|
|
Three-parent babies - new therapies of mitochondrial disorders
Helebrandtová, Veronika ; Pecinová, Alena (advisor) ; Ješina, Pavel (referee)
Mitochondria are essential parts of living cells, as they play a key role in cellular metabolism, especially in energy production. Due to their unique structure, the energy released during the oxidation of the substrates can be used to form the ATP. Mitochondria also contain their own DNA (mtDNA), which is maternally inherited and encodes catalytic subunits of oxidative phosphorylation complexes. Mitochondrial disorders of nuclear or mitochondrial origin, are common causes of inherited diseases and affect mainly the tissues with high energy requirements, such as heart or brain. Treatment of mitochondrial diseases is usually symptomatic and does not lead to complete recovery of the patient. As a result, new causal therapies, such as a gene therapy, are currently investigated. However, using this approach it is necessary to consider the origin of the mutation. Gene therapy of mitochondrial diseases of mtDNA origin is very complicated, therefore the new treatment strategy, mitochondrial replacement therapy, has been proposed. The principle of this technique is to prevent the transmission of mutated mtDNA from mother to offspring by transferring the nuclear genome of mother with mitochondrial disorder into donor's denucleated oocyte with healthy mitochondria. In this way, the child has genetic...
|
|
|
Genetic and functional characterisation of mitochondrial diseases caused by ATP synthase defects
Tauchmannová, Kateřina ; Houštěk, Josef (advisor) ; Flachs, Pavel (referee) ; Kutejová, Eva (referee)
Disorders of ATP synthase, the key enzyme of mitochondrial energy provision belong to the most severe metabolic diseases presenting mostly as early-onset mitochondrial encephalo-cardio-myopathies. Mutations in four nuclear genes can result in isolated deficiency of ATP synthase, all sharing a similar biochemical phenotype - pronounced decrease in the content of fully assembled and functional ATP synthase complex. The thesis summarises studies on two distinct causes of ATP synthase deficiency. First is TMEM70 protein, a novel ancillary factor of ATP synthase, which represents most frequent determinant of severe inborn deficiency of ATP synthase. TMEM70 is a 21 kDa protein of the inner mitochondrial membrane, facilitating the biogenesis of mitochondrial ATP synthase, possibly through TMEM70 protein region exposed to the mitochondrial matrix, but the proper regulatory mechanism remains to be elucidated. In TMEM70-lacking patient fibroblasts the low content of ATP synthase induces compensatory adaptive upregulation of mitochondrial respiratory chain complexes III and IV, interestingly by a posttranscriptional mechanisms. The second type of ATP synthase deficiency studied was mtDNA m.9205delTA mutation affecting maturation of MT-ATP8/MT-ATP6/MT-CO3 mRNA and thus biosynthesis of Atp6 (subunit a) and Cox3...
|
|
|
Genetic and functional characterisation of mitochondrial diseases caused by ATP synthase defects
Tauchmannová, Kateřina ; Houštěk, Josef (advisor) ; Flachs, Pavel (referee) ; Kutejová, Eva (referee)
Disorders of ATP synthase, the key enzyme of mitochondrial energy provision belong to the most severe metabolic diseases presenting mostly as early-onset mitochondrial encephalo-cardio-myopathies. Mutations in four nuclear genes can result in isolated deficiency of ATP synthase, all sharing a similar biochemical phenotype - pronounced decrease in the content of fully assembled and functional ATP synthase complex. The thesis summarises studies on two distinct causes of ATP synthase deficiency. First is TMEM70 protein, a novel ancillary factor of ATP synthase, which represents most frequent determinant of severe inborn deficiency of ATP synthase. TMEM70 is a 21 kDa protein of the inner mitochondrial membrane, facilitating the biogenesis of mitochondrial ATP synthase, possibly through TMEM70 protein region exposed to the mitochondrial matrix, but the proper regulatory mechanism remains to be elucidated. In TMEM70-lacking patient fibroblasts the low content of ATP synthase induces compensatory adaptive upregulation of mitochondrial respiratory chain complexes III and IV, interestingly by a posttranscriptional mechanisms. The second type of ATP synthase deficiency studied was mtDNA m.9205delTA mutation affecting maturation of MT-ATP8/MT-ATP6/MT-CO3 mRNA and thus biosynthesis of Atp6 (subunit a) and Cox3...
|
guest ::
