Hypoxia-reoxygenation of primary astrocytes results in a redistribution of mitochondrial size and mitophagy

Abstract

Astrocytes serve to maintain proper neuronal function and support neuronal viability, but remain largely understudied in research of cerebral ischemia. Astrocytic mitochondria are core participants in the metabolic activity of astrocytes. The objective of this study is to assess astrocyte mitochondrial competence during hypoxia and post-hypoxia reoxygenation and to determine cellular adaptive and pathological changes in the mitochondrial network. We hypothesize that during metabolic distress in astrocytes; mitochondrial networks undergo a shift in fission-fusion dynamics that results in a change in the morphometric state of the entire mitochondrial network. This mitochondrial network shift may be protective during metabolic distress by priming mitochondrial size and facilitating mitophagy. We demonstrated that hypoxia and post-hypoxia reoxygenation of rat primary astrocytes results in a redistribution of mitochondria to smaller sizes evoked by increased mitochondrial fission. Excessive mitochondrial fission corresponded to Drp-1 dephosphorylation at Ser 637, which preceded mitophagy of relatively small mitochondria. Reoxygenation of astrocytes marked the initiation of elevated mitophagic activity primarily reserved to the perinuclear region where a large number of the smallest mitochondria occurred. Although, during hypoxia astrocytic ATP content was severely reduced, after reoxygenation ATP content returned to near normoxic values and these changes mirrored mitochondrial superoxide production. Concomitant with these changes in astrocytic mitochondria, the number of astrocytic extensions declined only after 10-hours post-hypoxic reoxygenation. Overall, we posit a drastic mitochondrial network change that is triggered by a metabolic crisis during hypoxia; these changes are followed by mitochondrial degradation and retraction of astrocytic extensions during reoxygenation.

Deletion of mitochondrial uncoupling protein 2 exacerbates mitophagy and cell apoptosis after cerebral ischemia and reperfusion injury in mice

“…It refers to selective sequestration of mitochondria by autophagosomes and subsequently delivers them to lysosomes for destruction and material recycle [10]. Previous studies have shown that mitophagy is mainly evident in neurons [36] and astrocytes [37] of the ischemic brain. However, it is controversial whether I/R-triggered mitophagy is beneficial or detrimental to the tissue.…”

The Role of Mitophagy in Ischemic Stroke

“…In the early stage of cerebral ischemic injury, the activation of glial cells can play a certain neuroprotective effect, but the excessive activation of glial cells can produce a series of inflammatory factors or mediators to mediate neuronal degeneration (90). Previous study has found that hypoxia and reoxygenation of astrocytes caused increased mitochondrial fission and mitophagy (91). In the rat cortex after cerebral ischemia and reperfusion, the activation of mitophagy in astrocytes is also found (83).…”

Unraveling the Link Between Mitochondrial Dynamics and Neuroinflammation

“…During brain injury, astrocytes may release damaged mitochondria to minimize the amount of detrimental ROS and dysregulated Ca 2+ balance (66). Conversely, healthy mitochondria may also be donated from astrocytes to damaged neighboring neurons, increasing its viability (67). Moreover, Davis et al (68), firstly demonstrated that the exchange of mitochondria among neurons and astrocytes seem to work in a bidirectional way (68).…”