The Experts below are selected from a list of 276 Experts worldwide ranked by ideXlab platform
Bernd Fritzsch - One of the best experts on this subject based on the ideXlab platform.
-
Interaction with ectopic cochlear Crista sensory epithelium disrupts basal cochlear sensory epithelium development in Lmx1a mutant mice
Cell and Tissue Research, 2020Co-Authors: David H. Nichols, Israt Jahan, Kirk W. Beisel, Judith E. Bouma, Benjamin J. Kopecky, Huizhan Liu, Bernd FritzschAbstract:The LIM homeodomain transcription factor Lmx1a shows a dynamic expression in the developing mouse ear that stabilizes in the non-sensory epithelium. Previous work showed that Lmx1a functional null mutants have an additional sensory hair cell patch in the posterior wall of a cochlear duct and have a mix of vestibular and cochlear hair cells in the basal cochlear sensory epithelium. In E13.5 mutants, Sox2 -expressing posterior canal Crista is continuous with an ectopic “Crista sensory epithelium” located in the outer spiral sulcus of the basal cochlear duct. The medial margin of cochlear Crista is in contact with the adjacent Sox2 -expressing basal cochlear sensory epithelium. By E17.5, this contact has been interrupted by the formation of an intervening non-sensory epithelium, and Atoh1 is expressed in the hair cells of both the cochlear Crista and the basal cochlear sensory epithelium. Where cochlear Crista was formerly associated with the basal cochlear sensory epithelium, the basal cochlear sensory epithelium lacks an outer hair cell band, and gaps are present in its associated Bmp4 expression. Further apically, where cochlear Crista was never present, the cochlear sensory epithelium forms a poorly ordered but complete organ of Corti. We propose that the core prosensory posterior Crista is enlarged in the mutant when the absence of Lmx1a expression allows JAG1-NOTCH signaling to propagate into the adjacent epithelium and down the posterior wall of the cochlear duct. We suggest that the cochlear Crista propagates in the mutant outer spiral sulcus because it expresses Lmo4 in the absence of Lmx1a .
-
In situ hybridization of the mouse inner ear with an antisense Srrm4 probe.
2012Co-Authors: Yoko Nakano, Bernd Fritzsch, Israt Jahan, Gregory Bonde, Xingshen Sun, Michael S. Hildebrand, John F. Engelhardt, Richard J. H. Smith, Robert A. Cornell, Botond BánfiAbstract:(A) Whole-mount in situ hybridization of the inner ear revealing Srrm4 detection in each balance organ (i.e. Crista ampullaris, saccule, and utricle), in the organ of Corti (OC), and in the spiral ganglion (SG). (B) In the cochlea, the antisense Srrm4 probe labeled all three rows of OHCs, the row of IHCs, and the spiral ganglion (SG). (C) In the utricular macula, the Srrm4 signal was present throughout, but weaker in the central (i.e. striolar) region than in the periphery. The dotted line indicates the estimated center of the striola. (D) In the Crista amupllaris, Srrm4 signal was present in the sensory-cell layer. The anterior (A) and lateral (L) Cristae are shown. Asterisk indicates the unstained, non-sensory septum cruciatum of the anterior Crista. An adjacent segment of the utricular macula is also shown. Scale bars: 100 µm.
