Figure 1.

Proteins involved in mitochondrial bioenergetics, oxygen radical metabolism and Ca²⁺ regulation. The electron transport chain consists of four protein complexes (I-IV) and the ATP synthase (complex V) located in the mitochondrial inner membrane. The activity of complex I converts NADH to NAD⁺ and the activity of complex II converts succinate to fumarate. Complexes I, III and IV transport protons (H⁺) across the membrane and complexes I and III generate superoxide anion radical (O₂^-.) during the electron transfer process. The enzymatic activity of mitochondrial manganese superoxide dismutase (MnSOD) converts O₂^-. to hydrogen peroxide (H₂O₂) which may then diffuse to the cytoplasmic compartments where glutathione peroxidase and catalase convert H₂O₂ to H₂O. However, H₂O₂ can interact with Fe²⁺ or Cu⁺ to generate hydroxyl radical (OH^.), a highly reactive free radical that can induce lipid peroxidation and oxidative damage to proteins and DNA. Mitochondrial uncoupling proteins (UCP) function as H⁺ leak channels which decrease mitochondrial membrane potential results in decreased generation of O₂^-. and ATP. Several mitochondrial proteins are involved in regulating movement of Ca²⁺ into and out of the mitochondria including the Ca²⁺ uniporter which moves Ca²⁺ into the mitochondrial matrix and the Ca²⁺ antiporter which extrudes Ca²⁺ into the cytosol. In addition, movement of K⁺ through ATP-sensitive potassium channels (KATP) in the inner membrane can result in decreased mitochondrial Ca²⁺ uptake. An important transmembrane protein complex which includes the voltage-dependent anion channel (VDAC) forms large permeability transition pores (PTP). The PTP open during the process of apoptosis resulting in the release of cytochrome c into the cytoplasm. Several cytoplasmic proteins may also interact with mitochondrial membranes resulting in a change its permeability including Bcl-2 and BH-only proteins such as Bax, Bid and Bik. Finally, there are interactions between mitochondria and the endoplasmic reticulum (ER) such that Ca²⁺ released through ER IP₃ receptors and ryanodine receptors (RyR) is rapidly transferred into mitochondria. On the other hand, cytochrome c released from mitochondria can trigger the release of Ca²⁺ from the ER.