Multiple acyl-CoA dehydrogenase deficiency (MADD) is a fatty acid and amino acid oxidation defect... more Multiple acyl-CoA dehydrogenase deficiency (MADD) is a fatty acid and amino acid oxidation defect caused by a deficiency of the electron-transfer flavoprotein (ETF) or the electron-transfer flavoprotein dehydrogenase (ETFDH). There are three phenotypes of the disease, two neonatal forms and one late-onset. Previous studies have suggested that there is a phenotype–genotype correlation. We report on six patients from a single Bedouin tribe, five of whom were sequenced and found to be homozygous to the same variant in the ETFDH gene, with variable severity and age of presentation. The variant, NM_004453.3 (ETFDH): c.524G>A, p.(R175H), was previously recognized as pathogenic, although it has not been reported in the literature in a homozygous state before. R175H is located near the FAD binding site, likely affecting the affinity of FAD for EFT:QO. The single homozygous ETFDH pathogenic variant was found to be causing MADD in this cohort with an unexpectedly variable severity of prese...
Omaveloxolone (RTA408) is a second-generation oleanane triterpenoid Nrf2 inducer with antioxidant... more Omaveloxolone (RTA408) is a second-generation oleanane triterpenoid Nrf2 inducer with antioxidant and anti-inflammatory properties and was reported to improve mitochondrial bioenergetics. It is currently being tested in medical trials for Friedrich ataxia, a genetic, multi-organ disease involving mitochondrial dysfunction. Thus, omaveloxolone could potentially be beneficial for additional disorders involving mitochondrial dysfunction. To this end, we investigated its effect on primary fibroblasts derived from patients with mitochondrial complex I deficiency, mitochondrial cytochrome oxidase deficiency, and two recessive forms of Parkinson’s disease. Patients and control cells were incubated in the presence or absence of 50 nM omaveloxolone for 72 h prior to measurements. Generally, growth on galactose medium and ATP production were unaltered. Mitochondrial membrane potential was slightly but significantly decreased, while reactive oxygen species (ROS) production was variably decreas...
Vesicular transport is a means of communication. While cells can communicate between each other v... more Vesicular transport is a means of communication. While cells can communicate between each other via secretion of extracellular vesicles, less is known regarding organelle-to organelle communication, in particularly in the case of mitochondria. Mitochondria are responsible for the production of energy and for essential metabolic pathways in the cell, as well as fundamental processes such as apoptosis and aging. Here we show that functional mitochondria, isolated from Saccharomyces cerevisiae release vesicles, independent of the fission machinery. We were then able for the first time to isolate these Mitochondrial Derived Vesicles (MDVs) and found that they are relatively uniform in size, of about 100nm and carry selective protein cargo including enrichment of ATP synthase subunits. Remarkably, we further found that these MDVs harbor a functional ATP synthase complex. Moreover, we demonstrate that these vesicles have a membrane potential, produce ATP, and seem to fuse with naive mitoc...
Mitochondrial respiratory chain complex I (CI) performs the first step of oxidative phosphorylati... more Mitochondrial respiratory chain complex I (CI) performs the first step of oxidative phosphorylation (OXPHOS), essential for cellular energy production. This large intricate protein complex is composed of multiple subunits encoded both by the mitochondrial and nuclear genomes and its assembly depends on several nuclear-encoded factors. Isolated CI deficiency due to mutations in nuclear-encoded subunits or assembly factors is a relatively common mitochondrial disorder; however, many patients remain without a molecular diagnosis. Clinical symptoms may vary but are mostly neurological with early manifestation and a grave prognosis. Despite increasing knowledge of CI assembly function and pathomechanism gained by the study of patient’s cells and animal models, a satisfactory treatment, is presently unavailable. Therefore, identification of the underlying molecular cause is imperative in order to provide genetic counseling.
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a fatty acid and amino acid oxidation defect... more Multiple acyl-CoA dehydrogenase deficiency (MADD) is a fatty acid and amino acid oxidation defect caused by a deficiency of the electron-transfer flavoprotein (ETF) or the electron-transfer flavoprotein dehydrogenase (ETFDH). There are three phenotypes of the disease, two neonatal forms and one late-onset. Previous studies have suggested that there is a phenotype–genotype correlation. We report on six patients from a single Bedouin tribe, five of whom were sequenced and found to be homozygous to the same variant in the ETFDH gene, with variable severity and age of presentation. The variant, NM_004453.3 (ETFDH): c.524G>A, p.(R175H), was previously recognized as pathogenic, although it has not been reported in the literature in a homozygous state before. R175H is located near the FAD binding site, likely affecting the affinity of FAD for EFT:QO. The single homozygous ETFDH pathogenic variant was found to be causing MADD in this cohort with an unexpectedly variable severity of prese...
Omaveloxolone (RTA408) is a second-generation oleanane triterpenoid Nrf2 inducer with antioxidant... more Omaveloxolone (RTA408) is a second-generation oleanane triterpenoid Nrf2 inducer with antioxidant and anti-inflammatory properties and was reported to improve mitochondrial bioenergetics. It is currently being tested in medical trials for Friedrich ataxia, a genetic, multi-organ disease involving mitochondrial dysfunction. Thus, omaveloxolone could potentially be beneficial for additional disorders involving mitochondrial dysfunction. To this end, we investigated its effect on primary fibroblasts derived from patients with mitochondrial complex I deficiency, mitochondrial cytochrome oxidase deficiency, and two recessive forms of Parkinson’s disease. Patients and control cells were incubated in the presence or absence of 50 nM omaveloxolone for 72 h prior to measurements. Generally, growth on galactose medium and ATP production were unaltered. Mitochondrial membrane potential was slightly but significantly decreased, while reactive oxygen species (ROS) production was variably decreas...
Vesicular transport is a means of communication. While cells can communicate between each other v... more Vesicular transport is a means of communication. While cells can communicate between each other via secretion of extracellular vesicles, less is known regarding organelle-to organelle communication, in particularly in the case of mitochondria. Mitochondria are responsible for the production of energy and for essential metabolic pathways in the cell, as well as fundamental processes such as apoptosis and aging. Here we show that functional mitochondria, isolated from Saccharomyces cerevisiae release vesicles, independent of the fission machinery. We were then able for the first time to isolate these Mitochondrial Derived Vesicles (MDVs) and found that they are relatively uniform in size, of about 100nm and carry selective protein cargo including enrichment of ATP synthase subunits. Remarkably, we further found that these MDVs harbor a functional ATP synthase complex. Moreover, we demonstrate that these vesicles have a membrane potential, produce ATP, and seem to fuse with naive mitoc...
Mitochondrial respiratory chain complex I (CI) performs the first step of oxidative phosphorylati... more Mitochondrial respiratory chain complex I (CI) performs the first step of oxidative phosphorylation (OXPHOS), essential for cellular energy production. This large intricate protein complex is composed of multiple subunits encoded both by the mitochondrial and nuclear genomes and its assembly depends on several nuclear-encoded factors. Isolated CI deficiency due to mutations in nuclear-encoded subunits or assembly factors is a relatively common mitochondrial disorder; however, many patients remain without a molecular diagnosis. Clinical symptoms may vary but are mostly neurological with early manifestation and a grave prognosis. Despite increasing knowledge of CI assembly function and pathomechanism gained by the study of patient’s cells and animal models, a satisfactory treatment, is presently unavailable. Therefore, identification of the underlying molecular cause is imperative in order to provide genetic counseling.
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Papers by Ann Saada