Doxorubicin-induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy.

Doxorubicin (Dox) is a widely used antineoplastic agent that can cause heart failure. Dox cardiotoxicity is closely associated with mitochondrial damage. Mitochondrial fission and mitophagy are quality control mechanisms that normally help maintain a pool of healthy mitochondria. However, unchecked mitochondrial fission and mitophagy may compromise the viability of cardiomyocytes, predisposing them to cell death. Here, we tested this possibility by using Dox-treated H9c2 cardiac myoblast cells expressing either the mitochondria-targeted fluorescent protein MitoDsRed or the novel dual-fluorescent mitophagy reporter mt-Rosella. Dox induced mitochondrial fragmentation as shown by reduced form factor, aspect ratio, and mean mitochondrial size. This effect was abolished by short interference RNA-mediated knockdown of dynamin-related protein 1 (DRP1), a major regulator of fission. Importantly, DRP1 knockdown decreased cell death as indicated by the reduced number of propidium iodide-positive cells and the cleavage of caspase-3 and poly (ADP-ribose) polymerase. Moreover, DRP1-deficient mice were protected from Dox-induced cardiac damage, strongly supporting a role for DRP1-dependent mitochondrial fragmentation in Dox cardiotoxicity. In addition, Dox accelerated mitophagy flux, which was attenuated by DRP1 knockdown, as assessed by the mitophagy reporter mt-Rosella, suggesting the necessity of mitochondrial fragmentation in Dox-induced mitophagy. Knockdown of parkin, a positive regulator of mitophagy, dramatically diminished Dox-induced cell death, whereas overexpression of parkin had the opposite effect. Together, these results suggested that Dox cardiotoxicity was mediated, at least in part, by the increased mitochondrial fragmentation and accelerated mitochondrial degradation by the lysosome. Strategies that limit mitochondrial fission and mitophagy in the physiologic range may help reduce Dox cardiotoxicity.-Catanzaro, M. P., Weiner, A., Kaminaris, A., Li, C., Cai, F., Zhao, F., Kobayashi, S., Kobayashi, T., Huang, Y., Sesaki, H., Liang, Q. Doxorubicin-induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy.

Incidence of Cellulitis in Lower Extremity Burns: 6-Year Analysis.

INTRODUCTION: Patients with burn wounds of the lower extremities are at increased risk of developing cellulitis. The probability of developing burn-associated cellulitis is presumed to be correlated with a medical history of diabetes, the etiology of the burn, delay in hospitalization of the patient during their initial presentation, and depth of the burn itself. This study aims to identify factors that place patients at increased risk for developing lower extremity burn wound cellulitis. MATERIALS AND METHODS: A retrospective chart review was performed of all Nassau University Medical Center Burn Center admissions from January 2010 to January 2016. All patients admitted with burns of any etiology isolated to the lower extremity were included in this study. Patients who were evaluated and followed as an outpatient were not included in this study. Pediatric patients less than or equal to 12 years of age were excluded from this study. RESULTS: Of the 218 admissions for lower extremity burns during the 6-year study period, 34% of patients developed cellulitis. Risk factors for developing lower extremity burn wound cellulitis included being male, greater depth of burn, and burn-to-admission delay. This was true in both univariate and multivariate analysis. total body surface area was a risk factor on univariate analysis but was not found to be an independent risk factor on multivariate analysis. No difference was observed in the development of cellulitis in patients discharged on oral antibiotics compared with those not given antibiotics. CONCLUSIONS: Burn wound cellulitis is the second most common complication observed in burns. Identification of patients at risk for developing cellulitis is important. Admitting these patients at increased risk and excising and grafting the burned area is a reasonable solution in preventing this costly complication.