Cutting-Edge Research on Mitochondrial Toxicity

By Cynthia Browning posted 03-22-2018 15:31


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Subcellular toxic effects are getting more and more attention as the field of toxicology delves further into subcellular mechanisms of toxicity. As my own research has recently focused on the effects of 2D manganese dioxide nanomaterials on mitochondria, I was excited to see several sessions at the 2018 Annual Meeting and ToxExpo focused on mitochondrial toxicity.

In the past, a lot of research has focused on the role of mitochondrial injury and autophagy in neurons and other brain cells. The 2018 session titled “Mitochondria: Critical Targets in Pharmaceutical and Environmental Toxicity” was unique in that it focused on the role of mitochondrial damage in less-studied organ systems, such as the heart. The speakers stressed that mitochondria are very important for any organ that has a high energy demand, including the brain, heart, and liver. For instance, myocytes are densely packed with mitochondria. One underlying theme of the session was that new discoveries in the molecular mechanisms of autophagy and mitochondrial maintenance can further enhance our understanding of how pharmaceuticals and toxicants act on mitochondria.

Dr. Åsa Gustafsson, University of California San Diego, discussed the importance of removing damaged mitochondria from the cell. While autophagy and its key protein PARKIN are essential to recognition and removal of damaged mitochondria by the autophagosome, other pathways can provide this function when autophagy is knocked out. Dr. Gustafsson discussed research demonstrating that the endosomal-lysosomal pathway is effective in clearing damaged mitochondria and appears to respond before autophagy following mitochondrial damage. As toxicologists continue to delve further into the effects of toxicants on mitochondria and autophagy, it is important to consider alternative clearing pathways and the long-term cellular consequences.

An exciting part of studying mitochondria is that there are very strong chemical inhibitors for each of the mitochondrial complexes. These inhibitors are actively utilized to investigate how inhibition of each complex affects mitochondrial membrane potential, ATP production, and cell death. Complex I, II, and III inhibitors have been shown to be effective across different cellular systems, enabling toxicologists to utilize them as positive controls as we determine the mechanism of action of mitochondrial toxicants. Using these positive controls, Dr. Frans Russel, RIMLS, showed that statins used clinically to reduce cholesterol in patients with cardiovascular disease inhibit mitochondrial complex II. Patients taking statins have reduced mitochondrial oxidative capacity, leading to drug-induced myopathy.

I think sessions like this one exemplify SOT’s strength in bridging toxicology with interdisciplinary research. This keeps toxicologists at the cutting-edge of research and enables us to identify new subcellular targets to investigate.

This blog was prepared by an SOT Reporter. SOT Reporters are SOT members who volunteer to write about sessions and events they attend during the SOT Annual Meeting and ToxExpo. If you are interested in participating in the SOT Reporter program in the future, please email SOT Communications Director Michelle Werts.