent of Ca 2+ uptake across the inner mitochondrial membrane. Conclusions: Here, we provide the first experimental evidence of an intermembrane space Ca 2+ - sensor regulating mitochondrial membrane dynamics, independent of changes in matrix Ca 2+ content. This study provides a novel paradigm to understand Ca 2+ -dependent regulation of mitochondrial structure and function and may help explain the mitochondrial remodeling reported to occur in numerous disease states.

scholarly journals On a bender—BARs, ESCRTs, COPs, and finally getting your coat

2011 ◽  
Vol 193 (6) ◽  
pp. 963-972 ◽  
Author(s):  
Mark C. Field ◽  
Andrej Sali ◽  
Michael P. Rout
Keyword(s):  
Comparative Genomics ◽  
Protein Complexes ◽  
Eukaryotic Cell ◽  
Intracellular Membrane ◽  
Membrane Systems ◽  
Profound Impact ◽  
Form And Function ◽  
Evolutionary Origins ◽  
And Function ◽  
Internal Architecture

Tremendous variety in form and function is displayed among the intracellular membrane systems of different eukaryotes. Until recently, few clues existed as to how these internal membrane systems had originated and diversified. However, proteomic, structural, and comparative genomics studies together have revealed extensive similarities among many of the protein complexes used in controlling the morphology and trafficking of intracellular membranes. These new insights have had a profound impact on our understanding of the evolutionary origins of the internal architecture of the eukaryotic cell.

Composition and function of PDZ protein complexes during cell polarization

2003 ◽  
Vol 285 (3) ◽  
pp. F377-F387 ◽  
Author(s):  
Michael H. Roh ◽  
Ben Margolis
Keyword(s):  
Epithelial Cells ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Cell Types ◽  
Cell Polarization ◽  
Differential Distribution ◽  
Pdz Proteins ◽  
Homologous Protein ◽  
Pdz Protein ◽  
And Function

Complexes consisting of PDZ proteins have been implicated in a variety of cellular processes. In recent years, it has become increasingly clear that PDZ proteins play essential roles during the establishment of spatial asymmetry in various metazoan cell types such as epithelial cells. Epithelial cells possess asymmetry with respect to the apicobasal axis reflected by the differential distribution of proteins and lipids in the apical and basolateral surfaces. In Drosophila, three PDZ protein complexes have been shown to play crucial functions during the establishment of cell-cell adhesions and epithelial cell polarity: Bazooka/Dm-Par6/DaPKC, Crumbs/Stardust/Discs Lost, and Scribble/Discs Large/Lethal Giant Larvae. In this review, we focus primarily on our current knowledge of the localization and function of these complexes in Drosophila epithelia. We also discuss recent data that enhance our understanding of the homologous protein complexes and their roles during junctional assembly and polarization of mammalian epithelial cells.

Protein import into mitochondria

2005 ◽  
Vol 33 (5) ◽  
pp. 1019-1023 ◽  
Author(s):  
D. Mokranjac ◽  
W. Neupert
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane ◽  
Protein Import ◽  
Molecular Machines ◽  
Energy Sources ◽  
Inner Mitochondrial Membrane ◽  
Inner Membrane ◽  
Preprotein Translocation ◽  
Almost All

Mitochondria comprise approx. 1000–3000 different proteins, almost all of which must be imported from the cytosol into the organelle. So far, six complex molecular machines, protein translocases, were identified that mediate this process. The TIM23 complex is a major translocase in the inner mitochondrial membrane. It uses two energy sources, namely membrane potential and ATP, to facilitate preprotein translocation across the inner membrane and insertion into the inner membrane. Recent research has led to the discovery of a number of new constituents of the TIM23 complex and to the unravelling of the mechanisms of preprotein translocation.

scholarly journals Amyloid-Beta Interaction with Mitochondria

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Lucia Pagani ◽  
Anne Eckert
Keyword(s):  
Mitochondrial Dysfunction ◽  
Amyloid Beta ◽  
Mitochondrial Membrane ◽  
Current Knowledge ◽  
Mitochondrial Dynamics ◽  
Intracellular Localization ◽  
Protein A ◽  
Postmortem Brain ◽  
Intermembrane Space ◽  
Inner Mitochondrial Membrane

Mitochondrial dysfunction is a hallmark of amyloid-beta(Aβ)-induced neuronal toxicity in Alzheimer's disease (AD). The recent emphasis on the intracellular biology of Aβand its precursor protein (AβPP) has led researchers to consider the possibility that mitochondria-associated and/or intramitochondrial Aβmay directly cause neurotoxicity. In this paper, we will outline current knowledge of the intracellular localization of both Aβand AβPP addressing the question of how Aβcan access mitochondria. Moreover, we summarize evidence from AD postmortem brain as well as cellular and animal AD models showing that Aβtriggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species (ROS) production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. In particular, we focus on Aβinteraction with different mitochondrial targets including the outer mitochondrial membrane, intermembrane space, inner mitochondrial membrane, and the matrix. Thus, this paper establishes a modified model of the Alzheimer cascade mitochondrial hypothesis.

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