Mitochondria have long been involved in several cellular processes beyond its role in energy production. The importance of this organelle for cardiac tissue homeostasis has been greatly investigated and its impairment can lead to cell death and consequent organ failure. Several compounds have been described in the literature as having direct effects on cardiac mitochondria which can provide a mechanistic explanation for their toxicological or pharmacological effects. The present review describes one classic example of druginduced cardiac mitochondrial toxicity and another case of drug-induced mitochondrial protection. For the former, we present the case of doxorubicin, an anticancer agent whose treatment is associated with a cumulative and dose-dependent cardiomyopathy with a mitochondrial etiology. Following this, we present the case of carvedilol, a β-blocker with intrinsic antioxidant activity, which has been described to protect cardiac mitochondria from oxidative injury. The final part of the review integrates information from the previous chapters, demonstrating how carvedilol can contribute to reduce doxorubicin toxicity on cardiac mitochondria. The two referred examples result in important take-home messages: a) drug-induced cardiac mitochondrial dysfunction is an important contributor for drug-associated organ failure, b) protection of mitochondrial function is involved in the beneficial impact of some clinically-used drugs and c) a more accurate prediction of toxic vs. beneficial effects should be an important component of drug development by the pharmaceutical industry.

The use of engineered cardiac tissue for high-throughput drug screening/toxicology assessment remains largely unexplored. Here we propose a scaffold that mimics aspects of cardiac extracellular matrix while preserving the contractility of cardiomyocytes. The scaffold is based on a poly(caprolactone) (PCL) nanofilm with magnetic properties (MNF, standing for magnetic nanofilm) coated with a layer of piezoelectric (PIEZO) microfibers of poly(vinylidene fluoride-trifluoroethylene) (MNF+PIEZO). The nanofilm creates a flexible support for cell contraction and the aligned PIEZO microfibers deposited on top of the nanofilm creates conditions for cell alignment and electrical stimulation of the seeded cells. Our results indicate that MNF+PIEZO scaffold promotes rat and human cardiac cell attachment and alignment, maintains the ratio of cell populations overtime, promotes cell-cell communication and metabolic maturation, and preserves cardiomyocyte (CM) contractility for at least 12 days. The engineered cardiac construct showed high toxicity against doxorubicin, a cardiotoxic molecule, and responded to compounds that modulate CM contraction such as epinephrine, propranolol and heptanol.

Mitochondria are recognized as the producers of the majority of energy cells need for their normal activity. After the initial comprehension of how mitochondrial oxidative phosphorylation produces energy, mitochondrial research was not a priority for most cell biologists until novel mitochondrial functions were identified. In fact, it is now known that mitochondria are not only involved in cell calcium homeostasis, intermediate metabolism and free radical generation but are also a crucial crossroad for several cell death pathways. The notion that several clinically used drugs and other xenobiotics induce organ degeneration through damaging mitochondrial bioenergetics led to the use of the organelle as an effective and reliable bio-sensor to predict drug safety. Classic methods used to test the toxicity of a wide range of compounds on isolated mitochondrial fractions were later replaced by novel high-throughput methods to investigate the safety of a very large number of new molecules. Without surprise, the assessment of “mitochondrial safety” for new discovered molecules is of clear interest for pharmaceutical companies which can now select compounds lacking mitochondrial toxicity to undergo further trials, thus avoiding the possibility of later human toxicity due to mitochondrial liabilities.