Cardiac cytochrome c and cardiolipin depletion during anthracycline-induced chronic depression of mitochondrial function

Gonçalo C. Pereira, Susana P. Pereira, Ludgero C. Tavares, Filipa S. Carvalho, Silvia Magalhães-Novais, Inês A. Barbosa, Maria S. Santos, James Bjork, António J. Moreno, Kendall B. Wallace, Paulo J. Oliveira

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Abstract

Aims It is still unclear why anthracycline treatment results in a cardiac-specific myopathy. We investigated whether selective doxorubicin (DOX) cardiotoxicity involving mitochondrial degeneration is explained by different respiratory complexes reserves between tissues by comparing and contrasting treatment effects in heart vs liver and kidney. Alternatively, we have also explored if the degeneration is due to alterations of mitochondrial thresholds to incompatible states. Methods and results Heart, liver and kidney mitochondria were isolated from male Wistar rats weekly injected with DOX during 7 weeks. Global flux and isolated step curves were obtained for Complex I, III, IV, as well as for the adenine nucleotide translocator. We show treatment-related alterations in global flux curve for Complex III in all analyzed tissues and in Complex IV activity curve solely in heart. However, all mitochondrial threshold curves remained unchanged after treatment in the analyzed tissues. No treatment-related differences were detected on transcript or protein analysis of selected respiratory complexes subunits. However, a specific loss of cytochrome c and cardiolipin was measured in heart, but not other organs, mitochondria from DOX-treated animals. Conclusions Contrary to our hypothesis, impaired mitochondrial respiration could not be explained by intrinsic differences in respiratory complexes reserves among tissues or, by alterations in mitochondrial thresholds after treatment. Instead, we propose that loss of cytochrome c and cardiolipin are responsible for the depressed mitochondrial respiration observed after chronic DOX treatment. Moreover, cardiac cytochrome c and cardiolipin depletion decreases metabolic network buffering, hindering cardiac ability to respond to increased workload, accelerating cardiac aging.

Original languageEnglish (US)
Pages (from-to)95-104
Number of pages10
JournalMitochondrion
Volume30
DOIs
StatePublished - Sep 1 2016

Keywords

  • Animal model
  • Anthracycline
  • Cardiolipin
  • Cardiotoxicity
  • Metabolic reserve

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    Pereira, G. C., Pereira, S. P., Tavares, L. C., Carvalho, F. S., Magalhães-Novais, S., Barbosa, I. A., Santos, M. S., Bjork, J., Moreno, A. J., Wallace, K. B., & Oliveira, P. J. (2016). Cardiac cytochrome c and cardiolipin depletion during anthracycline-induced chronic depression of mitochondrial function. Mitochondrion, 30, 95-104. https://doi.org/10.1016/j.mito.2016.07.005