New Grant Funding

Congratulations to Dr. John Hollander who was awarded a grant from the National Institutes of Health on 9/9/2015 for his project titled “miRNA Regulation of the Mitochondrial Genome”. Dr. Hollander’s group is studying the role of mitochondria in diabetes and ways to correct mitochondrial dysfunction in this disease. With a particular attention on regulation of the mitochondrial genome, the group is focused on restoring the loss of ATP generating capacity which is compromised in the heart of type 2 diabetic patients, through the use of rapidly evolving therapies that rely on targeted manipulation of miRNAs. In their most recent publication in the journal, Circulation: Cardiovascular Genetics (http://www.ncbi.nlm.nih.gov/pubmed/26377859), the group identified a pool of miRNAs that were redistributed in spatially-distinct mitochondrial subpopulations in an inverse manner following diabetic insult. Using a number of bioinformatics tools, the group developed a predictive platform for potential miRNA interactions with the mitochondrial genome which included interactions with all 13 mitochondrial genome-encoded electron transport chain complex proteins.

The research team includes Dr. Kevin Tveter who is a cardiac surgeon at the WVU Heart Institute. A brief synopsis of the grant is indicated below.

The dramatic increase in type 2 diabetes mellitus incidence worldwide is staggering. Cardiovascular complications including heart failure are common in these individuals, and they are precipitated by bioenergetic dysfunction. Diabetic patients display a 2-5 fold greater risk of developing heart failure as compared to non-diabetic patients despite correction for age, hypertension, obesity and coronary artery disease. In an evaluation of mouse (db/db) and human (patient) type 2 diabetic models, we observed marked mitochondrial dysfunction which culminated in decreased cardiac ATP generating capacity. MicroRNAs (miRs) are non-coding RNAs that orchestrate protein translation. MiR manipulation is emerging as a promising therapeutic approach for treating pathologies, such as diabetes mellitus. As a result, miR interventional strategies are being considered as prophylactic options in human clinical trials. Using advanced cross-linking immunoprecipitation coupled with next generation sequencing, we made the exciting observation, in both db/db mice and type 2 diabetic patients that miRs translocate into and out of cardiac mitochondria. We also determined that mitochondrial miRs were interacting with the mitochondrial transcriptome and influencing protein translation. Among the observed interactions was an increased presence of miR-378 in a functional regulatory context with mitochondrial genome-encoded ATP6 mRNA. ATP6 is a subunit of the F0 proton motor which resides in the inner mitochondrial membrane and is part of the ATP synthase complex. Bioenergetic deficit results from decreased ATP synthase functionality, ultimately compromising the heart’s ability to generate ATP for contraction. In preliminary studies, we generated a stable cell line overexpressing miR-378 which displayed decreased ATP6 protein content and reduced ATP synthase function, all of which were associated with increased mitochondrial miR-378 presence. Though these findings provided convincing evidence of this regulatory axis, it remains unclear as to whether manipulation of miR-378 levels in a pathological type 2 diabetic human patient model provides therapeutic relief against ATP synthase dysfunction by targeting the regulation of the mitochondrial transcriptome. The studies being proposed address this critical gap in knowledge in a translational manner by applying the experimental approach to diagnosed human type 2 diabetic patient samples.