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

Dominic D. Quintana, Jorge A. Garcia, Saumyendra N. Sarkar, Sujung Jun, Elizabeth B. Engler-Chiurazzi, Ashley E. Russell, John Z. Cavendish, James W. Simpkins

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)244-255
Number of pages12
JournalMitochondrion
Volume47
DOIs
StatePublished - Jul 2019
Externally publishedYes

Keywords

  • Astrocytes
  • Drp-1
  • Fission and fusion
  • LC3
  • Mitochondria
  • Mitophagy
  • Oxygen deprivation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Quintana, D. D., Garcia, J. A., Sarkar, S. N., Jun, S., Engler-Chiurazzi, E. B., Russell, A. E., Cavendish, J. Z., & Simpkins, J. W. (2019). Hypoxia-reoxygenation of primary astrocytes results in a redistribution of mitochondrial size and mitophagy. Mitochondrion, 47, 244-255. https://doi.org/10.1016/j.mito.2018.12.004