Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice

Abstract

SUMMARY The basis for region-specific neuronal toxicity in Huntington disease is unknown. Here, we show that region-specific neuronal vulnerability is a substrate-driven response in astrocytes. Glucose is low in HdhQ(150/150) animals, and astrocytes in each brain region adapt by metabolically reprogramming their mitochondria to use endogenous, non-glycolytic metabolites as an alternative fuel. Each region is characterized by distinct metabolic pools, and astrocytes adapt accordingly. The vulnerable striatum is enriched in fatty acids, and mitochondria reprogram by oxidizing them as an energy source but at the cost of escalating reactive oxygen species (ROS)-induced damage. The cerebellum is replete with amino acids, which are precursors for glucose regeneration through the pentose phosphate shunt or gluconeogenesis pathways. ROS is not elevated, and this region sustains little damage. While mhtt expression imposes disease stress throughout the brain, sensitivity or resistance arises from an adaptive stress response, which is inherently region specific. Metabolic reprogramming may have relevance to other diseases.

Pleiotropic Mitochondria: The Influence of Mitochondria on Neuronal Development and Disease

“…In brain tissue, the ability to adapt cellular metabolism to challenging conditions is generally restricted to glia, given the central function of these cells in supplying energy metabolites to neurons for fueling synaptic transmission (Pellerin and Magistretti, 1994;Bélanger et al, 2011;Fünfschilling et al, 2012) and their competence in sustaining glycolytic metabolism for extended periods of time (Supplie et al, 2017). In disease, the metabolic plasticity of astrocytes is emphasized by their unique ability to reversibly adapt the structure of their mitochondrial network via regulated fusion-fission dynamics and to efficiently rewire their mitochondrial metabolism in vivo (Motori et al, 2013;Polyzos et al, 2019). In contrast, it is still unknown whether neurons exhibit similar metabolic plasticity in response to mitochondrial dysfunction in vivo and which pathways are primarily affected.…”

Cellular Specificity and Inter-cellular Coordination in the Brain Bioenergetic System: Implications for Aging and Neurodegeneration

“…While such a lack of success may be ascribed to multiple reasons including window of intervention and translatability of existing animal models (Murphy and Hartley, 2018), for neurodegenerative diseases that typically harbor complex and dynamic etiologies, precision strategies targeting specific cells or inter-cellular metabolic interactions may be needed at different disease stages. For stages when reactive astrocytes and microglia are playing a central role, interventions that facilitate their metabolic reprogramming could be more effective than direct OXPHOS enhancers (Baik et al, 2019;Polyzos et al, 2019). Recent methodological advances have started to enable targeted delivery of therapeutics to different brain cells via nanoparticles or viral carriers (Zhang et al, 2016;Sharma et al, 2018).…”

Design principles of ROS dynamic networks relevant to precision therapies for age-related diseases

“…Metabolic reprogramming, due to a shift to nutrients that increase ROS production, change the rate at which mitochondria generate ROS and ATP; nutritional shifts may vary the NADH/ATP/ROS ratio as well as the sensitivity to oxidative stress (Polyzos et al, 2019). Such metabolic reprogramming corresponds to the changes in the operating regime of our blueprint model, for example where we use the NADH redox level as our model's input and the ATP hydrolysis work load as one of our model's output.…”