-
Lmx1a is required for segregation of sensory epithelia and normal ear histogenesis and morphogenesis
Cell and Tissue Research, 2008Co-Authors: David H. Nichols, Sarah Pauley, Israt Jahan, Kirk W. Beisel, Kathleen J. Millen, Bernd FritzschAbstract:At embryonic day 8.5, the LIM-homeodomain factor Lmx1a is expressed throughout the otic placode but becomes developmentally restricted to non-sensory epithelia of the ear (endolymphatic duct, ductus reuniens, cochlea lateral wall). We confirm here that the ears of newborn dreher ( Lmx1a ^dr) mutants are dysmorphic. Hair cell markers such as Atoh1 and Myo7 reveal, for the first time, that newborn Lmx1a mutants have only three sensory epithelia: two enlarged canal Cristae and one fused epithelium comprising an amalgamation of the cochlea, saccule, and utricle (a “cochlear-gravistatic” endorgan). The enlarged anterior canal Crista develops by fusion of horizontal and anterior Crista, whereas the posterior Crista fuses with an enlarged papilla neglecta that may extend into the cochlear lateral wall. In the fused endorgan, the cochlear region is distinguished from the vestibular region by markers such as Gata3 , the presence of a tectorial membrane, and cochlea-specific innervation. The cochlea-like apex displays minor disorganization of the hair and supporting cells. This contrasts with the basal half of the cochlear region, which shows a vestibular epithelium-like organization of hair cells and supporting cells. The dismorphic features of the cochlea are also reflected in altered gene expression patterns. Fgf8 expression expands from inner hair cells in the apex to most hair cells in the base. Two supporting cell marker proteins, Sox2 and Prox1, also differ in their cellular distribution between the base and the apex. Sox2 expression expands in mutant canal Cristae prior to their enlargement and fusion and displays a more diffuse and widespread expression in the base of the cochlear region, whereas Prox1 is not detected in the base. These changes in Sox2 and Prox1 expression suggest that Lmx1a expression restricts and sharpens Sox2 expression, thereby defining non-sensory and sensory epithelium. The adult Lmx1a mutant organ of Corti shows a loss of cochlear hair cells, suggesting that the long-term maintenance of hair cells is also disrupted in these mutants.
-
Expression and function of FGF10 in mammalian inner ear development
Developmental dynamics : an official publication of the American Association of Anatomists, 2003Co-Authors: Sarah Pauley, Kirk W. Beisel, Tracy J. Wright, Ulla Pirvola, David M. Ornitz, Bernd FritzschAbstract:We have investigated the expression of FGF10 during ear development and the effect of an FGF10 null mutation on ear development. Our in situ hybridization data reveal expression of FGF10 in all three canal Crista sensory epithelia and the cochlea anlage as well as all sensory neurons at embryonic day 11.5 (E11.5). Older embryos (E18.5) displayed strong graded expression in all sensory epithelia. FGF10 null mutants show complete agenesis of the posterior canal Crista and the posterior canal. The posterior canal sensory neurons form initially and project rather normally by E11.5, but they disappear within 2 days. FGF10 null mutants have no posterior canal system at E18.5. In addition, these mutants have deformations of the anterior and horizontal Cristae, reduced formation of the anterior and horizontal canals, as well as altered position of the remaining sensory epithelia with respect to the utricle. Hair cells form but some have defects in their cilia formation. No defects were detected in the organ of Corti at the cellular level. Together these data suggest that FGF10 plays a major role in ear morphogenesis. Most of these data are consistent with earlier findings on a null mutation in FGFR2b, one of FGF10's main receptors.
-
partial segregation of posterior Crista and saccular fibers to the nodulus and uvula of the cerebellum in mice and its development
Developmental Brain Research, 2003Co-Authors: Adel Maklad, Bernd FritzschAbstract:Abstract The projection of the posterior canal Crista and saccular afferents to the cerebellum of embryonic and neonatal mice was investigated using carbocyanine dyes. Anterograde tracing from these two endorgans reveals a partial segregation of these two sets of afferents. The saccule projects predominantly to the uvula, with very minor input to the nodulus. The posterior canal projects mainly to the nodulus and, to a lesser extent, to the uvula. Retrograde tracing from the uvula and nodulus confirms this partial segregation for these two endorgans and extends it to other vestibular endorgans. Uvular injections result in many more labeled fibers in the gravistatic maculae than in the canals’ Cristae. In contrast, nodular injection reveals many more labeled fibers in the canal Cristae than in the gravistatic maculae. This partial segregation may play a role in the information processing in these folia. Our developmental data suggest that the initial segregation at E17 coincides with the formation of the postero-lateral fissure. This embryonic segregation of the primary vestibular mossy fibers to the uvula and nodulus commences long before the maturity of their targets, the granule cells and unipolar brush cells. Thus, the segregation of the primary vestibular projection to the uvula and nodulus does not depend on cues related to the target cells. Rather, the segregation may reflect more global cerebellar patterning mechanisms involving guidance for the vestibular afferent fibers independent of the future target cells.
David H. Nichols - One of the best experts on this subject based on the ideXlab platform.
