Humanin and its derivatives are
peptides known for their protective antiapoptotic effects against
Alzheimer's disease. Herein, we identify a novel function of the
humanin-derivative AGA(C8R)-HNG17 (namely, protection against cellular
necrosis).
Necrosis is one of the main modes of cell death, which was until recently considered an unmoderated process. However, recent findings suggest the opposite. We have found that AGA(C8R)-HNG17 confers protection against
necrosis in the neuronal cell lines PC-12 and NSC-34, where
necrosis is induced in a
glucose-free medium by either chemohypoxia or by a shift from apoptosis to
necrosis. Our studies in
traumatic brain injury models in mice, where
necrosis is the main mode of neuronal cell death, have shown that AGA(C8R)-HNG17 has a protective effect. This result is demonstrated by a decrease in a neuronal severity score and by a reduction in
brain edema, as measured by magnetic resonance imaging (MRI). An insight into the
peptide's antinecrotic mechanism was attained through measurements of cellular
ATP levels in PC-12 cells under necrotic conditions, showing that the
peptide mitigates a
necrosis-associated decrease in
ATP levels. Further, we demonstrate the
peptide's direct enhancement of the activity of
ATP synthase activity, isolated from rat-liver mitochondria, suggesting that AGA(C8R)-HNG17 targets the mitochondria and regulates cellular
ATP levels. Thus, AGA(C8R)-HNG17 has potential use for the development of
drug therapies for
necrosis-related diseases, for example,
traumatic brain injury,
stroke,
myocardial infarction, and other conditions for which no efficient
drug-based treatment is currently available. Finally, this study provides new insight into the mechanisms underlying the antinecrotic mode of action of AGA(C8R)-HNG17.