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April 5, 2016

Novel Technology Allows Assessment of Drug-Induced Mitochondrial Damage

  • Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity. However, current methods to evaluate mitochondrial activity still rely on traditional tests called endpoint assays, which provide limited prognostic information.

    Scientists, however, from The Hebrew University of Jerusalem have described a new generation of Liver-on-Chip devices, in which the researchers add glucose and lactate microsensors, allowing them to measure minuscule changes in central carbon metabolism in real time (seconds to minutes). Their microfluidic platform is composed of submillimeter human tissues, which are characterized as "bionic" because they contain optoelectronic sensors for oxygen and are maintained under conditions simulating the human physiological environment. The platform includes a computer-controlled switchboard and permits the automated measurement of glucose and lactate using clinical-grade microsensors. The sensor-integrated platform permits real-time tracking of the dynamics of metabolic adaptation to any type of mitochondrial damage for over a month in culture.

    The team's study ("Real-time Monitoring of Metabolic Function in Liver-on-Chip Microdevices Tracks the Dynamics of Mitochondrial Dysfunction") appears in the Proceedings of the National Academy of Sciences. 

    "Central carbon, or glucose and amino acid, metabolism is by far the most important source of energy and materials for our cells. It is the backbone of cellular function," said the study's lead author Prof. Yaakov Nahmias, Director of the Alexander Grass Center for Bioengineering at the Hebrew University of Jerusalem. "This metabolic pathway is very sensitive, and any toxic damage will either directly or ultimately lead to changes in glucose metabolism."

    This approach has already enabled Prof. Nahmias and his team to identify a new mode of acetaminophen (Tylenol®) toxicity back in June, suggesting the drug could directly block respiration in the kidneys and skin.

    In the current research, the team used an array of microsensors to measure small changes in metabolic fluxes. In other words, the sensor-integrated "bionic" microlivers actively told researchers how they change their metabolic pathways (what they "eat," "digest," and "spew out") when exposed to new drugs. This allows researchers to identify new causes for idiosyncratic toxicity, one of the biggest problems in drug discovery and the main cause for postmarket drug withdrawal.

    Idiosyncratic toxicity occurs without obvious reason to about 1:100,000 in the population, forcing new warning labels or complete withdraw of the drug (costing billions).

    The researchers tested the new technology on troglitazone (Rezulin®), an antidiabetic and anti-inflammatory drug that was removed from the U.S. market in 2000 due to severe drug-induced liver injury, costing Pfizer Inc. over $750 million in lawsuits. The results showed that even at low troglitazone concentrations previously regarded as safe, in which traditional tests don't reveal any damage to the cells, the new liver-on-chip technology was able to detect mitochondrial stress that forces the liver to increase its reliance on glucose metabolism.

    By revealing the dynamics of cellular adaptation to mitochondrial damage, this organ-on-chip technology permits detection of chemical toxicity before any effects on cell or tissue viability can be observed, according to Prof. Nahmias.

    "The ability to measure metabolic fluxes using small numbers of cells under physiological conditions can redefine the study of neurodegenerative disease, stem cells and cancer, in addition to drug discovery. In contrast to other instruments, our sensors do not require calibration and our cells do not undergo hypoxia or become exposed to decaying chemical signals due to nonspecific absorption," he explained.  "Our microfluidic system could be of significant interest to biological and clinical laboratories, whose work can range from the study of mitochondria and oxidative stress in neurological disorders (Alzheimer's, Parkinson's), to metabolic disease (diabetes, obesity), stem cell biology (pluripotency), virology, and cancer."

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