Figure 9.

Proposed mechanism for the striatum vulnerability to OXPHOS defects. The upper panels depict a model under normal conditions. Control striatal mitochondria would have robust OXPHOS function, membrane potential, and would be more sensitive to a calcium stimulus as compared to cortical/hippocampal mitochondria. The lower panels depict the consequences of mito-PstI expression. Mito-PstI leads to mtDNA damage and decreases in OXPHOS. OXPHOS-dependent ΔΨm is relatively high in the striatum, and the OXPHOS defect leads to a marked collapse in ΔΨm with a consequent impairment in Ca²⁺ buffering. This leads to increased cytosolic Ca²⁺, which activates Ca²⁺-sensitive proteases causing neuronal death. Astrocytosis, observed mostly in cortex and hippocampus after mito-PstI expression, may have a protective effect by supplying neurons with metabolic substrates (e.g., lactate) or other prosurvival factors.