Effects of doxorubicin on cardiac muscle subsarcolemmal and intermyofibrillar mitochondria.
Doxorubicin (DOX) is a highly effective chemotherapeutic used in the treatment of a broad spectrum of malignancies. However, clinical use of DOX is highly limited by cumulative and irreversible cardiomyopathy that occurs following DOX treatment. The pathogenesis of DOX-induced cardiac muscle dysfunction is complex. However, it has been proposed that the etiology of this myopathy is related to mitochondrial dysfunction, as a result of the dose-dependent increase in the mitochondrial accumulation of DOX. In this regard, cardiac muscle possesses two morphologically distinct populations of mitochondria. Subsarcolemmal (SS) mitochondria are localized just below the sarcolemma, whereas intermyofibrillar (IMF) mitochondria are found between myofibrils. Mitochondria in both regions exhibit subtle differences in biochemical properties, giving rise to differences in respiration, lipid composition, enzyme activities and protein synthesis rates. Based on the heterogeneity of SS and IMF mitochondria, we hypothesized that acute DOX administration would have distinct effects on each cardiac mitochondrial subfraction. Therefore, we isolated SS and IMF mitochondria from the hearts of female Sprague-Dawley rats 48h after administration of DOX. Our results demonstrate that while SS mitochondria appear to accumulate greater amounts of DOX, IMF mitochondria demonstrate a greater apoptotic and autophagic response to DOX exposure. Thus, the divergent protein composition and function of the SS and IMF cardiac mitochondria result in differential responses to DOX, with IMF mitochondria appearing more susceptible to damage after DOX treatment.
School of Kinesiology, Auburn University, Auburn, AL, United States.
Andreas N
AN
Kavazis
Department of Applied Physiology and Kinesiology, University of Florida, Room 25 Florida Gym, , Gainesville, FL 32611, United States.
Aaron B
AB
Morton
Department of Kinesiology, Boise State University, Boise, ID, United States.
Stephanie E
SE
Hall
Department of Applied Physiology and Kinesiology, University of Florida, Room 25 Florida Gym, , Gainesville, FL 32611, United States. Electronic address: asmuder@ufl.edu.
Ashley J
AJ
Smuder
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D008928:Mitochondria / Q000187:drug effects*; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D004317:Doxorubicin
Anthracycline; Apoptosis; Heart