Background: Bnip3, a protein involved in initiation of cardiovascular disease and cancer, induces autophagy of damaged organelles by a poorly understood mechanism. Results: Bnip3 homodimerization and binding to LC3 induces selective autophagy of mitochondria and ER. Conclusion: Bnip3 plays a direct and selective role in autophagy. Significance: Our studies will advance future studies investigating the role of Bnip3 in human disease.
Bnip3 is a mitochondrial BH3-only protein that contributes to cell death through activation of the mitochondrial pathway of apoptosis. Bnip3 is also known to induce autophagy but the functional role of autophagy is unclear. In this study, we investigated the relationship between mitochondrial dysfunction and upregulation of autophagy in response to Bnip3 in cells lacking Bax and Bak. We found that Bnip3 induced mitochondrial autophagy in the absence of mitochondrial membrane permeabilization and Bax/Bak. Also, co-immunoprecipitation experiments showed that Bnip3 interacted with the autophagy protein LC3. Although Bax/Bak deficient cells were resistant to Bnip3-mediated cell death, inhibition of mitochondrial autophagy induced necrotic cell death. When investigating why these mitochondria had to be removed by autophagy, we discovered that Bnip3 reduced both nuclear and mitochondria-encoded proteins involved in oxidative phosphorylation. Interestingly, Bnip3 had no effect on other mitochondrial proteins such as Tom20 and MnSOD, or actin and tubulin in the cytosol. Bnip3 did not appear to reduce transcription or translation of these proteins. However, we found that Bnip3 caused an increase in mitochondrial protease activity, suggesting that Bnip3 might promote degradation of proteins in the mitochondria. Thus, Bnip3-mediated impairment of mitochondrial respiration induces mitochondrial turnover by activating mitochondrial autophagy.
Background-The anthracycline doxorubicin is an effective chemotherapeutic agent used to treat pediatric cancers but is associated with cardiotoxicity that can manifest many years after the initial exposure. To date, very little is known about the mechanism of this late-onset cardiotoxicity. Methods and Results-To understand this problem, we developed a pediatric model of late-onset doxorubicin-induced cardiotoxicity in which juvenile mice were exposed to doxorubicin, using a cumulative dose that did not induce acute cardiotoxicity. These mice developed normally and had no obvious cardiac abnormalities as adults. However, evaluation of the vasculature revealed that juvenile doxorubicin exposure impaired vascular development, resulting in abnormal vascular architecture in the hearts with less branching and decreased capillary density. Both physiological and pathological stress induced late-onset cardiotoxicity in the adult doxorubicin-treated mice. Moreover, adult mice subjected to myocardial infarction developed rapid heart failure, which correlated with a failure to increase capillary density in the injured area. Progenitor cells participate in regeneration and blood vessel formation after a myocardial infarction, but doxorubicin-treated mice had fewer progenitor cells in the infarct border zone. Interestingly, doxorubicin treatment reduced proliferation and differentiation of the progenitor cells into cells of cardiac lineages. Conclusions-Our data suggest that anthracycline treatment impairs vascular development as well as progenitor cell function in the young heart, resulting in an adult heart that is more susceptible to stress. (Circulation. 2010;121:675-683.)
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