Mitochondrial Function Inhibitors
In addition to being the energy generators in the cell, mitochondria play an important role in cell survival and cell death. In fact, any abnormality in the mitochondrial energy generation machinery can lead to cell death. Mitochondria are highly vulnerable to inhibition or uncoupling of the energy harnessing process and their structural and functional characteristics provide a number of primary targets for xenobiotic-induced bioenergetic failure. Inhibitors of mitochondrial function include compounds that act as electron transport inhibitors, uncouplers of oxidative phosphorylation, respiratory chain inhibitors, phosphorylation inhibitors, ionophores, and Krebs cycle inhibitors. The study of mitochondrial metabolism using these compounds has led to the identification of bioenergetic control points for cell replication, cell differentiation, and cell death. Use of specific inhibitors has also helped to distinguish the electron transport system from the phosphorylation system and define the sequence of redox carriers along the respiratory chain. Five different enzyme complexes have been recognized in the mitochondria. Complexes I, II, III, and IV are the electron transfer complexes, whereas complex V is an energy-conserving complex. It catalyzes ATP-Pi exchange and ATP hydrolysis.
Electron transport inhibitors act by preventing the passage of electrons from one carrier to the next. Irreversible inhibitors may cause a complete stoppage of respiration, whereas competitive inhibitors may allow some oxygen consumption and passage of electrons, but the conditions are not optimum to maintain a chemiosmotic gradient. Hence, the addition of ADP does not affect respiration. Electron transport system (ETS) accepts energy from carriers in the mitochondrial matrix and stores it to a form that can be used to phosphorylate ADP. NAD and FAD are the two energy carriers that donate energy to ETS. NAD carries energy to complex I (NADH-Coenzyme Q reductase) of the electron transport chain, whereas FAD is a part of the succinate dehydrogenase complex (complex II).
Uncouplers of oxidative phosphorylation, such as CCCP and 2,4-dintirophenol, inhibit mitochondrial function by abolishing the obligatory linkage between the respiratory chain and the phosphorylation system in intact mitochondria. Here the electron transport system is uninhibited due to complete and irreversible dissipation of the chemiosmotic gradient.