Targeting Mitochondrial RNase P in Heart Failure

Abstract

Decades of research has shown significant energetic crisis in failing hearts. It has been proposed that impaired mitochondrial biogenesis greatly contributes to energy deficiency and thought to be a pivotal player in disease progression. Strategies aimed at improving mitochondrial biogenesis in failing heart are urgently needed. Previously, we uncovered a significant defect in the processing of mitochondrial RNA in failing heart that is sensitive to the NAD+/NADH redox state. We speculate that downregulation of one of the critical subunits of mitochondrial RNase P, mitochondrial ribonuclease P protein 2 (Mrpp2), is the culprit. Mrpp2 is encoded by the HSD17B10 gene. It is well known that RNase P is NAD+ dependent, but the exact role of this subunit and its catalytic activity is currently unknown. It has been hypothesized, however, that mrpp2 serves a scaffolding function allowing for the enzymatic activity of the other two subunits: Mrpp1 and Mrpp3. We have found that in cases of reduced Mrpp2 levels, cardiac hypertrophy was present, and methylation of mitochondrial RNA was also downregulated in these hypertrophic cardiac cells. Knowing that downregulation of Mrpp2 levels and the presence of cardiac hypertrophy are closely linked, we hypothesized that the overexpression of the Hsd17b10 gene would help rescue cardiac health. Using an established murine model of heart failure, we were able to see a restoration of fractional shortening percentage, a reduction of the left ventricular diameter, and lowered presence of lung edema when delivering a viral vector carrying the Hsd17b10 gene specifically to failing cardiac muscle, indicating restored cardiac health.