Hypothetical scheme for diminished complex I activity in presynaptic nerve terminals of Spg7^–/– mice. (a) Schematic of a mitochondrion with a normal morphologic phenotype is depicted in a presynaptic nerve terminal, with an enlarged schematic of mitochondrial structure. Within the inner mitochondrial membrane, the nuclear-encoded product of Spg7, paraplegin (PP), forms an approximately 900-kDa complex with AFG3L2 (AFG) (7). In this hypothetical scheme, this complex has proteolytic activity that is necessary for the normal physiologic activity of NADH-ubiquinone oxidoreductase (complex I), such that the normal proton gradient is maintained between the mitochondrial matrix and the intermembrane space. This in turn allows for normal functioning of oxidative phosphorylation, and preservation of the mitochondrial membrane potential (Δψ_m). However, in the absence of paraplegin in nerve terminals from an Spg7^–/– mouse (b), an abnormal complex of AFG3L2 with a molecular weight of about 250 kDa (7) forms in the inner mitochondrial membrane that is unable to induce the necessary sequence of proteolytic events such that complex I has normal activity. This in turn results in a decrease in the proton gradient between the matrix and intermembrane space, with a presumed change in Δψ_m. As the animal ages, the net effect of diminished complex I activity in presynaptic nerve terminals is likely to be impairment of neurotransmitter release, pathologic generation of reactive oxygen species (ROS), and decreased retrograde transport of trophic substances.