Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation

Abstract

Understanding the role of astrocytes in the development of the nervous system and neurodegenerative disorders implies a necessary knowledge of the oxidative metabolism of proliferating astrocytes. The electron flux through mitochondrial respiratory complexes and oxidative phosphorylation may impact the growth and viability of these astrocytes. Here, we aimed at assessing to which extent mitochondrial oxidative metabolism is required for astrocyte survival and proliferation. Primary astrocytes from the neonatal mouse cortex were cultured in a physiologically relevant medium with the addition of piericidin A or oligomycin at concentrations that fully inhibit complex I-linked respiration and ATP synthase, respectively. The presence of these mitochondrial inhibitors for up to 6 days in a culture medium elicited only minor effects on astrocyte growth. Moreover, neither the morphology nor the proportion of glial fibrillary acidic protein-positive astrocytes in culture was affected by piericidin A or oligomycin. Metabolic characterization of the astrocytes showed a relevant glycolytic metabolism under basal conditions, despite functional oxidative phosphorylation and large spare respiratory capacity. Our data suggest that astrocytes in primary culture can sustainably proliferate when their energy metabolism relies only on aerobic glycolysis since their growth and survival do not require electron flux through respiratory complex I or oxidative phosphorylation.

Copper induces neuron‐sparing, ferredoxin 1‐independent astrocyte toxicity mediated by oxidative stress

“…Although there is some data to support low levels of MT3 expression in astrocytes (Hidalgo et al, 2001), these cells primarily express metallothionein 1 (MT1) and metallothionein 2 (MT2) (Aschner et al, 1997). Importantly, MT1 and MT2 are expressed at low levels basally but their expression can be substantially induced by zinc (Silva et al, 2023). Therefore, we hypothesized that MT expression may buffer excess cytosolic copper and partially account for the differential sensitivity of neurons and astrocytes to CuES mediated injury.…”

“…Astrocytes, however, are more metabolically flexible, utilizing oxidative phosphorylation, glycolysis, and β‐oxidation of fatty acids, amongst other pathways, for energy production (Arend et al, 2019; Harders et al, 2023; Hertz et al, 2007; Juaristi et al, 2019). Of note, a recent study found proliferating astrocytes in culture are not dependent on oxidative phosphorylation for growth or survival (Silva et al, 2023). Moreover, respiration deficient astrocytes can survive by glycolysis in vivo (Supplie et al, 2017).…”

Mitochondrial complex I ROS production and redox signaling in hypoxia

“…Astrocytes have a metabolic signature distinct from neurons. Astrocytes have a functional ETC, but depend more on glycolysis compared with neurons [ [248] , [249] , [250] , [251] , [252] ]. Furthermore, astrocytes unlike neurons have the capacity for FAO, and oxidize fatty acids as an alternative fuel to augment energy supply during metabolic stress [ [253] , [254] , [255] ].…”