Abstract
Mitochondria can be released by astrocytes as part of a help-me signaling process in stroke. In this study, we investigated the molecular mechanisms that underlie mitochondria secretion, redox status, and functional regulation in the extracellular environment. Exposure of rat primary astrocytes to NAD or cADPR elicited an increase in mitochondrial calcium through ryanodine receptor (RyR) in the endoplasmic reticulum (ER). Importantly, CD38 stimulation with NAD accelerated ATP production along with increasing glutathione reductase (GR) and dipicolinic acid (DPA) in intracellular mitochondria. When RyR was blocked by Dantrolene, all effects were clearly diminished. Mitochondrial functional assay showed that these activated mitochondria appeared to be resistant to H2O2 exposure and sustained mitochondrial membrane potential, while inhibition of RyR resulted in disrupted membrane potential under oxidative stress. Finally, a gain- or loss-of-function assay demonstrated that treatment with DPA in control mitochondria preserved GR contents and increased mitochondrial membrane potential, whereas inhibiting GR with carmustine decreased membrane potentials in extracellular mitochondria released from astrocytes. Collectively, these data suggest that ER-mitochondrial interaction mediated by CD38 stimulation may support mitochondrial energy production and redox homeostasis during the mode of mitochondrial transfer from astrocytes.