A1 Refereed original research article in a scientific journal
Deficit in PINK1/PARKIN-mediated mitochondrial autophagy at late stages of dystrophic cardiomyopathy
Authors: Kang CF, Badr MA, Kyrychenko V, Eskelinen EL, Shirokova N
Publisher: OXFORD UNIV PRESS
Publication year: 2018
Journal: Cardiovascular Research
Journal name in source: CARDIOVASCULAR RESEARCH
Journal acronym: CARDIOVASC RES
Volume: 114
Issue: 1
First page : 90
Last page: 102
Number of pages: 13
ISSN: 0008-6363
DOI: https://doi.org/10.1093/cvr/cvx201
Abstract
Aims Duchenne muscular dystrophy (DMD) is an inherited devastating muscle disease with severe and often lethal cardiac complications. Emerging evidence suggests that the evolution of the pathology in DMD is accompanied by the accumulation of mitochondria with defective structure and function. Here, we investigate whether defects in the housekeeping autophagic pathway contribute to mitochondrial and metabolic dysfunctions in dystrophic cardiomyopathy.Methods and results We employed various biochemical and imaging techniques to assess mitochondrial structure and function as well as to evaluate autophagy, and specific mitochondrial autophagy (mitophagy), in hearts of mdx mice, an animal model of DMD. Our results indicate substantial structural damage of mitochondria and a significant decrease in ATP production in hearts of mdx animals, which developed cardiomyopathy. In these hearts, we also detected enhanced autophagy but paradoxically, mitophagy appeared to be suppressed. In addition, we found decreased levels of several proteins involved in the PINK1/PARKIN mitophagy pathway as well as an insignificant amount of PARKIN protein phosphorylation at the S65 residue upon induction of mitophagy.Conclusions Our results suggest faulty mitophagy in dystrophic hearts due to defects in the PINK1/PARKIN pathway.
Aims Duchenne muscular dystrophy (DMD) is an inherited devastating muscle disease with severe and often lethal cardiac complications. Emerging evidence suggests that the evolution of the pathology in DMD is accompanied by the accumulation of mitochondria with defective structure and function. Here, we investigate whether defects in the housekeeping autophagic pathway contribute to mitochondrial and metabolic dysfunctions in dystrophic cardiomyopathy.Methods and results We employed various biochemical and imaging techniques to assess mitochondrial structure and function as well as to evaluate autophagy, and specific mitochondrial autophagy (mitophagy), in hearts of mdx mice, an animal model of DMD. Our results indicate substantial structural damage of mitochondria and a significant decrease in ATP production in hearts of mdx animals, which developed cardiomyopathy. In these hearts, we also detected enhanced autophagy but paradoxically, mitophagy appeared to be suppressed. In addition, we found decreased levels of several proteins involved in the PINK1/PARKIN mitophagy pathway as well as an insignificant amount of PARKIN protein phosphorylation at the S65 residue upon induction of mitophagy.Conclusions Our results suggest faulty mitophagy in dystrophic hearts due to defects in the PINK1/PARKIN pathway.
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