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dc.contributor.advisorD'Silva, Patrick
dc.contributor.authorSaha, Prasenjit Prasad
dc.date.accessioned2018-09-04T05:13:34Z
dc.date.accessioned2018-09-06T07:16:56Z
dc.date.available2018-09-04T05:13:34Z
dc.date.available2018-09-06T07:16:56Z
dc.date.issued2018-09-04
dc.date.submitted2015
dc.identifier.urihttps://etd.iisc.ac.in/handle/2005/4025
dc.identifier.abstracthttp://etd.iisc.ac.in/static/etd/abstracts/4888/G27225-Abs.pdfen_US
dc.description.abstractMitochondrial dysfunction has been implicated for a wide range of human diseases. One of the major biosynthetic processes in human mitochondria is the biogenesis of Iron-Sulfur (Fe-S) clusters which primarily involves in electron transfer reactions during oxidative phosphorylation (OXPHOS). Defects in Fe-S cluster biogenesis process leads to mitochondrial dysfunction and that eventually results in various human mitochondrial disorders. One of the major mitochondrial disorders associated with Fe-S cluster biogenesis impairment is exercise intolerance disorder ISCU myopathy, which is a result of loss of function of Fe-S cluster scaffold protein ISCU. Our biochemical results using yeast model system and HeLa cells lines suggests that ISCU Myopathy results in defective Fe-S cluster biogenesis in mitochondrial compartment. As a result, electron transport chain (ETC) complexes demonstrate significant reduction in their redox properties, leading to loss of cellular respiration. Furthermore, in ISCU Myopathy, mitochondria display enhancement in iron levels and reactive oxygen species, thereby causing oxidative stress leading to impairment in the mitochondrial functions. On the other hand, in mammalian mitochondria, the initial step of Fe-S cluster assembly process is assisted by NFS1-ISD11 complex, which delivers sulfur to the scaffold protein ISCU during Fe-S cluster synthesis. In humans, loss of ISD11 function leads to development of respiratory distress disorder, Combined Oxidative Phosphorylation Deficiency 19 (COXPD19). Our study maps the important ISD11 amino acid residues critical for in vivo Fe-S cluster biogenesis. Importantly, mutation of these critical ISD11 residues to alanine leads to its compromised interaction with NFS1, which results in reduced stability and enhanced aggregation of NFS1 in the mitochondria. Moreover, our findings highlight that, COXPD19 associated R68L ISD11 mutant displays reduced affinity to form a stable sub-complex with NFS1, thereby fails to prevent NFS1 aggregation, resulting impairment of Fe-S cluster biogenesis. The prime affected machinery is the ETC complex which demonstrates compromised redox properties, causing diminished mitochondrial respiration in COXPD19 patients. In summary, our findings provide compelling evidence that respiration defect due to impaired biogenesis of Fe-S clusters in ISCU myopathy patients, leads to manifestation of complex clinical symptoms. Additionally, our study highlights the role of ISD11 protein in Fe-S cluster biogenesis and maps the surface residues of ISD11 protein that are involved in interaction with sulfur donor protein NFS1. Moreover, we have demonstrated the molecular basis of disease progression of COXPD19 as a result of R68L ISD11 mutation.en_US
dc.language.isoen_USen_US
dc.relation.ispartofseriesG27225en_US
dc.subjectMitochondrial Iron Sulfuren_US
dc.subjectCluster Biogenesisen_US
dc.subjectHuman Health and Diseaseen_US
dc.subjectIron Sulfur Proteinsen_US
dc.subjectFe-S Cluster Biogenesisen_US
dc.subjectFe-S Clustersen_US
dc.subjectISCU Myopathyen_US
dc.subjectNFS1-ISD11en_US
dc.subjectIron-sulfur Cluster Scaffold Protein (ISCU)en_US
dc.subjectCombined Oxidative Phosphorylation Deficiency 19 (COXPD19)en_US
dc.subjectMitochondrial Matrix Protein ISD11en_US
dc.subjectInfantile Mitochondrial Complex II/III Deficiency (IMC23D)en_US
dc.subject.classificationBiochemistryen_US
dc.titleUncovering the Role of Mitochondrial Iron-sulfur (Fe-S) Cluster Biogenesis in Human Health and Diseaseen_US
dc.typeThesisen_US
dc.degree.namePhDen_US
dc.degree.levelDoctoralen_US
dc.degree.disciplineFaculty of Scienceen_US


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