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"Impaired mitophagy in dystrophic cardiomyopathy"

Chifei Kang
Pharmacology, Physiology and Neuroscience Program
B.S. 2007, Beijing Forestry University, Beijing, China
M.S. 2010, University of Connecticut, Storrs, CT

Thesis Advisor: Natalia Shirokova, Ph.D.
Associate Professor
Department of Pharmacology, Physiology and Neuroscience

Tuesday, August 30, 2016
1:00 P.M., MSB Room H609


Duchenne Muscular Dystrophy (DMD) is an inherited devastating muscle disease with severe and often lethal cardiac complications. It seems that progression of the disease is associated with increased oxidative stress as well as with cellular Ca2+ overload. Moreover, the evolution of pathology in DMD is accompanied by the accumulation of mitochondria with defective structure/function. Mitochondrial autophagy (mitophagy) is a robust housekeeping cellular pathway with capacity to degrade the unnecessary or damaged organelles. Here we investigate if defects in autophagic pathway contribute to mitochondrial and metabolic dysfunctions in dystrophic cardiomyopathy. We employed various biochemical and imaging techniques to assess mitochondrial structure/function as well as to evaluate autophagic fluxed and extent of mitophagy in hearts of mdx mice, an animal model of DMD. Our results indicate substantial structural damage of mitochondria and significant decrease in ATP production in hearts of senescent mdxanimals with severe cardiomyopathy. In these hearts we also detected enhanced autophagic fluxes, probably in response to the metabolic starvation as well as other cellular stress signals associated with a disease. However, mitophagy seems to be suppressed in dystrophic hearts. Decreased levels of several proteins involved in PINK1/PARKIN mitophagy pathway as well as negligible amount of PARKIN phosphorylation at S65 residue upon induction of mitophagy suggest defective mitophagy if dystrophic hearts due to defects in PINK1/PARKIN pathway.
In summary, our results suggested the impaired mitophagy results in insufficient ability to degrade the impaired organelles and contributes to the progressive accumulation of damaged mitochondria and deterioration of cardiac functions in dystrophic hearts.

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