Hexokinase 1 forms rings that constrict mitochondria during energy stress

Abstract

Despite progress in understanding cellular energy stress responses, the role of metabolic enzymes in these processes remains understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, clusters into ring-like structures around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and prevent mitochondrial fission by displacing the dynamin-related protein 1 (Drp1) from mitochondrial constriction sites. Mechanistically, we identified that the lack of ATP and glucose-6-phosphate (G6P) promotes the clustering of HK1. We found several structural features that are critical for the formation of HK1-rings. Our findings highlight that HK1 is a robust energy stress sensor that regulates the shape, position, and connectivity of mitochondria. Thus, the formation of HK1-rings may affect mitochondrial function in energy stress-related pathologies.