Abstract
Mitochondrial dysfunction has been regarded as one of the major contributors of ischemic neuronal death after stroke. Recently, intercellular mitochondrial transfer between different cell types has been widely studied and suggested as a potential therapeutic approach. However, whether mitochondria are involved in the neuron-glia cross-talk following ischemic stroke and the underlying mechanisms have not been explored yet. In this study, we demonstrated that under physiological condition, neurons release few mitochondria into the extracellular space, and the mitochondrial release increased when subjected to the challenges of acidosis, hydrogen peroxide (H2O2), N-methyl-D-aspartate (NMDA), or glutamate. Acidosis reduced the mitochondrial basal respiration and lowered the membrane potential in primary-cultured mouse cortical neurons. These defective mitochondria were prone to be expelled to the extracellular space by the injured neurons, and were engulfed by adjacent astrocytes, leading to increased astrocytic expressions of mitochondrial Rho GTPase 1 (Miro 1) and mitochondrial transcription factor A (TFAM) at mRNA level. In mice subjected to transient focal cerebral ischemia, the number of defective mitochondria in the cerebrospinal fluid increased. Our results suggested that the neuron-derived mitochondria may serve as a “help-me” signaling and mediate the neuron-astrocyte cross-talk following ischemic stroke. Promoting the intercellular mitochondrial transfer by accelerating the neuronal releasing or astrocytic engulfing might be a potential and attractive therapeutic strategy for the treatment of ischemic stroke in the future.
Highlights
Stroke is one of the major causes of death and permanent disability worldwide, and ischemic stroke accounts for approximately 80% of stroke incidences (Powers et al, 2019)
Treatment with pH 6.5 induced an increase of mitochondria (MitoTracker Green positive) in the culture medium (CM) when compared with the pH 7.4 group
We concluded that when confronting with metabolic stresses, neurons might release the defective mitochondria to act as a “help-me” signaling and recruit the adjacent astrocytes for energy support by promoting astrocytic mitochondrial biogenesis (Figure 8)
Summary
Stroke is one of the major causes of death and permanent disability worldwide, and ischemic stroke accounts for approximately 80% of stroke incidences (Powers et al, 2019). Recombinant tissue plasminogen activator (rt-PA)-mediated thrombolysis is clinically effective after acute ischemic stroke. Neurons Release Injured Mitochondria After Stroke limit its clinical application (Gao et al, 2020). Exploring the molecular mechanisms underlying endogenous neuroprotection and finding a novel therapeutic strategy are of great significance for the treatment of ischemic stroke. Mitochondrial dysfunction is the most immediate response to glucose and oxygen deprivation after ischemia and is closely associated with the early events following ischemic stroke, including reactive oxygen species (ROS)-mediated oxidative stress, acidosis, and N-methyl-D-aspartate (NMDA), and glutamate-induced excitotoxicity (Liu et al, 2018; Chen et al, 2020). Numerous studies have evidenced that maintaining the mitochondrial function is essential for the neuronal activity and survival (Huang and Jiang, 2019; Chen et al, 2020). Mitochondria might be a promising neuroprotective target for the treatment of ischemic stroke
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