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MITOCHONDRIAL COMPLEX 1 ACTIVITY IN MYOCARDIAL-SPECIFIC CHF1 DEFICIENT MICE

MITOCHONDRIAL COMPLEX 1 ACTIVITY IN MYOCARDIAL-SPECIFIC CHF1 DEFICIENT MICE. Jeffrey Gordon 11/23/2010. CHF1 – A Brief Overview. CHF1 is a basic-HLH transcription repressor which plays an important role in cardiovascular development CHF1 deficient mice are more susceptible to heart failure

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MITOCHONDRIAL COMPLEX 1 ACTIVITY IN MYOCARDIAL-SPECIFIC CHF1 DEFICIENT MICE

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  1. MITOCHONDRIAL COMPLEX 1 ACTIVITY IN MYOCARDIAL-SPECIFIC CHF1 DEFICIENT MICE Jeffrey Gordon 11/23/2010

  2. CHF1 – A Brief Overview • CHF1 is a basic-HLH transcription repressor which plays an important role in cardiovascular development • CHF1 deficient mice are more susceptible to heart failure • CHF1 myocardial transgenic mice are less susceptible to heart failure

  3. My Project • Hypothesis: differences of mitochondrial complex 1 activity may explain the phenotypic difference in susceptibility to heart failure in the myocardial specific CHF1 deficient mouse model • Why investigate complex 1? • Who cares / to what end?

  4. Why Test Complex 1 ? • In heart failure, decreased mitochondrial content and overall mitochondrial dysfunction exist • There are increased RNA transcripts of complex 1 in CHF1 transgenic mice • Preliminary data suggests decreased mitochondrial respiration in CHF1 deficient mice • Complex I is a manageable target

  5. Mitochondria • Mitochondria generate most of a cell’s ATP. • Mitochondria have a more broad function • Made of 4 complexes and ATP synthase http://en.wikipedia.org/wiki/File:ETC_electron_transport_chain.svg

  6. Complex I • Largest complex – 45 different polypeptides • Redox reaction – NADH + H(+) + ubiquinone (Q) NAD(+) + dihydroubiquinone (QH2)

  7. Who Cares / to what end? • Further characterize the mechanism responsible for increased susceptibility to heart failure of CHF1 deficient mice • Further understand mitochondria, which may offer therapeutic targets in the future

  8. Overview of My Project • Breed wild-type controls and myocardial-specific CHF1 deficient mice • Isolate left ventricular mitochondrial tissue • Measure complex 1 activity via spectrophotometry • Normalize this to total mitochondrial activity • Compare the two groups

  9. Spectrophotometry for Complex 1 • Beer - Lambert Law • Measure light absorbance of a material to calculate concentration. • For complex 1: NADH + H(+) + ubiquinone (Q) NAD(+) + dihydroubiquinone (QH2) http://www.adinstruments.com/solutions/experiments/labchart_experiments/full.php?exp_id=187&section_id=13&name_id=245&template=teaching

  10. Results -C1 = complex 1. CS = citrate synthase. -C1 Activity measured in nm/ (min *mg)

  11. Results P Value: 0.314564499 CHF1 Deficient WT

  12. Conclusions Complex 1 activity is not significantly different between wild-type and myocardial specific CHF-1 deficient mice Thus, differences in complex 1 are unlikely to explain the increased susceptibility to heart failure between these groups

  13. Future Avenues • CHF1 deficient mice have abnormal with calcium signaling and apoptosis. Further studies into mitochondrial dysfunction may lead to better understandings of these mechanisms.

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