-
Interaction with ectopic cochlear Crista sensory epithelium disrupts basal cochlear sensory epithelium development in Lmx1a mutant mice
Cell and Tissue Research, 2020Co-Authors: David H. Nichols, Israt Jahan, Kirk W. Beisel, Judith E. Bouma, Benjamin J. Kopecky, Huizhan Liu, Bernd FritzschAbstract:The LIM homeodomain transcription factor Lmx1a shows a dynamic expression in the developing mouse ear that stabilizes in the non-sensory epithelium. Previous work showed that Lmx1a functional null mutants have an additional sensory hair cell patch in the posterior wall of a cochlear duct and have a mix of vestibular and cochlear hair cells in the basal cochlear sensory epithelium. In E13.5 mutants, Sox2 -expressing posterior canal Crista is continuous with an ectopic “Crista sensory epithelium” located in the outer spiral sulcus of the basal cochlear duct. The medial margin of cochlear Crista is in contact with the adjacent Sox2 -expressing basal cochlear sensory epithelium. By E17.5, this contact has been interrupted by the formation of an intervening non-sensory epithelium, and Atoh1 is expressed in the hair cells of both the cochlear Crista and the basal cochlear sensory epithelium. Where cochlear Crista was formerly associated with the basal cochlear sensory epithelium, the basal cochlear sensory epithelium lacks an outer hair cell band, and gaps are present in its associated Bmp4 expression. Further apically, where cochlear Crista was never present, the cochlear sensory epithelium forms a poorly ordered but complete organ of Corti. We propose that the core prosensory posterior Crista is enlarged in the mutant when the absence of Lmx1a expression allows JAG1-NOTCH signaling to propagate into the adjacent epithelium and down the posterior wall of the cochlear duct. We suggest that the cochlear Crista propagates in the mutant outer spiral sulcus because it expresses Lmo4 in the absence of Lmx1a .
-
Lmx1a is required for segregation of sensory epithelia and normal ear histogenesis and morphogenesis
Cell and Tissue Research, 2008Co-Authors: David H. Nichols, Sarah Pauley, Israt Jahan, Kirk W. Beisel, Kathleen J. Millen, Bernd FritzschAbstract:At embryonic day 8.5, the LIM-homeodomain factor Lmx1a is expressed throughout the otic placode but becomes developmentally restricted to non-sensory epithelia of the ear (endolymphatic duct, ductus reuniens, cochlea lateral wall). We confirm here that the ears of newborn dreher ( Lmx1a ^dr) mutants are dysmorphic. Hair cell markers such as Atoh1 and Myo7 reveal, for the first time, that newborn Lmx1a mutants have only three sensory epithelia: two enlarged canal Cristae and one fused epithelium comprising an amalgamation of the cochlea, saccule, and utricle (a “cochlear-gravistatic” endorgan). The enlarged anterior canal Crista develops by fusion of horizontal and anterior Crista, whereas the posterior Crista fuses with an enlarged papilla neglecta that may extend into the cochlear lateral wall. In the fused endorgan, the cochlear region is distinguished from the vestibular region by markers such as Gata3 , the presence of a tectorial membrane, and cochlea-specific innervation. The cochlea-like apex displays minor disorganization of the hair and supporting cells. This contrasts with the basal half of the cochlear region, which shows a vestibular epithelium-like organization of hair cells and supporting cells. The dismorphic features of the cochlea are also reflected in altered gene expression patterns. Fgf8 expression expands from inner hair cells in the apex to most hair cells in the base. Two supporting cell marker proteins, Sox2 and Prox1, also differ in their cellular distribution between the base and the apex. Sox2 expression expands in mutant canal Cristae prior to their enlargement and fusion and displays a more diffuse and widespread expression in the base of the cochlear region, whereas Prox1 is not detected in the base. These changes in Sox2 and Prox1 expression suggest that Lmx1a expression restricts and sharpens Sox2 expression, thereby defining non-sensory and sensory epithelium. The adult Lmx1a mutant organ of Corti shows a loss of cochlear hair cells, suggesting that the long-term maintenance of hair cells is also disrupted in these mutants.
Kirk W. Beisel - One of the best experts on this subject based on the ideXlab platform.
