Fig. 5.

Proposed pathogenic scenario induced by complex I deficiency. Pharmacological or genetic inhibition of complex I disrupts mitochondrial respiration and stimulates the mitochondrial production of ROS. As a consequence, an array of molecules is likely oxidatively modified in response to complex I defect, including the inner mitochondrial membrane lipid cardiolipin. Cardiolipin peroxidation, in turn, affects the binding of cytochrome c to the mitochondrial inner membrane, leading to an increased soluble pool of cytochrome c in the intermembrane space. Consequently, upon permeabilization of the outer mitochondrial membrane by activated Bax, a larger amount of mitochondrial cytochrome c can be released, making it more likely for a compromised neuron to undergo apoptosis (see Discussion for more details).