The Mitochondria-Derived Peptide Humanin Improves Recovery from Intracerebral Hemorrhage: Implication of Mitochondria Transfer and Microglia Phenotype Change

Abstract

Astrocytes are an integral component of the neurovascular unit where they act as homeostatic regulators, especially after brain injuries, such as stroke. One process by which astrocytes modulate homeostasis is the release of functional mitochondria (Mt) that are taken up by other cells to improve their function. However, the mechanisms underlying the beneficial effect of Mt transfer are unclear and likely multifactorial. Using a cell culture system, we established that astrocytes release both intact Mt and humanin (HN), a small bioactive peptide normally transcribed from the Mt genome. Further experiments revealed that astrocyte-secreted Mt enter microglia, where they induce HN expression. Similar to the effect of HN alone, incorporation of Mt by microglia (1) upregulated expression of the transcription factor peroxisome proliferator-activated receptor gamma and its target genes (including mitochondrial superoxide dismutase), ( 2 ) enhanced phagocytic activity toward red blood cells (an in vitro model of hematoma clearance after intracerebral hemorrhage [ICH]), and(3) reduced proinflammatory responses. ICH induction in male mice caused profound HN loss in the affected hemisphere. Intravenously administered HN penetrated perihematoma brain tissue, reduced neurological deficits, and improved hematoma clearance, a function that normally requires microglia/macrophages. This study suggests that astrocytic Mt-derived HN could act as a beneficial secretory factor, including when transported within Mt to microglia, where it promotes a phagocytic/reparative phenotype. These findings also indicate that restoring HN levels in the injured brain could represent a translational target for ICH. These favorable biological responses to HN warrant studies on HN as therapeutic target for ICH.

Tobacco Use: A Major Risk Factor of Intracerebral Hemorrhage

“…136,139 Increased ROS/RNS release and increased activation of proinflammatory pathways and mitochondrial dysfunction are known to play a role in brain damage following hemorrhagic stroke. [140][141][142][143][144][145][146] Others also established the role of free radicals in sICH-induced brain damage. [147][148][149] Because nicotine exposure increases the activation of pathways involved in post-sICH brain damage, it is plausible that elevated activation of those pathways is enhanced post-sICH, which in turn leads to increased brain damage.…”

Effects of O-GlcNAcylation on functional mitochondrial transfer from astrocytes

“…12 In the CNS, intercellular mitochondrial transfer between astrocytes and neurons or microglia may regulate transcellular mitophagy, 13 neuroprotection, 14,15 and immunomodulation. 16 Additionally, neuroglial interaction via fragmented dysfunctional mitochondrial transfer may cause neurodegeneration. 17 Furthermore, given the presence of extracellular mitochondria in cerebrospinal fluid, their function and integrity may reflect brain metabolic state and recovery after CNS injury.…”

Mechanisms of protection of retinal pigment epithelial cells from oxidant injury by humanin and other mitochondrial-derived peptides: Implications for age-related macular degeneration

“…In astrocytes, pretreatment with HN decreased the level of proinflammatory cytokines, IL-6, IL-1β, and TNFα induced by lipopolysaccharide [ 82 ]. In an intracerebral hemorrhage model, activated astrocytes release mitochondria and HN which are incorporated into microglia and promote a "reparative" microglia phenotype characterized by enhanced phagocytosis and reduced pro-inflammatory responses [ 83 ]. Treatment with HNG reduced myocardial fibrosis by activating the Akt/GSK-3β pathway and may play a role in myocardial remodeling [ 84 ].…”

“… [ 108 ] Alzheimer's disease Brain Rats HN Amelioration of memory deficits induced by Aβ (1-42). [ 109 ] Glucocorticoid-induced Bone growth impairment Metatarsal bones/growth plate biopsies/chondrocytes Rats, Human, HN-Tg mice HN Prevention of GC-induced growth impairment in cultured bones [ 110 ] Arthritis Articular and growth plate cartilage Mice HNG Decreased chondrocyte apoptosis [ 110 ] Stroke Brain Mice HN Reduction of neurological deficits, and improved hematoma clearance [ 83 ] Endothelial dysfunction Umbilical vein endothelial cells Human HNG Decrease in lipid aggregation and apoptosis [ 76 ] Obesity Plasma Mice HNG Regulation of glutathione and sphingolipid metabolism [ 111 ] Atherosclerosis/diabetes Umbilical vein endothelial cells Human HN Prevention of hyperglycemia-associated endothelial dysfunction [ 112 ] Diabetes Umbilical vein endothelial cells Human HNG Reduction in apoptosis induced by high glucose ...…”