Mitochondrial medicine: pharmacological targeting of mitochondria in disease

Abstract

Mitochondria play a central role in cell life and death and are known to be important in a wide range of diseases including the cancer, diabetes, cardiovascular disease, and the age-related neurodegenerative diseases. The unique structural and functional characteristics of mitochondria enable the selective targeting of drugs designed to modulate the function of this organelle for therapeutic gain. This review discusses mitochondrial drug targeting strategies and a variety of novel mitochondrial drug targets including the electron transport chain, mitochondrial permeability transition, Bcl-2 family proteins and mitochondrial DNA. Mitochondrial drug-targeting strategies will open up avenues for manipulating mitochondrial functions and allow for selective protection or eradication of cells for therapeutic gain in a variety of diseases.

Figure 1

Title: pharmacological targeting of mitochondria in disease. (a) Mitochondria accumulate delocalized lipophilic cations (DLCs) because of the large membrane potential across their inner membrane (negative on the inside). DLCs can be linked to a variety of bioactive compounds including derivatives of antioxidants such as coenzyme Q and vitamin E yielding MitoQ and MitoVit E, respectively. Some DLCs are selectively toxic to cancer cells due to their increased Δψ_m including Rh123 or AA1, whereas others such as the cyanine dye MKT-077 can be photoexited to yield toxic species. (b) Szeto–Schiller (SS) peptides selectively partition into the inner mitochondrial membrane independent of the Δψ_m and possess intrinsic antioxidant and cytoprotective properties. They contain an aromatic–cationic sequence motif in which the aromatic group, either tyrosine (SS01) or a dimethyltyrosine group (SS31), alternates with a basic amino acid. (c) Dequalinium is a dicationic mitochondriotropic compound that self-assembles and forms vesicle-like aggregates called DQAsomes. These vesicles have been shown to be actively taken up by endocytosis and to fuse with the mitochondrial outer membrane allowing mitochondria signal peptide (MSP)-tagged cargo to enter the matrix via the protein import system. The anticancer drug paclitaxel has been successfully delivered to mitochondria using this approach. (d) Mitochondria can be targeted by linking a MSP to a nonmitochondrial protein to create a chimeric protein that is taken up in to the mitochondrial matrix via the protein import pathway. This strategy can target drugs, proteins and covalently linked MSP-DNA to mitochondria.