-
Interaction with ectopic cochlear Crista sensory epithelium disrupts basal cochlear sensory epithelium development in Lmx1a mutant mice
Cell and Tissue Research, 2020Co-Authors: David H. Nichols, Israt Jahan, Kirk W. Beisel, Judith E. Bouma, Benjamin J. Kopecky, Huizhan Liu, Bernd FritzschAbstract:The LIM homeodomain transcription factor Lmx1a shows a dynamic expression in the developing mouse ear that stabilizes in the non-sensory epithelium. Previous work showed that Lmx1a functional null mutants have an additional sensory hair cell patch in the posterior wall of a cochlear duct and have a mix of vestibular and cochlear hair cells in the basal cochlear sensory epithelium. In E13.5 mutants, Sox2 -expressing posterior canal Crista is continuous with an ectopic “Crista sensory epithelium” located in the outer spiral sulcus of the basal cochlear duct. The medial margin of cochlear Crista is in contact with the adjacent Sox2 -expressing basal cochlear sensory epithelium. By E17.5, this contact has been interrupted by the formation of an intervening non-sensory epithelium, and Atoh1 is expressed in the hair cells of both the cochlear Crista and the basal cochlear sensory epithelium. Where cochlear Crista was formerly associated with the basal cochlear sensory epithelium, the basal cochlear sensory epithelium lacks an outer hair cell band, and gaps are present in its associated Bmp4 expression. Further apically, where cochlear Crista was never present, the cochlear sensory epithelium forms a poorly ordered but complete organ of Corti. We propose that the core prosensory posterior Crista is enlarged in the mutant when the absence of Lmx1a expression allows JAG1-NOTCH signaling to propagate into the adjacent epithelium and down the posterior wall of the cochlear duct. We suggest that the cochlear Crista propagates in the mutant outer spiral sulcus because it expresses Lmo4 in the absence of Lmx1a .
-
Lmx1a is required for segregation of sensory epithelia and normal ear histogenesis and morphogenesis
Cell and Tissue Research, 2008Co-Authors: David H. Nichols, Sarah Pauley, Israt Jahan, Kirk W. Beisel, Kathleen J. Millen, Bernd FritzschAbstract:At embryonic day 8.5, the LIM-homeodomain factor Lmx1a is expressed throughout the otic placode but becomes developmentally restricted to non-sensory epithelia of the ear (endolymphatic duct, ductus reuniens, cochlea lateral wall). We confirm here that the ears of newborn dreher ( Lmx1a ^dr) mutants are dysmorphic. Hair cell markers such as Atoh1 and Myo7 reveal, for the first time, that newborn Lmx1a mutants have only three sensory epithelia: two enlarged canal Cristae and one fused epithelium comprising an amalgamation of the cochlea, saccule, and utricle (a “cochlear-gravistatic” endorgan). The enlarged anterior canal Crista develops by fusion of horizontal and anterior Crista, whereas the posterior Crista fuses with an enlarged papilla neglecta that may extend into the cochlear lateral wall. In the fused endorgan, the cochlear region is distinguished from the vestibular region by markers such as Gata3 , the presence of a tectorial membrane, and cochlea-specific innervation. The cochlea-like apex displays minor disorganization of the hair and supporting cells. This contrasts with the basal half of the cochlear region, which shows a vestibular epithelium-like organization of hair cells and supporting cells. The dismorphic features of the cochlea are also reflected in altered gene expression patterns. Fgf8 expression expands from inner hair cells in the apex to most hair cells in the base. Two supporting cell marker proteins, Sox2 and Prox1, also differ in their cellular distribution between the base and the apex. Sox2 expression expands in mutant canal Cristae prior to their enlargement and fusion and displays a more diffuse and widespread expression in the base of the cochlear region, whereas Prox1 is not detected in the base. These changes in Sox2 and Prox1 expression suggest that Lmx1a expression restricts and sharpens Sox2 expression, thereby defining non-sensory and sensory epithelium. The adult Lmx1a mutant organ of Corti shows a loss of cochlear hair cells, suggesting that the long-term maintenance of hair cells is also disrupted in these mutants.
