The Mechanism of Inhibition of Necrosis by Humanin Derivatives: A Potential Treatment for Ischemia and Related Diseases

In the past, necrosis, which is associated with many diseases was considered to be an uncontrolled process; however, recent data support the notion that necrosis is a regulated process, yet, the only available treatment for necrosis is applying high oxygen pressure. Humanin (HN) is a 24-amino acid peptide, known for its anti-apoptotic activity, especially against neuronal cell death by Alzheimer insults. Recent studies showed that HN has other protective actions such as in myocardial ischemia, atherosclerosis and more; most of the activities were related to anti-apoptotic action. HN was also shown to increase cellular ATP levels. Our study reveals that, in addition to their anti-apoptotic activities, HN and some of its peptide derivatives exhibits a protective effect against necrotic insults in neuronal cell lines (PC-12 and NSC-34). Additionally, we found that HN affects ATP levels in cells undergoing necrosis, and interacts directly with mitochondrial ATP synthase enhancing its activity. Results obtained by fluorescence lifetime imaging microscopy (FLIM) and super-resolution microscopy with fluorescein-labeled HN, support the aforementioned findings. Furthermore, in vivo studies in traumatic brain injury on C57BL/6J mice, show a protective effect of HN, as demonstrated by improved motor performance and by MRI study done in a 1 Tesla small animals device. Thus, the present study may reveal a novel anti-necrotic mechanism of action of HN and its derivatives, and provide a new strategy for potential therapeutic treatment of ischemic states.