Abstract 101: Mitochondrial and Cardiac Protection Evoked by a Novel Mitochondria-targeting Peptide-idebenone Conjugate

Abstract

Dysfunction along the electron transport system contributes to cardiomyopathy in a number of mitochondrial diseases. Several pharmacological approaches are currently being tested for their ability to improve mitochondrial function, yet almost none of the leading candidates specifically target to mitochondria. In this study we determined the biological efficacy of a novel conjugate of idebenone and mitochondria-targeting peptide, SBT-61. Using a vertically-integrated approach we tested the ability of SBT-61 to improve functional recovery and bioenergetics in: perfused rat hearts subjected to ischemia-reperfusion, cultured cells exposed to hypoxia-reoxygenation injury, and isolated heart mitochondria where complexes I and/or III were inhibited. SBT-61 treatment preserved post-ischemic cardiac function as assessed by left ventricular developed pressure (40 ± 5 vs 24 ± 3 mmHg, P<0.0001), rate of contraction (1853 ± 236 vs. 1069 ± 109 mmHg/s, P<0.0001), rate of relaxation (-1349 ± 231 vs. -792 ± 52 mmHg/s, P<0.0001), and a 30% reduction in infarct size. In cells expressing an shRNA knockdown of glutathione reductase, treatment with SBT-61 normalized maximal mitochondrial respiration after hypoxia-reoxygenation. In isolated mitochondria with complexes I or III inhibited, SBT-61 stimulated respiration and was shown to directly reduce complex III and cytochrome c, indicating that SBT-61 can bypass defects in the electron transport system. These data highlight the cardioprotective potential of a mitochondria-targeted idebenone conjugate to stabilize mitochondrial bioenergetics.