-
Expression and function of FGF10 in mammalian inner ear development
Developmental dynamics : an official publication of the American Association of Anatomists, 2003Co-Authors: Sarah Pauley, Kirk W. Beisel, Tracy J. Wright, Ulla Pirvola, David M. Ornitz, Bernd FritzschAbstract:We have investigated the expression of FGF10 during ear development and the effect of an FGF10 null mutation on ear development. Our in situ hybridization data reveal expression of FGF10 in all three canal Crista sensory epithelia and the cochlea anlage as well as all sensory neurons at embryonic day 11.5 (E11.5). Older embryos (E18.5) displayed strong graded expression in all sensory epithelia. FGF10 null mutants show complete agenesis of the posterior canal Crista and the posterior canal. The posterior canal sensory neurons form initially and project rather normally by E11.5, but they disappear within 2 days. FGF10 null mutants have no posterior canal system at E18.5. In addition, these mutants have deformations of the anterior and horizontal Cristae, reduced formation of the anterior and horizontal canals, as well as altered position of the remaining sensory epithelia with respect to the utricle. Hair cells form but some have defects in their cilia formation. No defects were detected in the organ of Corti at the cellular level. Together these data suggest that FGF10 plays a major role in ear morphogenesis. Most of these data are consistent with earlier findings on a null mutation in FGFR2b, one of FGF10's main receptors.
Israt Jahan - One of the best experts on this subject based on the ideXlab platform.
-
Interaction with ectopic cochlear Crista sensory epithelium disrupts basal cochlear sensory epithelium development in Lmx1a mutant mice
Cell and Tissue Research, 2020Co-Authors: David H. Nichols, Israt Jahan, Kirk W. Beisel, Judith E. Bouma, Benjamin J. Kopecky, Huizhan Liu, Bernd FritzschAbstract:The LIM homeodomain transcription factor Lmx1a shows a dynamic expression in the developing mouse ear that stabilizes in the non-sensory epithelium. Previous work showed that Lmx1a functional null mutants have an additional sensory hair cell patch in the posterior wall of a cochlear duct and have a mix of vestibular and cochlear hair cells in the basal cochlear sensory epithelium. In E13.5 mutants, Sox2 -expressing posterior canal Crista is continuous with an ectopic “Crista sensory epithelium” located in the outer spiral sulcus of the basal cochlear duct. The medial margin of cochlear Crista is in contact with the adjacent Sox2 -expressing basal cochlear sensory epithelium. By E17.5, this contact has been interrupted by the formation of an intervening non-sensory epithelium, and Atoh1 is expressed in the hair cells of both the cochlear Crista and the basal cochlear sensory epithelium. Where cochlear Crista was formerly associated with the basal cochlear sensory epithelium, the basal cochlear sensory epithelium lacks an outer hair cell band, and gaps are present in its associated Bmp4 expression. Further apically, where cochlear Crista was never present, the cochlear sensory epithelium forms a poorly ordered but complete organ of Corti. We propose that the core prosensory posterior Crista is enlarged in the mutant when the absence of Lmx1a expression allows JAG1-NOTCH signaling to propagate into the adjacent epithelium and down the posterior wall of the cochlear duct. We suggest that the cochlear Crista propagates in the mutant outer spiral sulcus because it expresses Lmo4 in the absence of Lmx1a .
-
In situ hybridization of the mouse inner ear with an antisense Srrm4 probe.
2012Co-Authors: Yoko Nakano, Bernd Fritzsch, Israt Jahan, Gregory Bonde, Xingshen Sun, Michael S. Hildebrand, John F. Engelhardt, Richard J. H. Smith, Robert A. Cornell, Botond BánfiAbstract:(A) Whole-mount in situ hybridization of the inner ear revealing Srrm4 detection in each balance organ (i.e. Crista ampullaris, saccule, and utricle), in the organ of Corti (OC), and in the spiral ganglion (SG). (B) In the cochlea, the antisense Srrm4 probe labeled all three rows of OHCs, the row of IHCs, and the spiral ganglion (SG). (C) In the utricular macula, the Srrm4 signal was present throughout, but weaker in the central (i.e. striolar) region than in the periphery. The dotted line indicates the estimated center of the striola. (D) In the Crista amupllaris, Srrm4 signal was present in the sensory-cell layer. The anterior (A) and lateral (L) Cristae are shown. Asterisk indicates the unstained, non-sensory septum cruciatum of the anterior Crista. An adjacent segment of the utricular macula is also shown. Scale bars: 100 µm.
