Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex

Huynen, Martijn A.; Mühlmeister, Mareike; Gotthardt, Katherina; Guerrero–Castillo, Sergio; Brandt, Ulrich

doi:10.1016/j.bbamcr.2015.10.009

Cited by 170 publications

(212 citation statements)

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“…QIL1/MIC13 is a recently described core component of MICOS complex (Figure 3b) and a structural ortholog of yeast Mic12. 10 MICOS is proposed to act as a master regulator/integrator of IMM shape and organization. In human cells the MICOS complex forms from a stable MIC60-MIC19-MIC25 subcomplex that requires QIL1/ MIC13 for the binding of MIC10, MIC26 and MIC27.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9] Recently the Human protein QIL1/MIC13 was identified as the structural ortholog of yeast Mic12 and was shown to be required for MICOS complex stability. 8,10 Specifically, loss of QIL1/MIC13 in cells leads to destabilization of human MIC10, MIC26 and MIC27 and consequently severe IMM morphological defects. 8 Here we report that variants in QIL1/MIC13 cause a mitochondrial disease in humans, underscoring the conservation of MICOS in mitochondrial ultrastructure and its importance for mitochondrial function in human physiology.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit

et al. 2016

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The mitochondrial inner membrane possesses distinct subdomains including cristae, which are lamellar structures invaginated into the mitochondrial matrix and contain the respiratory complexes. Generation of inner membrane domains requires the complex interplay between the respiratory complexes, mitochondrial lipids and the recently identified mitochondrial contact site and cristae organizing system (MICOS) complex. Proper organization of the mitochondrial inner membrane has recently been shown to be important for respiratory function in yeast. Here we aimed at a molecular diagnosis in a brother and sister from a consanguineous family who presented with a neurodegenerative disorder accompanied by hyperlactatemia, 3-methylglutaconic aciduria, disturbed hepatocellular function with abnormal cristae morphology in liver and cerebellar and vermis atrophy, which suggest mitochondrial dysfunction. Using homozygosity mapping and exome sequencing the patients were found to be homozygous for the p.(Gly15Glufs*75) variant in the QIL1/MIC13 (C19orf70) gene. QIL1/MIC13 is a constituent of MICOS, a six subunit complex that helps to form and/or stabilize cristae junctions and determine the placement, distribution and number of cristae within mitochondria. In patient fibroblasts both MICOS subunits QIL1/MIC13 and MIC10 were absent whereas MIC60 was present in a comparable abundance to that of the control. We conclude that QIL1/MIC13 deficiency in human, is associated with disassembly of the MICOS complex, with the associated aberration of cristae morphology and mitochondrial respiratory dysfunction. 3-Methylglutaconic aciduria is associated with variants in genes encoding mitochondrial inner membrane organizing determinants, including TAZ, DNAJC19, SERAC1 and QIL1/MIC13.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit

et al. 2016

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“…In addition to OPA1, a large complex, the mitochondrial contact site and cristae organizing system (MICOS) regulates CJ biogenesis in multiple organisms (Herrmann, 2011, Huynen et al., 2016, Jans et al., 2013, John et al., 2005, van der Laan et al., 2016, Zerbes et al., 2012). In yeast, MICOS can be subdivided into a sub-complex formed by Mic27, Mic10, and Mic12 and a second one comprising Mic60 (mitofilin) and Mic19 (CHCHD3).…”

Section: Introductionmentioning

confidence: 99%

Optic Atrophy 1 Is Epistatic to the Core MICOS Component MIC60 in Mitochondrial Cristae Shape Control

et al. 2016

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SummaryThe mitochondrial contact site and cristae organizing system (MICOS) and Optic atrophy 1 (OPA1) control cristae shape, thus affecting mitochondrial function and apoptosis. Whether and how they physically and functionally interact is unclear. Here, we provide evidence that OPA1 is epistatic to MICOS in the regulation of cristae shape. Proteomic analysis identifies multiple MICOS components in native OPA1-containing high molecular weight complexes disrupted during cristae remodeling. MIC60, a core MICOS protein, physically interacts with OPA1, and together, they control cristae junction number and stability, OPA1 being epistatic to MIC60. OPA1 defines cristae width and junction diameter independently of MIC60. Our combination of proteomics, biochemistry, genetics, and electron tomography provides a unifying model for mammalian cristae biogenesis by OPA1 and MICOS.

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“…The MICOS/mitochondrial intermembrane space-bridging (MIB) proteins are critical for normal inner membrane morphology and cristae formation (46). However, little information was available for the MICOS complex, a subcomplex of the MIB complex.…”

Section: Protein Sitementioning

confidence: 99%

Mitochondrial protein interactome elucidated by chemical cross-linking mass spectrometry

Schweppe

Chavez

Lee

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

182

206

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Mitochondrial protein interactions and complexes facilitate mitochondrial function. These complexes range from simple dimers to the respirasome supercomplex consisting of oxidative phosphorylation complexes I, III, and IV. To improve understanding of mitochondrial function, we used chemical cross-linking mass spectrometry to identify 2,427 cross-linked peptide pairs from 327 mitochondrial proteins in whole, respiring murine mitochondria. In situ interactions were observed in proteins throughout the electron transport chain membrane complexes, ATP synthase, and the mitochondrial contact site and cristae organizing system (MICOS) complex. Cross-linked sites showed excellent agreement with empirical protein structures and delivered complementary constraints for in silico protein docking. These data established direct physical evidence of the assembly of the complex I-III respirasome and enabled prediction of in situ interfacial regions of the complexes. Finally, we established a database and tools to harness the cross-linked interactions we observed as molecular probes, allowing quantification of conformation-dependent protein interfaces and dynamic protein complex assembly. mitochondria | mass spectrometry | interactome | cross-linking | protein interaction reporter M itochondrial proteins play a diverse role in cellular biology and disease. Mitochondrial dysfunction directly causes multiple inherited diseases (1) and is implicated in common diseases, including neurological developmental disorders (2, 3), neurodegenerative and cardiovascular diseases (4-6), diabetes (7), asthma (8), cancer (9), and age-related disease (10). In mammals, these organelles have evolved to retain more than 1,000 proteins that interact within a complex, i.e., dual membrane architecture (11,12). Within the mitochondrial proteome, the "powerhouse" functions are carried out by the core constituents of the oxidative phosphorylation (OXPHOS) system [complexes I-IV of the electron transport chain (ETC) and ATP synthase (complex V)]. These proteins are necessary for creation of the mitochondrial electrochemical gradient that powers synthesis of ATP. This system includes critical protein-protein interactions within individual OXPHOS complexes as well as "supercomplex" interactions between ETC complexes I, III, and IV in the respirasome (13). Deficient supercomplex formation has been proposed as a critical mitochondrial defect in failing hearts (5,6,14,15), and dynamic rearrangement of supercomplexes has been implicated in noncanonical mitochondrial functions such as antibacterial innate immune responses (16). Assessing these interactions is further complicated by regulatory posttranslational modification and conformational changes of mitochondrial proteins (17)(18)(19)(20). Advances in this area have been impeded, in part, by the lack of large-scale detection of dynamic, sometimes transient, interactions between membrane proteins. Thus, large-scale determination of the protein interactome within mitochondria would provide a valuable tool to adv...

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Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex

Cited by 170 publications

References 82 publications

Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit

Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit

Optic Atrophy 1 Is Epistatic to the Core MICOS Component MIC60 in Mitochondrial Cristae Shape Control

Mitochondrial protein interactome elucidated by chemical cross-linking mass spectrometry

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