Mitochondrial function in doxorubicin-induced cardiotoxicity

Doxorubicin (DOX) is a chemotherapeutic drug that can cause serious cardiotoxic side effects leading to heart failure.

Different mechanisms have been proposed for this toxicity, though there is no specific cardioprotective drug available to prevent functional decline.

I previously established a clinically-relevant rat model of DOX-induced heart failure and characterised metabolic changes with non-invasive in vivo hyperpolarized magnetic resonance spectroscopy (MRS). These data show that cardiac oxidative metabolism is impaired before functional decline.

I have furthermore shown that activation of the adenosine monophosphate-activated kinase (AMPK) with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) prevents functional decline, but the mechanism for this remains elusive. AICAR is known to increase fatty acid uptake and oxidation, thereby improving mitochondrial function.

This could make mitochondrial energy generation more efficient, leading to adequate energy provision to maintain cardiac function.

Improved mitochondrial function could also prevent reactive oxygen species (ROS) production and mitochondrial permeability transition pore (mPTP) opening, indicative of the early stages of cell death.

I therefore propose to purchase a state-of-the-art mitochondrial bioanalyzer, the Oroboros O2k FluoRespirometer, which allows simultaneous measurements of mitochondrial substrate oxidation, ATP generation, ROS production and mPTP opening.

I will assess mitochondrial function in isolated cardiac mitochondria of saline control, DOX and DOX+AICAR rats at three time points in the chemotherapy regimen.

Before mitochondrial isolation I will measure cardiac function with CINE MRI and cardiac metabolic fluxes with hyperpolarized MRS to establish a clear picture of functional, metabolic and mitochondrial changes in the heart during DOX-chemotherapy and to elucidate the cardioprotective mechanism of AICAR.