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Signaling network alterations in mitochondrial disease

Signaling network alterations in mitochondrial disease . Xiaoyan Robert Bao Mootha lab Massachusetts General Hospital. Mitochondrial diseases. Most common inborn error of metabolism (~1/5000 live births)

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Signaling network alterations in mitochondrial disease

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  1. Signaling network alterations in mitochondrial disease Xiaoyan Robert Bao Mootha lab Massachusetts General Hospital

  2. Mitochondrial diseases • Most common inborn error of metabolism (~1/5000 live births) • Genetic heterogeneity (~75 known nuclear disease-causing genes; maternally inherited mtDNA syndromes) • Clinical heterogeneity: epilepsy, stroke-like episodes, vision loss, hearing loss, GI dismotility, lactic acidosis, hepatopathy • Diagnosis remains difficult, and no effective treatments exist subacute neurodegeneration myopathy

  3. An example of such a disease: Leigh Syndrome French Canadian Variant Described in 1993 in Saguenay Lac-Saint-Jean (SLSJ) Incidence ~ 1/2063 live births (1979-1990) Carrier rate ~ 1/23 in SLSJ Biochemical Features Cytochromecoxidase deficiency Clinical Features Brainstem gliosis, necrosis Mild developmental delay Ataxia Reye-like syndrome Facial dysmorphism Mortality due to acidotic crises Death between 6 mos and 12 yrs of age Morin et al Am J Hum Genet 1993

  4. Combining genomic information to discover the disease gene H2N COOH Exon 9 Exon 35 Protein 85,000 peptides DNA 2,000,000 nucleotides LRPPRC RNA 1,600,000 mRNA measures Lee et al Am J Hum Genet 2001 Mootha et al PNAS 2003

  5. Can we model disease in a dish? “Disease” cells Confirmation of knockdown Disease specific assay Physiological measurements 1. qRT-PCR 2. Western Blot 1. O2 Consumption 2. Acid production • Western Blot for respiratory chain proteins shRNA Gohil et al J BiolChem2010

  6. Systematically defining pathways that are altered Gohil et al J BiolChem2010

  7. RNAi against other OXPHOS disease genes SCO1 SCO2 SLC25A4 PUS1 LRPPRC POLG SURF1 DGUOK TK2 TAZ BCS1L FXN PEO1 COX10 COX15 ETHE1 V. Gohil, unpublished

  8. Chemical perturbation of OXPHOS function Metabolic profiling of cell culture media Shaham et al PNAS 2010

  9. Potential collaborations with LINCS centers • We have constructed different types of cellular models of mitochondrial disease: RNAi, dominant negative, chemical • In initial studies, we see robust transcriptional and metabolite changes in response to these genetic or chemical lesions. • We hypothesize that some of these transcriptional/metabolic changes are mediated by kinase signaling events • Such signaling events may contribute to disease pathogenesis. • We look forward to working with the LINCS centers to identify kinase signaling events that drive these changes, using mass spectrometry (Broad) and imaging based (HMS) methods

  10. Acknowledgments VamsiMootha Casey Belcher-Timme VishalGohil Olga Goldberger Roland Nilsson OdedShaham Nancy Slate Katherine Sims David E. Root Biao Luo Clary Clish ArvindRamanathan Amanda Souza NIH/NIDDK R01DK081457

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