Central Role of Mic10 in the Mitochondrial Contact Site and Cristae Organizing System

Bohnert, Maria; Zerbes, Ralf M.; Davies, Karen M.; Muhleip, A.; Rampelt, Heike; Horvath, Susanne E.; Boenke, Thorina; Kram, Anita M.; Perschil, Inge; Veenhuis, Marten; Kühlbrandt, Werner; Klei, Ida J. van der; Pfanner, Nikolaus; Laan, Martin van der

doi:10.1016/j.cmet.2015.04.007

Cited by 134 publications

(221 citation statements)

References 33 publications

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“…Interestingly, the MICOS subunit Mic10 was found to be strongly enriched at the sites where septa membranes meet the IBM and the bending of septa is strongest (Figure 5E). This observation is in line with the finding that this MICOS subunit has an important role in the formation of the narrow ring or slot like structure of the crista junctions (Barbot et al, 2015; Bohnert et al, 2015; Milenkovic and Larsson, 2015). …”

Section: Resultssupporting

confidence: 91%

“…Assembly of CJs can take place since a pool of MICOS subunits is present in the IBM (Harner et al, 2011). Interestingly, oligomeric forms of the MICOS subunit Mic10 can induce membrane curvature in vitro and were suggested to form CJs in vivo (Barbot et al, 2015; Bohnert et al, 2015; Milenkovic and Larsson, 2015). We propose that the shape of CJs formed by the MICOS complex determines the tubular shape of nascent cristae.…”

Section: Resultsmentioning

confidence: 99%

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An evidence based hypothesis on the existence of two pathways of mitochondrial crista formation

Harner

Unger

Geerts

et al. 2016

eLife

115

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Metabolic function and architecture of mitochondria are intimately linked. More than 60 years ago, cristae were discovered as characteristic elements of mitochondria that harbor the protein complexes of oxidative phosphorylation, but how cristae are formed, remained an open question. Here we present experimental results obtained with yeast that support a novel hypothesis on the existence of two molecular pathways that lead to the generation of lamellar and tubular cristae. Formation of lamellar cristae depends on the mitochondrial fusion machinery through a pathway that is required also for homeostasis of mitochondria and mitochondrial DNA. Tubular cristae are formed via invaginations of the inner boundary membrane by a pathway independent of the fusion machinery. Dimerization of the F1FO-ATP synthase and the presence of the MICOS complex are necessary for both pathways. The proposed hypothesis is suggested to apply also to higher eukaryotes, since the key components are conserved in structure and function throughout evolution.DOI: http://dx.doi.org/10.7554/eLife.18853.001

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

An evidence based hypothesis on the existence of two pathways of mitochondrial crista formation

Harner

Unger

Geerts

et al. 2016

eLife

115

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“…Mic19 connects the two sub-complexes (Friedman et al., 2015). This picture is less clear in mammals: first, a homolog of Mic12 has not been yet identified; second, the existence of these two sub-complexes remains unexplored (Huynen et al., 2016); third, silencing of the mammalian homolog of yeast Mic10 does not alter cristae shape, whereas in yeast, its deletion results in a thylakoid-like cristae morphology (Alkhaja et al., 2012, Barbot et al., 2015, Bohnert et al., 2015). Thus, MICOS complex composition and regulation may have changed during vertebrate evolution, perhaps to accommodate its recruitment into the process of apoptotic cristae remodeling.…”

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 complex is composed of six conserved core subunits, organized into at least two functionally non-redundant subcomplexes. [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.…”

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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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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Central Role of Mic10 in the Mitochondrial Contact Site and Cristae Organizing System

Cited by 134 publications

References 33 publications

An evidence based hypothesis on the existence of two pathways of mitochondrial crista formation

An evidence based hypothesis on the existence of two pathways of mitochondrial crista formation

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

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

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