Figure 1 (A) Diagram of oxidative phosphorylation in the mitochondria. Oxidative phosphorylation is a metabolic pathway which leads to the harnessing of energy as adenosine triphosphate (ATP). Complexes I–IV and complex V (ATP synthase) form the respiratory chain. All 5 complexes are affected in Leigh syndrome, leading to the inability to effectively produce ATP and provide energy to cells. Reactive oxygen species (ROS) (especially O2−) are also produced in high levels via the mitochondrial electron transport chain. Complexes I and III, in particular, are heavily involved in ROS disposal. The build-up of ROS leads to damage to the lipid membranes, nucleic acids, and proteins which is believed to lead to the development of mitochondrial disease [2]. (B) IDH is a component of the tricarboxylic acid (TCA) cycle (Krebs cycle/Citric acid cycle), which is linked to the respiratory chain via complex II. The TCA cycle is part of the glycolytic pathway and is essential for energy production under hypoxic conditions. IDH mutations shunt the production of alpha-ketoglutarate, a necessary substrate in the production of citrate, into D-2-hydroxyglutarate (D-2-HG). The production of D-2-HG inhibits the formation of NAD and glutamate, affecting cellular metabolism. IDH mutations also lead to increased production of ROS [11,17]. (C) In response to apoptosis signaling, cytochrome C permeates through the outer membrane of the mitochondria and initiates the apoptosis cascade. Transport of cytochrome C across the outer membrane is inhibited by excessive ROS [13].