Mutation Identified Leading to Mitochondrial Dysfunction and Heart Failure

A mutation in the gene that encodes for a protein thought to protect cells from stress-induced mitochondrial dysfunction has been linked to the chain of molecular events leading to heart failure.

Mutations in the PTEN-inducible kinase 1 (PINK1) gene cause one form of autosomal recessive early-onset Parkinson's disease. The mutations cause neurons to be more susceptible to reactive oxygen species (ROS) and more likely to undergo apoptosis.

As oxidative stress with associated mitochondrial dysfunction leads to cardiac dysfunction and heart failure (HF), investigators at the Peter Munk Cardiac Center (Toronto, Canada) elected to examine the role of the PINK1 gene in this process.

After observing that PINK1 protein levels were markedly reduced in end-stage human HF and that PINK1 localized exclusively to the mitochondria, the investigators genetically engineered a line of mice to lack the gene for PINK1.

They reported in the May 23, 2011, online edition of the journal Proceedings of the [US] National Academy of Sciences that PINK1 "knockout" mice developed left ventricular dysfunction and evidence of pathological cardiac hypertrophy as early as two months of age. The knockout mice had greater levels of oxidative stress and impaired mitochondrial function. There were also higher degrees of fibrosis, cardiomyocyte apoptosis, and a reciprocal reduction in capillary density.

"Our research suggests that PINK1 is an important switch that sets off a cascade of events affecting heart cell metabolism," said first author Dr. Phyllis Billia, a heart failure specialist at the Peter Munk Cardiac Center. "This could be one of the inciting events in the development of heart failure. We need to learn more about PINK1 and the other proteins it interacts with at the subcellular level, but if we have identified the inciting event that causes the chain of events leading to failure, research and drug development strategies should be focused in this new area of science."

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Peter Munk Cardiac Center