Abstract
This study is to investigate the underlying mechanisms of mitochondrial quality control (MQC) regulated by HtrA2/Omi during ischemia/reperfusion (I/R). We utilized the mnd2 mouse model, which has a missense mutation in HtrA2/Omi, to investigate the HtrA2/Omi regulation in mitochondria after I/R injury in the cerebral cortex. Compared to homozygous (HtrA2mnd2) mice, heterozygous (HtrA2Hetero) mice showed aging signs at a later age, increased HtrA2/Omi expression in the brain cortex, and lesser neurodegenerative signs. The brain cortex of HtrA2Hetero mice had increased superoxide dismutase (SOD) activity; lower levels of malondialdehyde (MDA); higher expressions of mitochondrial unfolded protein response (mtUPR)-related proteins, NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (Ndufs7), and uncoupling protein 2 (UCP2) proteins; more mitochondrial fission; higher levels of ATP and mtDNA copies; elevated sirtuin 3 (SIRT3) activity; and increased NAD+/NADH ratio. After 1.5 h of I/R, the brain cortex of HtrA2Hetero mice had a larger infarction size, reduced HtrA2/Omi expression, decreased S-X-linked inhibitor of apoptosis protein (XIAP), and increased C-Caspase3 than that of wild-type animals (WT). Mitochondria from the HtrA2Hetero brain cortex showed decreased ATP production and MQC deficiency after 1.5 h I/R. Genipin pre-treatment reduced the aforementioned I/R injury in the HtrA2Hetero brain cortex. In conclusion, mitochondrial function is compensated in the HtrA2Hetero brain cortex via the upregulation of the UCP2-SIRT3-PGC1 axis. Decreased HtrA2/Omi function damages mitochondrial quality in the HtrA2Hetero mouse brain cortex, leading to more brain I/R injury. Genipin pre-treatment ameliorates brain damages via the mitochondrial UCP2-SIRT3-PGC1 axis.