Figure 1.

Mitochondrial mechanisms of neural cell death and targets for neuroprotection. The inner membrane electrical potential established by electron transport chain (ETC)-driven proton efflux is responsible both for ATP formation and for uptake of Ca²⁺ by the mitochondrial Ca²⁺ uniporter (MCU). Excessive Ca²⁺ uptake can activate the permeability transition pore (PTP), which releases accumulated Ca²⁺ and dissipates the proton gradient, thus uncoupling ATP synthesis from respiration. A critical decline in cellular ATP can cause acute, necrotic cell death. Elevated intracellular Ca²⁺ can also initiate mitochondria-dependent programmed cell death by activating calpain-mediated proteolysis of apoptosis inducing factor (AIF), normally bound to the inner membrane, and of Bid, normally located in the cytosol. Truncated Bid (tBid) can induce a conformation change in Bax, stimulating its oligomerization and megapore formation. Outer membrane megapores formed by Bax or Bak allow for release of intermembrane proteins, e.g., cytochrome c (C), and truncated AIF (tAIF), into the cytosol. These proteins trigger caspase-dependent and caspase-independent programmed cell death, respectively. Elevated Ca²⁺ promotes mitochondrial fission by at least two mechanisms that involve mitochondrial fission/fusion proteins. Membrane depolarization in response to Ca²⁺-induced PTP opening stimulates proteolysis of Opa-1, an inner membrane fusion protein, which then promotes mitochondrial fragmentation. Extramitochondrial Ca²⁺ indirectly interacts with outer membrane dynamin-related protein 1 (Drp1), which also promotes fission. Reactive O₂ species (ROS) and nitrogen species produced by mitochondria and extramitochondrial sources target numerous mitochondrial molecules. Oxidative modification of proteins present in the ETC or the tricarboxylic acid (TCA) cycle inhibit aerobic energy metabolism. Oxidation of protein sulfhydryl groups also greatly increases sensitivity of PTP opening by Ca²⁺. Peroxidation of cardiolipin (CL) decreases the amount of membrane bound cytochrome c and therefore increases the amount available for release to the cytosol. Oxidized cardiolipin also translocates to the outer membrane, where it enhances the ability of extramitochondrial Bax to bind and cause outer membrane pores to form.