2016 Continuing Education Course: Contribution of Mitochondria to Drug-Induced Organ Toxicities (Part 2)

Chairperson(s): Varsha G. Desai, NCTR, US Food and Drug Administration, Jefferson, AR; and Yvonne Will, Pfizer R&D, Groton, CT.

Drug Discovery Toxicology Specialty Section
Mechanisms Specialty Section Regulatory and Safety Evaluation Specialty Section

Mitochondria generate more than 90% of energy essential for the cell. Impaired mitochondrial function, therefore, can affect virtually every tissue and organ in the living organism. Tissues with the highest energy needs, such as the heart, brain, liver, kidney, and skeletal muscle are particularly vulnerable to the defects in mitochondrial bioenergetics that can manifest into tissue-specific pathologies. A distinctive feature of mitochondria is that, besides the nucleus, these organelles contain
their own genome (mitochondrial DNA). However, coordination between nuclear and mitochondrial genomes is crucial in regulating mitochondrial function. It is also becoming increasingly evident that mitochondria are a prime target of many therapeutic drugs and environmental toxins
that can alter their function through different mechanisms, leading to cellular injury, resulting in organ toxicity, and, in the worst case, death. Additionally, mitochondria serve as an important player in the execution of apoptosis (programmed cell death), a process that serves as a major
defense mechanism to remove unwanted and potentially dangerous cells. Collectively, these functions highlight a critical role of mitochondria in the life and death of the cell. This course will provide an in-depth overview of mitochondrial biology
and different mechanisms in which drugs can affect mitochondrial function. Particular emphasis is given to mitochondrial toxicity causing heart, liver, and kidney injury. In addition, we will describe novel highthroughput in vitro screening technologies in isolated mitochondria and cell models to elucidate potential mitochondrial toxicity. Several other methodologies will also be discussed that can reveal the mitochondrial target(s) of drug toxicity in different organs. The utility and limitations of these approaches will also be described. This course concludes by providing the participants with in-depth knowledge of basic mitochondrial function and important insights into how subtle changes in
mitochondrial activity can progress to overt pathology in tissues and help identify potential biomarkers of early stages of mitochondrial toxicity.
Moreover, this course will present how preclinical data on mitochondrial toxicity can help in understanding toxicities in humans.