Abstract TP345: Humanin, a Mitochondria-Derived Peptide Improves Outcome after Intracerebral Hemorrhage: Implication of Mitochondria Transfer and Microglia Phenotype Change

Background and Purpose: Astrocytes are the integral components of neurovascular unit where they act as homeostatic regulator, including after brain injury such as stroke. One mechanism by which astrocytes could improve homeostasis is through release of the functional mitochondria (Mt) that subsequently enter the recipient brain cell, adopt to the environment, and provide homeostatic effect. However, the mechanisms underlying beneficial effect of Mt transfer is unclear. Methods and Results: Using cell culture system, we found that the astrocytes release not only intact mitochondria, but also a small bioactive peptide, humanin (HN), a transcriptional product of Mt genome. We further discovered that secreted astrocytic Mt can incorporate into microglia, where they lead to: (1) increased HN level, (2) upregulation of transcription factor PPARγ, and its gene targets including manganese-superoxide dismutase, (3) enhanced phagocytic activities toward red blood cells ( in vitro model of hematoma clearance), and (4) reduced pro-inflammatory responses. This properties of HN suggest its potential beneficial role in intracerebral hemorrhage (ICH). First we found that ICH causes a profound loss of HN in the ICH-affected hemisphere. Next we established that intravenously administered recombinant HN (rHN) reaches the peri-hematoma brain tissue, and when we used it as treatment rHN reduced neurological deficits and improved hematoma clearance, function that normally implicates microglia/macrophages. Conclusions: This study suggests that Mt-derived HN could act as a beneficial secretory factor, including when transferred through Mt to microglia, where it promotes an adaptation to a phagocytic/reparative phenotype. Overall, these studies suggests that the restoration of HN in injured brain may represent a translational target for ICH.