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Mitochondria regulate ATP production, calcium buffering, and apoptotic signaling, and clearing dysfunctional mitochondria by mitophagy is essential for cellular homeostasis. While PINK1-dependent mitophagy is well-characterized in neurons, its function in glial cells such as astrocytes is less understood. Our study demonstrates that PINK1-mitophagy in astrocytes occurs faster and with less spatial restriction compared to neurons. This pathway was specifically regulated in astrocytes by the glycolytic enzyme, HK2 (hexokinase 2), which forms a glucose-dependent complex with PINK1 following mitochondrial damage. Inflammation also induces HK2-PINK1 mitophagy, and its activation in astrocytes protects against cytokine-induced neuronal death. Our findings characterize a novel HK2-PINK1 pathway in astrocytes that bridges mitophagy, metabolism, and immune signaling.Abbreviation: HK2: hexokinase 2; PD: Parkinson disease; PINK1: PTEN induced kinase 1; S65: serine 65.
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