-
Lmx1a is required for segregation of sensory epithelia and normal ear histogenesis and morphogenesis
Cell and Tissue Research, 2008Co-Authors: David H. Nichols, Sarah Pauley, Israt Jahan, Kirk W. Beisel, Kathleen J. Millen, Bernd FritzschAbstract:At embryonic day 8.5, the LIM-homeodomain factor Lmx1a is expressed throughout the otic placode but becomes developmentally restricted to non-sensory epithelia of the ear (endolymphatic duct, ductus reuniens, cochlea lateral wall). We confirm here that the ears of newborn dreher ( Lmx1a ^dr) mutants are dysmorphic. Hair cell markers such as Atoh1 and Myo7 reveal, for the first time, that newborn Lmx1a mutants have only three sensory epithelia: two enlarged canal Cristae and one fused epithelium comprising an amalgamation of the cochlea, saccule, and utricle (a “cochlear-gravistatic” endorgan). The enlarged anterior canal Crista develops by fusion of horizontal and anterior Crista, whereas the posterior Crista fuses with an enlarged papilla neglecta that may extend into the cochlear lateral wall. In the fused endorgan, the cochlear region is distinguished from the vestibular region by markers such as Gata3 , the presence of a tectorial membrane, and cochlea-specific innervation. The cochlea-like apex displays minor disorganization of the hair and supporting cells. This contrasts with the basal half of the cochlear region, which shows a vestibular epithelium-like organization of hair cells and supporting cells. The dismorphic features of the cochlea are also reflected in altered gene expression patterns. Fgf8 expression expands from inner hair cells in the apex to most hair cells in the base. Two supporting cell marker proteins, Sox2 and Prox1, also differ in their cellular distribution between the base and the apex. Sox2 expression expands in mutant canal Cristae prior to their enlargement and fusion and displays a more diffuse and widespread expression in the base of the cochlear region, whereas Prox1 is not detected in the base. These changes in Sox2 and Prox1 expression suggest that Lmx1a expression restricts and sharpens Sox2 expression, thereby defining non-sensory and sensory epithelium. The adult Lmx1a mutant organ of Corti shows a loss of cochlear hair cells, suggesting that the long-term maintenance of hair cells is also disrupted in these mutants.
Andreas S. Reichert - One of the best experts on this subject based on the ideXlab platform.
-
opa1 functionally interacts with mic60 but is dispensable for Crista junction formation
FEBS Letters, 2016Co-Authors: Miguel Barrera, Andreas S. Reichert, Frank Vogel, Sebastian Koob, Daniel DikovAbstract:Remodeling of Crista junctions (CJs) is observed in numerous human disorders and during apoptosis. The functional interplay of OPA1 and MIC60, two key players in this context, is unclear. We show that OPA1 modulates Cristae morphology but is dispensable for CJ formation. MIC60 is strongly enriched at CJs, whereas OPA1 is distributed evenly across the inner membrane. MIC60 levels are increased in OPA1-/- cells which show increased cellular resistance to apoptosis induction. Endogenous OPA1 and MIC60 show a physical interaction. Overall, we suggest that the regulation of CJ remodeling during apoptosis is mediated via an interplay between OPA1 and MIC60.
-
Mic13 Is Essential for Formation of Crista Junctions in Mammalian Cells.
PloS one, 2016Co-Authors: Ruchika Anand, Valentina Strecker, Jennifer Urbach, Ilka Wittig, Andreas S. ReichertAbstract:Mitochondrial Cristae are connected to the inner boundary membrane via Crista junctions which are implicated in the regulation of oxidative phosphorylation, apoptosis, and import of lipids and proteins. The MICOS complex determines formation of Crista junctions. We performed complexome profiling and identified Mic13, also termed Qil1, as a subunit of the MICOS complex. We show that MIC13 is an inner membrane protein physically interacting with MIC60, a central subunit of the MICOS complex. Using the CRISPR/Cas method we generated the first cell line deleted for MIC13. These knockout cells show a complete loss of Crista junctions demonstrating that MIC13 is strictly required for the formation of Crista junctions. MIC13 is required for the assembly of MIC10, MIC26, and MIC27 into the MICOS complex. However, it is not needed for the formation of the MIC60/MIC19/MIC25 subcomplex suggesting that the latter is not sufficient for Crista junction formation. MIC13 is also dispensable for assembly of respiratory chain complexes and for maintaining mitochondrial network morphology. Still, lack of MIC13 resulted in a moderate reduction of mitochondrial respiration. In summary, we show that MIC13 has a fundamental role in Crista junction formation and that assembly of respiratory chain supercomplexes is independent of mitochondrial Cristae shape.
