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Towheed 2012 Abstract IOC72

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Towheed MA (2012) Elucidating pathogenesis of ATP synthase dysfunction in a Drosophila model of mitochondrial encephalomyopathy. Mitochondr Physiol Network 17.13.

Link: IOC72 Open Access

Towheed MA, Celotto AM, Palladino MJ (2012)

Event: IOC72

Mohammad Atif Towheed

Mitochondrial missense mutations lead to devastating disorders in humans known as mitochondrial encephalomyopathies. Our lab has previously identified a pathogenic mutation (G116E) in Drosophila ATP6, which is a subunit of Complex V of the mitochondrial electron transport chain. This mutation causes progressive neuromuscular dysfunction and myodegeneration, and is a model for human mitochondrial disorders such as NARP (neuropathy, ataxia, and retinitis pigmentosa), MILS (maternally inherited Leigh's syndrome), and FBSN (familial bilateral striatal necrosis). The underlying pathophysiology of these mutant flies is not clearly understood. In addition to shortened lifespan, myopathy and neural dysfunction, these flies also exhibit abnormal mitochondrial morphology in ~60% of its mitochondria. The mitochondrial cristae are dilated as opposed to flat cristae in wild-type flies. Complex V is unable to efficiently dimerize and ATP synthase activity is severely diminished in ATP6 [1] flies. However, complex V ATPase activity is detectable and the membrane potential is not affected. These mutant flies also show an increase in ROS as a function of age. Earlier studies suggest that the complexes of the electron transport chain play a role in maintaining normal mitochondrial cristae morphology. We hypothesize that this missense mutation affects Complex V dimerization as it lies at the dimer interface and contributes significantly to the pathogenesis. To test our hypothesis, we use RNAi to knock down subunits ATPe and ATPg that are known to assist in ATP synthase dimerization. Since, mitochondrial disorders have a tissue specific pattern of presentation, we examine which tissue contributes to the pathophysiology most by using specific Gal4 fly lines. ATPe and/or ATPg are knocked down in either muscle or neuronal tissues and their motor function and life spans are tested. In addition, we are investigating the altered physiology of the mitochondria in these mutants. To determine how the ATP6 [1] flies use their mitochondrial electron transport chain, we will investigate the mitochondrial oxidative phosphorylation using high-resolution respirometry. Respirometry and measures of biochemical activities of mitochondrial specific enzymes will help to elucidate the pathophysiology of mitochondrial diseases in vivo.

β€’ Keywords: Mitochondrial missense mutations, Drosophila, Complex V

β€’ O2k-Network Lab: US PA Pittsburgh Palladino MJ


Labels:

Stress:Mitochondrial Disease; Degenerative Disease and Defect"Mitochondrial Disease; Degenerative Disease and Defect" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property.  Organism: Other Non-Mammal"Other Non-Mammal" is not in the list (Human, Pig, Mouse, Rat, Guinea pig, Bovines, Horse, Dog, Rabbit, Cat, ...) of allowed values for the "Mammal and model" property. 

Preparation: Intact Organism"Intact Organism" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property., Permeabilized tissue, Homogenate, Isolated Mitochondria"Isolated Mitochondria" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property.  Enzyme: Complex II; Succinate Dehydrogenase"Complex II; Succinate Dehydrogenase" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property., Complex V; ATP Synthase"Complex V; ATP Synthase" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property.  Regulation: Respiration; OXPHOS; ETS Capacity"Respiration; OXPHOS; ETS Capacity" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property., Flux Control; Threshold; Excess Capacity"Flux Control; Threshold; Excess Capacity" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property. 


HRR: Oxygraph-2k 




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