Investigating Glial Metabolic Pathways in Brain Metabolism and Cellular Resilience

Glial cells are the most abundant cells of the central nervous system (CNS), out-numbering neurons. These multifunctional cells are crucial for maintaining brain homeostasis and neuronal resilience. Astrocyte provides neural support by regulating neurotransmitter cycling, maintaining ion balance, fueling neuronal energy demands, and mounting robust antioxidant defenses to protect neurons from oxidative stress. Oligodendrocyte (OL) insulates axons to facilitate rapid electrical conduction with their myelin sheath while providing essential metabolic and trophic support to maintain neuronal health. Glial cells are highly plastic and undergo both structural and functional alterations in response to changes in the brain microenvironment. Glial phenotypes are intimately regulated by underlying metabolic machinery, which dictates the effector functions of these cells. During aging and in neurodegenerative disorders, glial metabolic dysfunction or compensation may contribute to compromised or enhanced neuronal support and accelerated or slower pathology, highlighting the critical importance of understanding glial metabolic pathways in brain health and disease. The first study explores astrocytic metabolic flexibility by inducibly deleting the canonical glucose transporter 1 (GLUT1), from adult astrocytes and monitoring intracellular glucose dynamics with two-photon microscopy (2PM) and a genetically encoded glucose sensor. Surprisingly, despite the absence of GLUT1, astrocytes maintain intracellular glucose and significantly upregulate glycolytic flux, revealing a robust compensatory adaptation in their energy. Moreover, astrocyte-specific GLUT1 deletion substantially reduced infarct volumes in ischemic stroke, suggesting that astrocytes confer neuroprotection by enhancing their glucose metabolism, thereby enhancing neuronal resilience. The second study examines OL mitochondrial redox homeostasis and its impact on axonal health in aging and neuroinflammation. By expressing mitochondrial catalase (mCat) specifically in OLs to reduce hydrogen peroxide (H2O2) levels, the study demonstrates that OL mitochondrial reactive oxygen species (mROS) directly compromise axonal function and white matter (WM) integrity. OL-specific mROS reduction preserved compound action potential (CAP) endurance, improved sensorimotor function, and maintained structural myelin integrity during both aging and experimental autoimmune encephalomyelitis (EAE). These findings implicate glial redox imbalance as a key contributor to neuronal vulnerability, revealing that OL mitochondrial health is a critical determinant of axonal resilience. Together, these studies redefine astrocytes and OLs as dynamic regulators of neuronal integrity - astrocytes by boosting glycolysis and OLs by strengthening mitochondrial antioxidant defenses. These findings highlight glial metabolism as a promising therapeutic axis, suggesting that systematic screening of existing pharmacological libraries and the development of glia-specific delivery platforms could unlock novel interventions to enhance neuroprotection and promote healthy brain aging. $\textit{Full-text embargoed until: 2026-11-17}$