-
the non glycosylated isoform of mic26 is a constituent of the mammalian micos complex and promotes formation of Crista junctions
Biochimica et Biophysica Acta, 2015Co-Authors: Sebastian Koob, Ruchika Anand, Andreas S. Reichert, Miguel BarreraAbstract:Abstract Mitochondrial membrane architecture is important for organelle function. Alterations thereof are linked to a number of human disorders including diabetes and cardiomyopathy. The MICOS complex was recently reported to be a central player determining Cristae structure and formation of Crista junctions. Here we investigated the functional role of MIC26, a lipoprotein formerly termed APOO. Its levels are increased in diabetic heart tissue and in blood plasma of patients suffering from acute coronary syndrome. We demonstrate that human MIC26 exists in three distinct forms: (1) a glycosylated and secreted 55 kDa protein, (2) an ER/Golgi-resident form thereof, and (3) a non-glycosylated 22 kDa mitochondrial protein. The latter isoform spans the mitochondrial inner membrane and physically interacts with several MICOS complex subunits such as MIC60, MIC27, and MIC10. We further demonstrate that MIC26 and MIC27, a homologous protein formerly termed APOOL, regulate their levels in an antagonistic manner. Both proteins are positively correlated with the levels of MIC10 as well as tafazzin, an enzyme required for cardiolipin remodeling. Overexpression of MIC26 induced fragmentation of mitochondria, promoted ROS formation and resulted in impaired mitochondrial respiration. Downregulation of MIC26 induced a decrease in mitochondrial oxygen consumption, whereas mitochondrial network morphology and ROS levels remained unaffected. MIC26 depletion led to alterations in mitochondrial ultrastructure and caused a significant reduction in the number of Crista junctions. In summary, we show that the human apolipoprotein MIC26 is a bona fide subunit of the MICOS complex and that MIC26 is linked to cardiolipin metabolism and promotes Crista junction formation.
-
the c terminal domain of fcj1 is required for formation of Crista junctions and interacts with the tob sam complex in mitochondria
Molecular Biology of the Cell, 2012Co-Authors: Christian Korner, Max Harner, Regina Rabl, Frank Vogel, Miguel Barrera, Jovana Dukanovic, Katharina Eydt, Doron Rapaport, Walter Neupert, Andreas S. ReichertAbstract:Crista junctions (CJs) are tubular invaginations of the inner membrane of mitochondria that connect the inner boundary with the Cristae membrane. These architectural elements are critical for mitochondrial function. The yeast inner membrane protein Fcj1, called mitofilin in mammals, was reported to be preferentially located at CJs and crucial for their formation. Here we investigate the functional roles of individual domains of Fcj1. The most conserved part of Fcj1, the C-terminal domain, is essential for Fcj1 function. In its absence, formation of CJ is strongly impaired and irregular, and stacked Cristae are present. This domain interacts with full-length Fcj1, suggesting a role in oligomer formation. It also interacts with Tob55 of the translocase of outer membrane β-barrel proteins (TOB)/sorting and assembly machinery (SAM) complex, which is required for the insertion of β-barrel proteins into the outer membrane. The association of the TOB/SAM complex with contact sites depends on the presence of Fcj1. The biogenesis of β-barrel proteins is not significantly affected in the absence of Fcj1. However, down-regulation of the TOB/SAM complex leads to altered Cristae morphology and a moderate reduction in the number of CJs. We propose that the C-terminal domain of Fcj1 is critical for the interaction of Fcj1 with the TOB/SAM complex and thereby for stabilizing CJs in close proximity to the outer membrane. These results assign novel functions to both the C-terminal domain of Fcj1 and the TOB/SAM complex.