KAUST Research Workshop on Innovative Technologies to Study Brain Energy Metabolism
University of Salamanca, Spain
Juan P Bolaños currently works at the Institute of Functional Biology and Genomics (IBFG), Universidad de Salamanca. Juan does research in Cell Biology, Neuroscience and Molecular Biology. Their most recent publication is 'Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases.'
Neurons tightly depend on mitochondrial oxidative (OXPHOS) metabolism for function and survival, whereas astrocytes mostly rely on glycolysis (1). A key factor that accounts for these cell-specific metabolic programs is PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3), i.e. the pro-glycolytic enzyme that activates PFK1 (6-phosphofructo-1-kinase). Being a substrate of the E3 ubiquitin ligase, anaphase-promoting complex/cyclosome (APC/C)-Cdh1 (1,2), PFKFB3 entirely controls the different glycolytic shapes of neurons and astrocytes (2). In astrocytes, APC/C-Cdh1 activity is very low, which allows PFKFB3 to be stable to keep glycolysis high (2). However, in neurons APC/C-Cdh1 activity is very high, which promotes continuous degradation of PFKFB3 to keep glycolysis low (2). Such glycolytic control by this APC/C-Cdh1–PFKFB3 axis supports a mechanistic ground for the astrocyte-neuronal lactate shuttle. Furthermore, genetically engineered mice to force PFKFB3 expression specifically in neurons in vivo exhibit cognitive decline and motor imbalance, which are rescued by selectively scavenging mitochondrial ROS in these neurons. Thus, neuronal glycolysis regulates mitochondrial redox metabolism and behaviour. Likewise, in the highly glycolytic astrocytes the OXPHOS energy efficiency is low and dictates high mitochondrial ROS under physiological conditions (3). Deciphering the physiological roles of mitochondrial ROS in the brain are currently being investigated in our laboratory using genetically engineered mice with attenuated mitochondrial ROS in astrocytes in vivo.References1. Almeida et al. (2004) Nat. Cell Biol. 6:45-51. 2. Herrero-Mendez et al. (2009) Nat. Cell Biol. 11:747-752. 3. Lopez-Fabuel et al. (2016) PNAS 113:13063-13068.