Although the development of mitochondrial therapies has largely focused on diseases caused by mutations in mitochondrial DNA or in nuclear genes encoding mitochondrial proteins, it has been found that mitochondrial dysfunction also contributes to the pathology of many common disorders, including neurodegeneration, metabolic disease, heart failure, ischaemia–reperfusion injury and protozoal infections. Mitochondria therefore represent an important drug target for these highly prevalent diseases. Several strategies aimed at therapeutically restoring mitochondrial function are emerging, and a small number of agents have entered clinical trials. This Review discusses the opportunities and challenges faced for the further development of mitochondrial pharmacology for common pathologies.
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The authors thank N. Burger, P. Chinnery, C. Frezza, E. C. Hinchy, T. Krieg, H. A. Prag, J. Prudent and K. Saeb-Parsy for critical comments and suggestions. The authors apologize to their many colleagues whose primary papers they were unable to cite owing to their frequent citing of reviews owing to the wide scope of the topic. M.P.M.'s laboratory is supported by a grant from the UK Medical Research Council (MRC; MC_U105663142) and by a Wellcome Trust investigator award (110159/Z/15/Z). R.C.H.'s laboratory is supported by a Wellcome Trust investigator award (110158/Z/15/Z).
M.P.M. has a financial interest in Antipodean Pharmaceuticals, a company that is developing mitochondria-targeted therapies. M.P.M. and R.C.H. also hold patents in the area of mitochondrial therapies. In addition, M.P.M. consults for Novintum Biotechnology, Cayman Chemicals and Takeda Pharmaceuticals, and R.C.H. consults for Cayman Chemicals.
- Mitochondrial permeability transition pore
(MPTP). The MPTP is a large conductance pore that opens in the mitochondrial inner membrane in response to oxidative stress and elevated calcium levels. This leads to mitochondrial swelling and cell death.
- Reactive oxygen species
(ROS). ROS such as superoxide and hydrogen peroxide are produced as a by-product of normal metabolism. They can cause nonspecific oxidative damage to proteins, DNA and lipids that contributes to pathologies and can also act as redox signals.
- Protonmotive force
(Δp). The mitochondrial respiratory chain passes electrons from NADH or flavins on to oxygen and in doing so pumps protons across the mitochondrial inner membrane, thereby establishing a Δp. The Δp is composed of a mitochondrial membrane potential (Δψ) of ~150 mV and a pH gradient of ~0.5 pH units.
- Citric acid cycle
(CAC). The CAC takes acetyl-CoA generated from the pyruvate produced by glycolysis to fuse with oxaloacetate to form citrate. The citrate is then broken down to release carbon dioxide while providing electrons to the respiratory chain and regenerating oxaloacetate to keep the CAC turning.
- Reverse electron transport
(RET). Complex I in the mitochondrial respiratory chain can produce superoxide by RET. This occurs when the protonmotive force (Δp) is high and the ratio of ubiquinol (QH2) to ubiquinone (Q) in the CoQ pool is high, causing electrons to flow backwards through complex I.
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Murphy, M., Hartley, R. Mitochondria as a therapeutic target for common pathologies. Nat Rev Drug Discov 17, 865–886 (2018). https://doi.org/10.1038/nrd.2018.174
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