Formation of cristae and crista junctions in mitochondria depends on antagonism between Fcj1 and Su <i>e</i>/<i>g</i>

Rabl, Regina; Soubannier, Vincent; Scholz, Roland; Vogel, Frank; Mendl, Nadine; Vasiljev-Neumeyer, Andreja; Körner, Christian; Jagasia, Ravi; Keil, Thomas A.; Baumeister, Wolfgang; Cyrklaff, Marek; Neupert, Walter; Reichert, Andreas S.

doi:10.1083/jcb.200811099

Cited by 282 publications

(516 citation statements)

References 65 publications

(103 reference statements)

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“…In addition, stacked IMM disconnected from the IBMs were observed in the liver mitochondria of our patient -a characteristic phenotype similar to that observed in yeast and human cells lacking MICOS function. [4][5][6]8,[11][12][13] The cause of deterioration in our patients could be the mitochondrial respiratory chain dysfunction, which mainly affected the central nervous system, the liver and the heart. The respiratory growth defect observed in yeast strains lacking MICOS has been attributed to impaired organization and/or position of the respiratory complex III and IV.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…Yeast strains W303, BY4742, Δe in W303, Δe in BY4742, Δg in W303, Δg in BY4742, Δk in W303 and 4ΔTM1 in D273-10B [EUROSCAF, (3,16)] were grown under nonfermentable conditions as described (43). Mitochondria were isolated by enzymatic digestion of the cell wall, followed by differential centrifugation as described (44).…”

Section: Methodsmentioning

confidence: 99%

Structure of the yeast F ₁ F _o -ATP synthase dimer and its role in shaping the mitochondrial cristae

Davies

Anselmi

Wittig

et al. 2012

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

438

510

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We used electron cryotomography of mitochondrial membranes from wild-type and mutant Saccharomyces cerevisiae to investigate the structure and organization of ATP synthase dimers in situ. Subtomogram averaging of the dimers to 3.7 nm resolution revealed a V-shaped structure of twofold symmetry, with an angle of 86°between monomers. The central and peripheral stalks are well resolved. The monomers interact within the membrane at the base of the peripheral stalks. In wild-type mitochondria ATP synthase dimers are found in rows along the highly curved cristae ridges, and appear to be crucial for membrane morphology. Strains deficient in the dimer-specific subunits e and g or the first transmembrane helix of subunit 4 lack both dimers and lamellar cristae. Instead, cristae are either absent or balloon-shaped, with ATP synthase monomers distributed randomly in the membrane. Computer simulations indicate that isolated dimers induce a plastic deformation in the lipid bilayer, which is partially relieved by their side-by-side association. We propose that the assembly of ATP synthase dimer rows is driven by the reduction in the membrane elastic energy, rather than by direct protein contacts, and that the dimer rows enable the formation of highly curved ridges in mitochondrial cristae.membrane-protein oligomerization | membrane deformation | molecular dynamics simulations | bioenergetics | ATP synthesis T he F 1 F o ATP synthase is a highly conserved molecular machine that catalyses the production of ATP from ADP and P i in energy-converting membranes of eukaryotes and bacteria.

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“…These data indicated that anchoring of mitofilin to the outer membrane is not sufficient for crista junction formation and that the role of mitofilin for crista junction formation likely involves further proteins. Indeed, earlier work had already suggested that mitofilin proteins are part of very large protein complexes, but the molecular composition of these structures had remained enigmatic (John et al , 2005 ;Rabl et al , 2009 ;Mun et al , 2010 ).…”

Section: Structural and Functional Links Of Crista Junctions And Membmentioning

confidence: 99%

“…The Saccharomyces cerevisiae mitofilin protein (also termed formation of crista junctions 1/Fcj1) was the first protein shown to be mainly located at crista junctions Harner et al , 2011 ). Depletion of mitofilin in human cells and worms or deletion of mitofilin in yeast leads to an extension of the inner membrane surface, a massive loss of crista junctions and to abnormal crista structures that appear as stacked lamellae disconnected from the inner boundary membrane (John et al , 2005 ;Rabl et al , 2009 ;Mun et al , 2010 ;Harner et al , 2011 ;Hoppins et al , 2011 ;von der Malsburg et al , 2011 ;Alkhaja et al , 2012 ). These observations point to a conserved function of mitofilin in the formation and/or maintenance of crista junctions.…”

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confidence: 99%

Mitofilin complexes: conserved organizers of mitochondrial membrane architecture

Zerbes¹,

Klei

Veenhuis

et al. 2012

Biological Chemistry

118

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: Mitofilin proteins are crucial organizers of mitochondrial architecture. They are located in the inner mitochondrial membrane and interact with several protein complexes of the outer membrane, thereby generating contact sites between the two membrane systems of mitochondria. Within the inner membrane, mitofilins are part of hetero-oligomeric protein complexes that have been termed the mitochondrial inner membrane organizing system (MINOS). MINOS integrity is required for the maintenance of the characteristic morphology of the inner mitochondrial membrane, with an inner boundary region closely apposed to the outer membrane and cristae membranes, which form large tubular invaginations that protrude into the mitochondrial matrix and harbor the enzyme complexes of the oxidative phosphorylation machinery. MINOS deficiency comes along with a loss of crista junction structures and the detachment of cristae from the inner boundary membrane. MINOS has been conserved in evolution from unicellular eukaryotes to humans, where alterations of MINOS subunits are associated with multiple pathological conditions.

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Formation of cristae and crista junctions in mitochondria depends on antagonism between Fcj1 and Su e/g

Cited by 282 publications

References 65 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

Structure of the yeast F ₁ F _o -ATP synthase dimer and its role in shaping the mitochondrial cristae

Mitofilin complexes: conserved organizers of mitochondrial membrane architecture

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Formation of cristae and crista junctions in mitochondria depends on antagonism between Fcj1 and Su e/g

Cited by 282 publications

References 65 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

Structure of the yeast F 1 F o -ATP synthase dimer and its role in shaping the mitochondrial cristae

Mitofilin complexes: conserved organizers of mitochondrial membrane architecture

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Structure of the yeast F ₁ F _o -ATP synthase dimer and its role in shaping the mitochondrial cristae