REDOX REGULATION BY MITOCHONDRIAL FISSION IN REACTIVE ASTROCYTES

Astrocytes are key responders to brain injury, yet the mechanisms regulating their state-specific activity remain incompletely defined. We previously showed that acute cortical injury induces distinct mitochondrial morphologies in reactive astrocytes, with extensive fragmentation in the lesion core contrasted by a preserved fused network in the penumbra, implicating mitochondrial dynamics in astrocyte state specification. Here, we identify dynamin-related protein 1 (Drp1)–mediated mitochondrial fission as a key regulator of mitochondrial integrity and astrocyte state-dependent function following acute brain injury. Astrocyte-specific deletion of Drp1 leads to swollen mitochondria with disrupted cristae and a sustained increase in mitochondrial reactive oxygen species (mROS), selectively within the lesion core, as measured by fluorescence lifetime imaging microscopy. These mitochondrial defects are rescued by expression of the alternative oxidase from Ciona intestinalis, which attenuates mROS. Notably, alternative oxidase elicits penumbra-like hallmarks of mitochondrial morphology and cell marker expression (high GFAP)in core astrocytes, indicating a contribution of mitochondrial redox state to astrocyte reactive identity. Functionally, loss of Drp1 reduces astrocyte abundance in the lesion core, impairs vascular repair, and promotes expansion of the GFAP-positive penumbra. Together, these findings establish mitochondrial fission as a determinant of mitochondrial integrity and astrocyte function during state specific reactivity.