Figure 3.

Proposed sequence of the mitochondrial disease migraine cascade. The percentages of the m.3243A > G mutation in vascular endothelial and smooth muscle cells, neurons and glia like astrocytes may vary in and between the different cell types. Long‐term exposure of toxic substances, as ROS, might contribute to the occurrence of migraine at later age. The mutation, when having passed the disease‐elucidating threshold, will lead to a hampered OXPHOS due to defective translation. A disturbance of the OXPHOS complexes, mainly complex I and III, will give rise to an increase in ROS and disturbed cellular redox‐state which cannot be compensated by the natural existent scavenger system like the superoxide dismutases. Presumably as an adaptive consequence to the altered mitochondrial architecture caused by increased lipid peroxidation, its decreased ATP generating capacity and other cell biological consequences, the affected cells will initially respond via increased mitochondrial biogenesis. In brain vascular endothelial and smooth cells narrowing of the lumen will take place (for further details see Figure 2). Next to the increased production of ROS the consequent hypoxia/ischemia, altered glutamate metabolism and ionic homeostasis might trigger cortical spreading depolarization (CSD). CSD is an activator of the trigeminovascular system leading to migraine pain27