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Functional characterisation of new components of mitochondrial proteome.
Kovalčíková, Jana ; Vrbacký, Marek (advisor) ; Červinková, Zuzana (referee) ; Ješina, Pavel (referee)
1 Abstract It has been estimated that the mammalian mitochondrial proteome consists of ~1500 distinct proteins and approximately one quarter of them is still not fully characterized. One of these proteins is TMEM70, protein involved in the biogenesis of the eukaryotic F1Fo-ATP synthase. TMEM70 mutations cause isolated deficiency of ATP synthase often resulting in a fatal neonatal mitochondrial encephalocardiomyopathies in patients. To understand the molecular mechanism of TMEM70 action, we generated constitutive Tmem70 knockout mice, which led to embryonic lethal phenotype with disturbed ATP synthase biogenesis. Subsequently generated inducible Tmem70 mouse knockout was lethal by the week 8 post induction. It exhibited primarily impaired liver function, which contrasts with the predominantly cardiologic phenotype at disease onset in humans. Liver mitochondria revealed formation of labile ATP synthase subcomplexes lacking subunit c. Thus, in case of TMEM70 deficiency c-oligomer was not incorporated into ATP synthase, which led to critical impairment of mitochondrial energy provision, analogous to TMEM70 dysfunction in humans. In TMEM70 deficient models, the ATP synthase deficiency reached the 'threshold' for its pathologic presentation, which we quantified at 30 %. We observed compensatory increases in the...
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The inner mitochondrial membrane cristae biogenesis
Efimova, Iuliia ; Mráček, Tomáš (advisor) ; Petrů, Markéta (referee)
Invaginations of the inner mitochondrial membrane originate cristae - important structural and bioenergetic mitochondrial compartments. Long-term observations of mitochondrial ultrastructure uncovered cristae dynamics, but did not identify mechanisms of cristae formation and maintenance. This thesis summarizes results of latest research on molecular mechanisms of mitochondrial cristae biogenesis, which are conserved from fungi to mammals including human. The emphasis is put on major remodeling factors: F1Fo-ATP synthase dimers, MICOS complex, OPA1 protein and cardiolipin. Their defects lead to extensive changes on cristae level, as well as on mitochondrial, cellular and organismal levels. Various pathophysiological conditions and human mitochondrial diseases are related to these defects. More detailed research of cristae biogenesis is therefore of high significance, new findings could assist in the development of new treatments for mitochondrial disorders.
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New components and functions of mitochondrial ATP synthase.
Ho, Dieu Hien ; Pecina, Petr (advisor) ; Kalous, Martin (referee)
The system of oxidative phosphorylation, or respiratory chain in mitochondria gives the eukaryotic cell total majority of the energy it receives and uses in the form of ATP. F1Fo-ATP synthase, powered by the proton-motive force is directly responsible for the ATP synthesis. Diseases connected to the ATP synthesis can have even lethal consequences. There is therefore no doubt about the need for a detailed analysis of the structure of this enzyme. What is left is to reveal the structure of the transmembrane domains, which are not involved in the synthesis itself, but they can for example work as stabilisers or assembly factors. Outside the synthesis activity the dimers of F1Fo-ATP synthase are apparently taking part in the formation of the cristae of the inner membrane of a mitochondrion. Recently, the role of the enzyme is also considered in the creation of the mitochondrial permeability transition pore.
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Functional characterisation of new components of mitochondrial proteome.
Kovalčíková, Jana ; Vrbacký, Marek (advisor) ; Červinková, Zuzana (referee) ; Ješina, Pavel (referee)
1 Abstract It has been estimated that the mammalian mitochondrial proteome consists of ~1500 distinct proteins and approximately one quarter of them is still not fully characterized. One of these proteins is TMEM70, protein involved in the biogenesis of the eukaryotic F1Fo-ATP synthase. TMEM70 mutations cause isolated deficiency of ATP synthase often resulting in a fatal neonatal mitochondrial encephalocardiomyopathies in patients. To understand the molecular mechanism of TMEM70 action, we generated constitutive Tmem70 knockout mice, which led to embryonic lethal phenotype with disturbed ATP synthase biogenesis. Subsequently generated inducible Tmem70 mouse knockout was lethal by the week 8 post induction. It exhibited primarily impaired liver function, which contrasts with the predominantly cardiologic phenotype at disease onset in humans. Liver mitochondria revealed formation of labile ATP synthase subcomplexes lacking subunit c. Thus, in case of TMEM70 deficiency c-oligomer was not incorporated into ATP synthase, which led to critical impairment of mitochondrial energy provision, analogous to TMEM70 dysfunction in humans. In TMEM70 deficient models, the ATP synthase deficiency reached the 'threshold' for its pathologic presentation, which we quantified at 30 %. We observed compensatory increases in the...
|
|
|
The inner mitochondrial membrane cristae biogenesis
Efimova, Iuliia ; Mráček, Tomáš (advisor) ; Petrů, Markéta (referee)
Invaginations of the inner mitochondrial membrane originate cristae - important structural and bioenergetic mitochondrial compartments. Long-term observations of mitochondrial ultrastructure uncovered cristae dynamics, but did not identify mechanisms of cristae formation and maintenance. This thesis summarizes results of latest research on molecular mechanisms of mitochondrial cristae biogenesis, which are conserved from fungi to mammals including human. The emphasis is put on major remodeling factors: F1Fo-ATP synthase dimers, MICOS complex, OPA1 protein and cardiolipin. Their defects lead to extensive changes on cristae level, as well as on mitochondrial, cellular and organismal levels. Various pathophysiological conditions and human mitochondrial diseases are related to these defects. More detailed research of cristae biogenesis is therefore of high significance, new findings could assist in the development of new treatments for mitochondrial disorders.
|
|
|
New components and functions of mitochondrial ATP synthase.
Ho, Dieu Hien ; Pecina, Petr (advisor) ; Kalous, Martin (referee)
The system of oxidative phosphorylation, or respiratory chain in mitochondria gives the eukaryotic cell total majority of the energy it receives and uses in the form of ATP. F1Fo-ATP synthase, powered by the proton-motive force is directly responsible for the ATP synthesis. Diseases connected to the ATP synthesis can have even lethal consequences. There is therefore no doubt about the need for a detailed analysis of the structure of this enzyme. What is left is to reveal the structure of the transmembrane domains, which are not involved in the synthesis itself, but they can for example work as stabilisers or assembly factors. Outside the synthesis activity the dimers of F1Fo-ATP synthase are apparently taking part in the formation of the cristae of the inner membrane of a mitochondrion. Recently, the role of the enzyme is also considered in the creation of the mitochondrial permeability transition pore.
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