Where is cristae located

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Dlaskova, A. The cristae respond to changes in the rate of movement of the head, being activated by pressure from the fluid in the semicircular canals. From: crista in Concise Medical Dictionary ». Subjects: Medicine and health. View all related items in Oxford Reference ». All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single entry from a reference work in OR for personal use for details see Privacy Policy and Legal Notice.

Filled and open bars represent mitofilin versus control siRNA-treated cells, respectively. The increased membrane potential and ROS production suggest a possible defect in energy production. To examine this hypothesis, we performed a metabolic flux assay Manning et al. Similar results were obtained using 3 H-labeled myristic acid as a metabolic substrate our unpublished data. However, when we performed polarographic measurement of digitonin-permeabilized HeLa cells Hofhaus et al. Although mitochondrial function was altered by mitofilin depletion in multiple parameters, the primary cause for these abnormalities remains elusive.

Because appropriate mitochondrial structure enables it to perform a diverse set of metabolic function, we wondered whether a structural defect may underlie and account for these functional abnormalities. To determine whether mitofilin is required for mitochondrial structural organization, cells treated with mitofilin or control siRNA were subjected to TEM. Although mitochondrial functional abnormalities were only evident after two rounds of mitofilin siRNA transfection, we observed major ultrastructural changes after a single treatment.

The defective mitochondria after the first round were typically characterized by inner membranes showing one to several layers of concentric spherical rings, resembling onion-like structure Figure 6, B and C. Further treatment second round resulted in an increase in the number of layers of tightly packed concentric membranous sheets. These abnormal membranes were partially collapsed and occupied the majority of the internal mitochondrial compartment Figure 6, E and F.

The mitochondria were either enveloped with the endoplasmic reticulum ER membrane, showing a dense matrix Supplemental Figure S5B , or were in more terminal stage of autophagy enveloped by multiple layers of ER membrane with empty matrix compartment Supplemental Figure S5C.

No autophagic mitochondria were detected in cells after the first round of mitofilin siRNA. Because of the tight packing of the membranes in these mitochondria, routine TEM could not provide information about membrane shape and organization. Therefore, electron tomography was used to generate highresolution three-dimensional images of abnormal mitochondria in the mitofilin siRNA-transfected cells. The tomograms also indicated that the densely packed inner membranes were not simply concentric sheets.

Rather, these membranes formed a maze of interconnected compartments, with numerous contact sites and openings between radially adjacent membranes Figure 7, D and E.

Figure 6. Loss of mitofilin results in drastically altered mitochondrial ultrastructure. Arrows indicate the multiple concentric sheets of the inner membrane. Bar, nm. Figure 7. Electron tomography of mitofilin-depleted mitochondria.

B Central 3-nm slice from the reconstructed volume. C Series of 3-nm slices spaced 15 nm apart, of the upper left region in B. The mitochondrial outer membrane OM is marked by arrows. HeLa cells were transiently transfected with either a mitofilin expression vector or a mitofilin RNAi short hairpin vector to generate gain-of-function or loss-of-function systems, respectively.

Western blotting of cell lysates obtained 48 h after two rounds of transfections with mitofilin expression vector or RNAi short hairpin vector shows overexpressed Figure 8A , lane 2 and depleted mitofilin Figure 8A , lane 4 respectively, whereas tubulin and mitochondrial complex II 70 KDa are not affected due to these transfections Figure 8A.

Overexpression or depletion of mitofilin did not alter the normal tubular network Figure 8, B and C. Therefore, loss or overexpression of mitofilin did not affect gross mitochondrial fission. To determine the impact of mitofilin on mitochondrial fusion, we used a polyethylene glycol PEG -based cell fusion assay Chen et al. HeLa cells with overexpressed or depleted mitofilin were independently marked with either Su9-GFP or Su9-RFP, fused by the application of PEG , and grown for another 8 h in cycloheximide-containing media to prevent further protein synthesis.

We examined fused cells under each condition, and mitochondrial fusion proceeded normally in control Figure 8F as well as in mitofilin -depleted Figure 8G or overexpressed cells Figure 8H , as indicated by colocalization of the green and red fluorescent signals.

Our data strongly suggest that gross mitochondrial fission and fusion are not directly affected by mitofilin. Figure 8. Effect of mitofilin on mitochondrial fission and fusion. Gross mitochondrial morphology in HeLa cells with mitofilin depletion B , mitofilin overexpression C , overexpression of Drp1 dominant-negative mutant D , and Drp1 overexpression E. Quantitative data obtained for the various mitochondrial phenotypes, after different treatments I.

The cells were analyzed for all treatments after 48 h of second-round transfections. Sequence analysis of mitofilin revealed three centrally located coiled coil domains Supplemental Figure S1B , which are frequently involved in protein—protein interactions Cohen and Parry, The simultaneous presence of FLAG-tagged and endogenous mitofilin in the immunoprecipitate Figure 9A suggested that mitofilin could either form homo-oligomers or interact with each other via bridging molecules.

To further test the selfassociation of mitofilin, we used the yeast two-hybrid system. The first 67 amino acids of mitofilin that contain the mitochondrial targeting signal and membrane anchoring sequence were removed to facilitate nuclear localization and the remaining protein was fused to either the Gal4 DNA binding or the activation domains Fields and Song, Figure 9. Mitofilin forms homotypic interactions and assembles into a high-molecular-weight protein complex. D Characterization of the mitofilin complex by glycerol density gradient centrifugation.

Fraction 1 corresponds to the top of the gradient. To estimate the size of the mitofilin protein complex, we extracted isolated mouse liver mitochondria with 1. Although respiratory chain complexes II kDa and ATP synthase kDa migrated according to their molecular weights, the mitofilin complex was barely resolved into the separation gel Figure 9C.

