Conference overview: Targeting Mitochondrial Dysfunction & Toxicity
Mark Bamberger of Stealth Peptides provides an overview of the recent 'Targeting Mitochondrial Dysfunction and Toxicity' conference, which addressed how much mitochondrial dysfunction can contribute to disease states, and also explored how to predict whether potential new drugs may negatively affect mitochondrial function.
Mitochondria play a role in a large number of diseases. Recently at the 'Targeting Mitochondrial Dysfunction and Toxicity' scientific symposium, organized by the Cambridge Healthtech Institute, a number of investigators came together to discuss two main topics: how mitochondrial dysfunction can lead to certain disease states, along with potential therapies, and secondly, ways to predict if potential drugs in clinical development will negatively impact mitochondrial function. I was asked to chair a session that covered the first topic, with an emphasis on cancer and metabolic disorders.
While everyone thinks of mitochondria as the 'powerhouse' of the cell, through the generation of ATP, they also play other important roles, including the production of reactive oxygen species and in the regulation of cell proliferation and death (apoptosis). The role mitochondrial function plays in cancer is just evolving, and data exists on both sides.
Specifically, if mitochondrial function in cancer cells is dysfunctional, then would restoring it to normal be good or bad? Cancer cells are known to 'hijack' mitochondrial function and undergo glycolysis in the presence of oxygen (the Warburg effect), which allows for provision of essential nutrients for cancer cell growth and proliferation, and resistance to apoptosis. They are also known to produce greater levels of reactive oxygen species (ROS). Somehow they must defeat or at least inhibit the intracellular mechanisms to continue their unregulated growth, which would normally tell them to either stop or slow down synthesis of new proteins and other essential molecules for replication.
As I mentioned, the story is certainly evolving, but some initial results suggest that restoring normal mitochondrial function may actually not only inhibit the proliferation of cancer cells, but also increase their susceptibility to chemotherapeutic agents such as doxorubicin. In particular are data suggesting that if mitochondria from normal mammary epithelial cells were transplanted into breast cancer cells, the growth of the breast cancer cells were inhibited. This is an important observation and suggests that the restoration or 'normalizing' mitochondrial function may be beneficial in cancer treatment.
Continuing along the same theme, animal models continue to be developed to study the etiology and efficacy of therapeutic agents as they may relate to mitochondrial function. An enzyme of increasing importance in mitochondrial and metabolic dysfunction is AMPK (AMP-activated protein kinase). AMPK plays an important role in cellular energy homeostasis and is a crucial sensor of cellular energy levels.
AMPK activation leads to increased mitochondrial fatty acid oxidation and increased flux of fatty acids through the mitochondria among other actions. In effect, it stimulates the energy producing pathways, and decreases the anabolic, or energy consuming pathways, which coincidentally, are needed by cancer cells. Animal models of cancer are being developed that include manipulation of genes that regulate the expression and regulation of AMPK, including reducing expression of LKB1. LKB1 inhibits growth when needed by activating AMPK, which suppresses anabolic pathways.
Importantly, animal models which have reduced or no expression of LKB1 are being developed as potential models to study the therapeutic potential of compounds to reverse mitochondrial dysfunction and cancer progression. Studies are underway to investigate several compounds as potential clinical candidates.
Along the same lines, data were presented on biguanides, a class of molecules which include the widely-used diabetes drug metformin. Metformin is known to affect mitochondrial function, and to partially inhibit complex I of the electron transport chain. Interestingly, there is pharmacoepidemiologic data that metformin (and biguanides in general) have antineoplastic activity. Part of this anti-cancer activity may be due to activity involving AMPK and mitochondrial stress, although more work is needed to clarify these observations.
As mentioned above, the role of mitochondrial dysfunction in multiple diseases, as well as a need for agents to meet this need, is becoming increasingly apparent. This not only includes the more common chronic conditions, such as heart failure, diabetes and neurological disease, but also the rare, just as much, if not more so debilitating, genetic mitochondrial diseases.
At present, there is little available to remedy these conditions. Available agents include over-the-counter products, such as CoEnyme-Q and lipoic acid, and molecules designed to target mitochondria, such as MitoQ, that have to date proven not to be efficacious in clinical trials.
Data was presented in a variety of animal models from independent laboratories on a novel molecule, Bendavia, which demonstrates that this molecule can protect cells and tissue from both acute and oxidative stress. This small molecule seems to have several advantages over other agents, including that it can target mitochondria that are dysfunctional, but also targets a basic function of the respiration machinery of mitochondria and the generation of ATP; that is, the integrity of the inner mitochondrial membrane and the ability of the multiple components of the electron transport chain to work together more efficiently.
Overall, the area of mitochondria and disease is an extremely exciting and rapidly emerging area of science. Stay Tuned!
About the author:
Mark Bamberger is the Chief Scientific Officer at Stealth Peptides. He has 25 years' experience in drug discovery and early clinical development. Prior to joining Stealth Peptides, he was the former Director of Cardiovascular, Metabolic and Endocrine disease at Pfizer.
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