Mitochondrial ferritin alleviates apoptosis by enhancing mitochondrial bioenergetics and stimulating glucose metabolism in cerebral ischemia reperfusion.

Oxidative stress and deficient bioenergetics are key players in the pathological process of cerebral ischemia reperfusion injury (I/R). As a mitochondrial iron storage protein, mitochondrial ferritin (FtMt) plays a pivotal role in protecting neuronal cells from oxidative damage under stress conditions. However, the effects of FtMt in mitochondrial function and activation of apoptosis under cerebral I/R are barely understood. In the present study, we found that FtMt deficiency exacerbates neuronal apoptosis via classical mitochondria-depedent pathway and the endoplasmic reticulum (ER) stress pathway in brains exposed to I/R. Conversely, FtMt overexpression significantly inhibited oxygen and glucose deprivation and reperfusion (OGD/R)-induced apoptosis and the activation of ER stress response. Meanwhile, FtMt overexpression rescued OGD/R-induced mitochondrial iron overload, mitochondrial dysfunction, the generation of reactive oxygen species (ROS) and increased neuronal GSH content. Using the Seahorse and O2K cellular respiration analyser, we demonstrated that FtMt remarkably improved the ATP content and the spare respiratory capacity under I/R conditions. Importantly, we found that glucose consumption was augmented in FtMt overexpressing cells after OGD/R insult; overexpression of FtMt facilitated the activation of glucose 6-phosphate dehydrogenase and the production of NADPH in cells after OGD/R, indicating that the pentose-phosphate pathway is enhanced in FtMt overexpressing cells, thus strengthening the antioxidant capacity of neuronal cells. In summary, our results reveal that FtMt protects against I/R-induced apoptosis through enhancing mitochondrial bioenergetics and regulating glucose metabolism via the pentose-phosphate pathway, thus preventing ROS overproduction, and preserving energy metabolism.