Abstract 409: Role of the Mitochondrial AAA+ Lon Protease in Cardioprotection
Mitochondrial Lon is an ATP-powered proteolytic machine that selectively degrades regulatory proteins as well as misfolded, unassembled and damaged proteins. Lon is a key mediator of mitochondrial quality control, adapting mitochondrial metabolism to hypoxic, oxidative, and proteotoxic stresses. Although studies imply that up-regulating Lon in the failing or ageing heart is ameliorative, there is little detailed in vivo data about its importance in cardiovascular health and disease. To test the hypothesis that Lon protects the heart in vivo, we generated transgenic mice with cardiac-specific overexpression of Lon under the control of the alpha-MHC promoter (Tg-Lon). Lon was specifically overexpressed in heart with no change in the levels of endogenous substrates TFAM or mitochondrial aconitase, or the mitochondrial ClpXP protease. Baseline analysis of 2-11 month old mice showed no significant difference in body or heart weight or ventricular weight/tibial length. At 2-3 months, no significant difference was observed by echocardiography or histology. However, Tg-Lon mice showed significantly reduced cardiac injury in response to ischemia reperfusion (I/R)- ischemia (45 min)/reperfusion (24 hr). At 6-9 months Tg-Lon, infarct size/area at risk (AAR) was 32%±2.3 SEM versus NTg that was 51%±3.2 SEM (p-value<0.003, n=9, n=4). At 3-5 months the infarct size/AAR for Tg-Lon was 37%±2.9 SEM versus NTg 51%±1.6 SEM, p<0.009, n=4, n=4); and at 3 months, Tg-Lon was 37%±2.0 SEM versus NTg 47% ± 1.4 SEM, p<0.008, n=3, n=4). In all cases, there was no change in AAR/left ventricle (AAR/LV), and no difference in LV/body weight (LV/BW). At baseline, mitochondria isolated from Tg-Lon hearts showed lower oxygen consumption rates (OCR, pmoles O2/min) as compared to NTg. Average OCR for Tg-Lon was 12,997±708 SD AUC (1 μg), by contrast to NTg that was 32,042±320 (1 μg) (p<0.001, n=5, n=5). Associated with lower OCR of Tg-Lon, was a significant reduction of Complex I subunit NDUFB8 of NADH dehydrogenase, which was reduced 2.2 fold (p<0.001) as compared to NTg in LV extracts as well as in isolated heart mitochondria. These data demonstrate that Lon overexpression promotes cardioprotection, and that this effect may be linked to a reduction in basal mitochondrial oxygen consumption.
Author Disclosures: M. Li: None. S. Venkatesh: None. E. Rashad: None. T. Saito: None. J. Sadoshima: None. C.K. Suzuki: None.
- © 2015 by American Heart Association, Inc.