Fractions were collected, and Western blotting was performed to estimate the molecular weight of the mitofilin complex. The mitofilin complex and the respiratory chain complex I showed the closest cosedimentation, and both were enriched around fraction 8. However, complex I also was enriched in fraction 9, whereas mitofilin also identified in fraction 7, suggesting a molecular weight of the mitofilin complex slightly less than that of the complex I kDa. Variations of the mitochondrial cristae architecture can be ascribed to the different metabolic states of the organelle.

Mitochondria can adapt remarkably well to the changing energetic needs by altering their metabolism, which is accompanied by the structural changes of the inner membrane. However, the molecular mechanisms governing the biogenesis and configuration of the inner membrane remain mysterious. Our studies have provided the first clues toward understanding the role of mitofilin in the regulation of mitochondrial cristae architecture.

Down-regulation of mitofilin resulted in a drastic change in the organization of the inner membrane. Rather than organizing into tubular cristae, the inner membrane formed concentric layers that interconnected at numerous sites. No discernible cristae junctions were identified. Therefore, mitofilin seems to be essential for the formation of normal tubular cristae as well as cristae junctions. Cristae formation is critical for achieving high surface-to-volume ratio of the inner membrane.

Although the concentric layering increased the inner membrane surface area, the tightly packed membranous sheets and internal compartmentation might hinder exchange for ions and metabolites, possibly leading to increased membrane potential and ROS production as well as defective oxidative phosphorylation.

The increased IM:OM ratio suggests that the inner membrane did not simply change its configuration, but exhibited further membrane biogenesis, which was accompanied by up-regulated metabolic flux. However, the increased metabolic output failed to generate a corresponding ATP production due to the defective oxidative phosphorylation.

Our data clearly established a temporal sequence of mitochondrial structural and functional abnormalities induced by mitofilin depletion.

The concentric membranous sheets began to occur after 48 h of the first round siRNA treatment; mitochondrial dysfunction ensued after another round of siRNA application. Therefore, the structural alterations seemed to precede the functional abnormality and are a primary defect of mitofilin depletion.

These abnormal mitochondria are occasionally consumed by autophagy in the viable cells and ultimately result in reduced proliferation and increased apoptosis in the decompensated cells. Although the molecular basis for cristae morphogenesis is still unknown, there is increasing evidence that the mitochondrial fission and fusion machinery plays an important role in this process.

In addition, down-regulation of OPA1 also resulted in altered cristae structure Olichon et al. These published data suggest a possible connection between the two molecules. However, several lines of evidence are against this association. First, the ultrastructural changes caused by OPA1 versus mitofilin deficiency are distinct.

Vesicle-like cristae with increased spaces between the membranes were observed in OPA1 -depleted mitochondria Olichon et al. Second, mitochondrial membrane potential was dissipated by the loss of OPA1. Third, the mitochondrial network was changed from a filamentous to a punctuated distribution due to the OPA1 depletion. In contrast, down- or up-regulation of mitofilin had no effect on the distribution of gross mitochondrial network. Therefore, it seems unlikely that mitofilin is part of the OPA1 complex.

Recently, the inner membrane protein Mdm33 was identified as a component of mitochondrial morphogenetic machinery and seems to mediate constriction of the inner membrane from the matrix side Messerschmitt et al. Mdm33 has extensive coiled coil domains and exhibits homotypic protein interaction on opposing membranes. In the Mmm1 mutant, ultrastructural analysis revealed stacks of intramitochondrial membrane sheets Hobbs et al. Our studies suggest that mitofilin is an indispensable part of intramitochondrial morphogenetic machinery.

Comparative proteomic analysis of the cerebral cortex of a seizure-sensitive strain of gerbil and its seizure-resistant SR counterpart revealed that gerbil mitofilin showed consistent differences in their isoelectric point between the two strains Omori et al. Sequence analysis of mitofilin cDNAs showed several mutations in the SR strains, including one that resides within a conserved region immediately carboxyl terminal of the membrane-anchoring domain. A recent study in cortical brain samples of fetal Down syndrome showed a double-fold reduction of mitofilin, highlighting its importance for normal mitochondrial function Myung et al.

In addition, concentric cristae have been reported to occur in myopathy, cardiomyopathy, rhabdomyosarcoma, and Warthin's tumor Ghadially, It will be interesting to determine whether mitofilin plays a role in the pathophysiology of these human diseases. E on January 12, We thank Dr. Douglas R. Wayne Lai for generating anti-mitofilin antibodies, Dr.

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OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q Identification of subunit g of yeast mitochondrial F1F0-ATP synthase, a protein required for maximal activity of cytochrome c oxidase.

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Q Rev Biophys. The structure of the membrane extrinsic region of bovine ATP synthase. Structure of the c 10 ring of the yeast mitochondrial ATP synthase in the open conformation. Nat Struct Mol Biol. Download references. You can also search for this author in PubMed Google Scholar. Movie S1. Mitochondria in a human endothelial cell.

Time-lapse movie of the dynamic mitochondrial network stained with a fluorescent dye. Long filamentous mitochondria occasionally undergo fission, while smaller parts of the network fuse into longer tubes.

Movie S2. Dimer rows of mitochondrial ATP synthase in cristae membranes. The three-dimensional volume of a small P. The outer membrane is grey , the inner membrane and cristae membranes are light blue.

The F 1 heads of the ATP synthase are indicated in yellow. Adapted from [ 17 ] MP4 kb. Reprints and Permissions. Structure and function of mitochondrial membrane protein complexes. BMC Biol 13, 89 Download citation. Published : 29 October Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.

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