Transplantation of Astrocytic Mitochondria Modulates Neuronal Antioxidant Defense and Neuroplasticity and Promotes Functional Recovery after Intracerebral Hemorrhage

Abstract

Astrocytes release functional mitochondria (Mt) that play regulatory and prosurvival functions on entering adjacent cells. We recently demonstrated that these released Mts could enter microglia to promote their reparative/prophagocytic phenotype that assists in hematoma cleanup and neurological recovery after intracerebral hemorrhage (ICH). However, the relevance of astrocytic Mt transfer into neurons in protecting brain after ICH is unclear. Here, we found that ICH causes a robust increase in superoxide generation and elevated oxidative damage that coincides with loss of the mitochondrial enzyme manganese superoxide dismutase (Mn-SOD). The damaging effect of ICH was reversed by intravenous transplantation of astrocytic Mt, which on entering the brain (and neurons), restored Mn-SOD levels and reduced neurological deficits in male mice subjected to ICH. Using an in vitro ICH-like injury model in cultured neurons, we established that astrocytic Mt on entering neurons prevented reactive oxygen species-induced oxidative stress and neuronal death by restoring neuronal Mn-SOD levels while at the same time promoted neurite extension and upregulation of synaptogenesis-related gene expression. Furthermore, we found that Mt genome-encoded small peptide humanin, which is normally abundant in Mt, could simulate Mt-transfer effect on neuronal Mn-SOD expression, oxidative stress, and neuroplasticity under ICH-like injury. This study demonstrates that adoptive astrocytic Mt transfer enhances neuronal Mn-SOD-mediated antioxidative defense and neuroplasticity in the brain, which potentiate functional recovery following ICH.

Mitochondria Transfer in Brain Injury and Disease

“…Follow-up studies showed that transplantation of placenta-derived mitochondria via intravenous infusion significantly decreased brain infarction after focal cerebral ischemia in mice [ 79 ]. Similar neuroprotective effects were reported by Tashiro and colleagues [ 80 ], who found reduced neurological deficits following intravenous transplantation of astrocytic mitochondria in mice subjected to intracerebral haemorrhage. Pourmohammadi-Bejarpasi and colleagues also observed that intracerebroventricular transplantation of isolated mitochondria from human umbilical-cord-derived mesenchymal stem cells decreased apoptosis and gliosis, reduced infarct size, and improved motor function in a rat model of middle cerebral artery occlusion (MCAO) [ 81 ].…”

“…Less invasive methods, such as intravenous infusion [ 49 , 78 , 79 , 80 , 85 , 88 ] and intranasal delivery [ 87 ], have also reported that transplanted mitochondria are present in the brain and exert protective effects. However, specific or targeted delivery of transplanted mitochondria may be difficult to achieve in the brain via these methods due to uneven cellular distribution and uptake of mitochondria as well as the difficulty in targeting specific cell populations and disease-affected brain regions.…”

Neurotoxicity of ischemic astrocytes involves STAT3‐mediated metabolic switching and depends on glycogen usage

“…Exposing healthy neurons to OGD/R astrocytes with impaired mitochondria leads to reduction of neuronal mitochondrial respiration. Growing evidence indicates that astrocyte‐neuronal mitochondrial transport is an essential neuroprotective mechanism that is impaired in neurodegenerative diseases (English et al, 2020; Gao et al, 2019; Tashiro et al, 2022). Mitochondria can be transferred from reactive astrocytes to neurons in stroke (Hayakawa et al, 2016), and transplantation of naïve astrocytic mitochondria reduced neurologic deficits after intracerebral hemorrhage (Tashiro et al, 2022).…”

“…Growing evidence indicates that astrocyte‐neuronal mitochondrial transport is an essential neuroprotective mechanism that is impaired in neurodegenerative diseases (English et al, 2020; Gao et al, 2019; Tashiro et al, 2022). Mitochondria can be transferred from reactive astrocytes to neurons in stroke (Hayakawa et al, 2016), and transplantation of naïve astrocytic mitochondria reduced neurologic deficits after intracerebral hemorrhage (Tashiro et al, 2022). Presumably, inhibition of STAT3 in ischemic astrocytes prevents synaptic degeneration at least partially due to the rescue of astrocytic mitochondria.…”

Young Astrocytic Mitochondria Attenuate the Elevated Level of CCL11 in the Aged Mice, Contributing to Cognitive Function Improvement

“…Hayakawa and his colleagues demonstrated that astrocytes in the brain secrete functional Mt into adjacent neurons to help neuronal survival by increasing ATP levels and recovery after ischemic stroke [ 47 ]. Recently, we demonstrated that astrocytes secrete functional Mt that can be taken up by microglia and neurons, where they promote a “healing phenotype” of microglia and increase neuronal connectivity through mechanisms involving the upregulation of anti-oxidative manganese superoxide dismutase (Mn-SOD) and production of small mitochondria peptide, humanin [ 48 , 49 ]. During aging, synaptic mitochondrial dysfunction in the hippocampus causing ROS overproduction, respiration rate decrease, and reduction in ATP generation contributes to memory loss and cognitive impairment [ 50 ].…”