HIG1, a novel regulator of mitochondrial γ-secretase, maintains normal mitochondrial function

The gamma-secretase complex (which contains presenilins, nicastrin, anterior pharynx defective-1, and presenilin enhancer-2) cleaves type I transmembrane proteins, including Notch and amyloid precursor protein. Dysregulated gamma-secretase activity has been implicated in the pathogenesis of Alzheimer's disease, stroke, atherosclerosis, and cancer. Tight regulation of gamma-secretase activity is required for normal physiology. Here, we isolated HIG1 (hypoxia inducible gene 1, domain member 1A) from a functional screen of gamma-secretase inhibitory genes. HIG1 was highly expressed in the brain. Interestingly, HIG1 was localized to the mitochondria and was directly bound to gamma-secretase components on the mitochondrial membrane in SK-N-SH neuroblastoma cells. Overexpresssion of HIG1 attenuated hypoxia-induced gamma-secretase activation on the mitochondrial membrane and the accumulation of intracellular amyloid beta. This accumulation was accompanied by hypoxia-induced mitochondrial dysfunction. The latter half domain of HIG1 was required for binding to the gamma-secretase complex and suppression of gamma-secretase activity. Moreover, depletion of HIG1 increased gamma-secretase activation and enhanced hypoxia-induced mitochondrial dysfunction. In summary, HIG1 is a novel modulator of the mitochondrial gamma-secretase complex, and may play a role in the maintenance of normal mitochondrial function.-Hayashi, H., Nakagami, H., Takeichi, M., Shimamura, M., Koibuchi, N., Oiki, E., Sato, N., Koriyama, H., Mori, M., Gerardo Araujo, R., Maeda, A., Morishita, R., Tamai, K., Kaneda, Y. HIG1, a novel regulator of mitochondrial gamma-secretase, maintains normal mitochondrial function. FASEB J. 26, 2306-2317 (2012). www.fasebj.org