Abstract 11187: Doxorubicin Provokes Maladaptive Autophagy and Necrotic Cell Death of Cardiac Myocytes by Disrupting Mitochondrial Respiration Chain Complex IV
Doxorubicin is known for its cardiotoxic effects and inducing cardiac failure, however, the underlying mechanisms remain cryptic. Earlier we established the inducible - death protein, Bcl-2-like Nineteen- Kilodalton- Interacting - Protein 3 (Bnip3) to be crucial for disrupting mitochondrial function and inducing cell death of cardiac myocytes. Whether Bnip3 underlies cardiotoxic effects of doxorubicin toxicity is unknown. Herein we demonstrate a novel signaling pathway that functionally links activation and preferential mitochondrial targeting of Bnip3 to the cardiotoxic properties of doxorubicin. Perturbations to mitochondria were observed in cardiac myocytes treated with doxorubicin. Impaired mitochondrial function was accompanied by an accumulated increase in autophagosomes and necrosis demonstrated by increase release of LDH, cTnT and loss of nuclear High Mobility Group Protein 1 (HMGB-1) immunoreactivity. Notably, mitochondrial associated Bnip3 in cells treated with doxorubicin formed strong protein interactions with Cytochrome c oxidase subunit1 (COX1) of respiratory chain. This displaced uncoupling protein 3 (UCP3) from COX1 resulting in increased ROS production, decline in maximal and reserved respiration capacity and cell viability. Interestingly, inhibition of autophagy with 3-methyl adenine (3-MA), or Atg7 knock-down suppressed doxorubicin induced necrotic cell death. Importantly genetic inhibition of Bnip3 preserved UCP3-COX complexes, mitochondrial respiratory integrity and abrogated doxorubicin induced necrotic cell death. Moreover, Bnip3-/- mice were resistant to doxorubicin cardiotoxicity displaying normal mitochondrial morphology, cardiac function and survival rates comparable to wild type vehicle treated litter mates. In this report, we demonstrate that doxorubicin provokes maladaptive autophagy resulting in necrotic cell death of ventricular myocytes by a mechanism that involves mitochondria dysfunction induced by the Bcl-2 death protein Bnip3.
Author Disclosures: R. Dhingra: None. H. Gang: None. V. Margulets: None. L. Kirshenbaum: None.
- © 2016 by American Heart Association, Inc.