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

Cell metabolism 2020
Open on PubMed

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.

48 Figures Extracted
Figure 1
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(A) Coronal section of a Nissl stained CBL illustrating dense neuronal-enriched layers in dark purple and astrocyte-enriched areas stained a diffuse p...
Figure 1
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(B) Magnified image of the boxed Nissl stained tissue section from (A). Scale bar is 100 μm.
Figure 1
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(D) Representative coronal section with prominent STR in a 15-week-old HdhQ(150/150) (HD) mouse brain. The left side is stained with NeuN antibody (ne...
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(F) Box plot of the distribution of bound NADH fraction of CBL and STR of WT and HD animals at young (Y) (12–16 weeks) and old (O) ages (>80 weeks)...
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Abnormalities in Mitochondrial Metabolism Occur in Striatal MT in Living Brain Sections
Figure 1
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(E) Stacked FLIM phasor plots (left) from young (12- to 16-week-old) and old (>80-week-old) comparison of WT and HD mice, as in (C) for the CBL. Re...
Figure 1
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(C) The two FLIM phasor distributions of NADH lifetimes (τϕ) for the neuron-rich (N) and astrocyterich (A) regions of the scanned CBL from HdhQ(150/15...
Figure 2
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(G) 3D STORM images of MT in astrocytes cultures from STR and CBL from HdhQ(wt/wt) (WT) and HdhQ(150/150) (HD) of 12–16 weeks. A representative conven...
Figure 2
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(E and F) SDS-PAGE resolution of ETC complexes CI–V in the STR (E) and CBL (F) detected by specific antibodies for each subunit (STAR Methods), measur...
Figure 2
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(H) Box-and-whisker plot of the density of mitochondrial CII STORM localizations per unit area of striatal MT in mouse astrocytes in (Figure 2G). A MA...
Figure 2
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There Are Region- and Genotype-Specific Defects in CII Activity in Striatal Astrocytes from HdhQ(150/150) Animals
Figure 2
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See also Figures S2 and S3.
Figure 2
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(I) Image of mouse striatal astrocytes from the STR and CBL of HdhQ(wt/wt) (WT) and HdhQ(150/150) (HD) littermates stained with MitoTracker Deep Red (...
Figure 2
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(A) Schematic representation of inhibitors and substrates for ETC complexes shown in a hypothetical inner mitochondrial membrane. The ETC complexes an...
Figure 2
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(D) Enzymatic rates for CI, CII, and CIV in astrocyte extracts of STR and CBL of HdhQ(wt/wt) (WT) and HdhQ(150/150) (HD) littermates, as indicated. Th...
Figure 3
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The Metabolic Features of HdhQ(wt/wt) (WT) and HdhQ(150/150) (HD) Littermates Differ with Genotype, Brain Region, and Age
Figure 3
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(B) The score scatter plots of each brain region (from left, STR, HIP, and CBL). The plot shows the clear separation of the metabolome as a function o...
Figure 3
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Score scatter plots of three brain regions in young and old animals of HdhQ(wt/wt) (WT) and HdhQ(150/150) (HD) animals (n = 6) based on orthogonal pro...
Figure 3
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(A) The score scatter plot combining 12 different datasets: STR, HIP, and CBL of WT and HD at young and old ages. The brain region is a primary factor...
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See also Figure S4; Table S1.
Figure 4
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(D) FA and AA fingerprints among brain regions are indicated. The arrow indicates the direction of increasing sensitivity (prominent metabolites are l...
Figure 4
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See also Figure S4.
Figure 4
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(B) MetaMapp of STR in 12- to 16-week-old animals (young) (n = 6 animals for each region). Node colors indicate significant changes of metabolite leve...
Figure 4
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(C) MetaMapp of CBL and HIP in young mice, same as (B).
Figure 4
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(A) Schematic representation of chemical class grouping of metabolites from MetaMapp analysis. The reconstructed metabolic network (MetaMapp) comprise...
Figure 4
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A Disease Fingerprint Identifies the Metabolites that Are Altered in the Disease State in Each Brain Region
Figure 5
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(C) Post-nuclear supernatants from brain regions were assayed for peroxisomal b-oxidation using [1-14C] lignoceric acid and for mitochondrial β-oxidat...
Figure 5
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See also Figure S5.
Figure 5
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Striatal Astrocytes Switch to Fatty Acid Oxidation as an Energy Source
Figure 5
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(A) Schematic representation of the electron transport chain, emphasizing FA oxidation, NADH production and NADH binding to CI. Dotted circles with β-...
Figure 5
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(B) Generation of CO2 (top) and acid-soluble intermediates (bottom) (mostly TCA intermediates) in striatal or cerebellar astrocytes from HdhQ(wt/wt) (...
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(D) MitoSOX staining intensity for striatal astrocytes from WT and HdhQ(150/150) animals. Shown are the mean and SDs for n = 3 biological replicates, ...
Figure 6
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(H) Comparison of OCR of HD astrocytes in media containing 25 mM (high) GL and 1 mM (low) LO glucose media. Error bars are SE.
Figure 6
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(I) Comparison of OCR of HD astrocytes cultured in GL 25 mM (high) glucose with (GL + FA) and without (GL) supplemented FAs. ROT, rotenone; SUCC, succ...
Figure 6
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FA Oxidation Restores the Succinate Response in MT of Striatal Astrocytes
Figure 6
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OCR for HdhQ(wt/wt) (WT) and HdhQ(150/150) (HD) astrocytes cultured in the indicated media. All data were analyzed using a two-tailed Student’s t test...
Figure 6
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See also Figures S6A–S6E.
Figure 6
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(B) Comparison of WT in (GL) with HD astrocytes grown in FA media (1 mM [low] glucose supplemented with FAs); Error bars are SE.
Figure 6
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(C) Comparison of HD astrocytes in GL and FA media. Error bars are SE. (p < 0.005 by two-tailed Student’s t test).
Figure 6
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(D–F) MitoSOX staining intensity of striatal WT or HD astrocytes in each media condition corresponding to (A–C). Error bars are SE.
Figure 6
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(G) Comparison of OCR of WT astrocytes in media containing 25 mM (high) GL and 1 mM (low) LO glucose media. Error bars are SE.
Figure 7
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(E) Model for metabolic reprogramming in HdhQ(150/150) animals, as described in the text. Neuron-glia cartoon modified from (Pierre J. Magistretti, Jo...
Figure 7
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(D) (Top) Images from STR (left) and CBL (right) (scale bar is 50 μm) and (bottom) magnified images (scale bar is 10 μm) of red insets illustrating th...
Figure 7
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Lipofuscin-Rich Granules Increase with Age in the Striatum of HD Animals and Are Inhibited with XJB-5–131 Treatment
Figure 7
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(A) Age-dependent perinuclear lipid granules (red), are quenched by TrueBlack (TB). The granules increase with age only in the STR of HD mice. Age-dep...
Figure 7
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(B) Quantification of lipofuscin signal intensity in the STR from (A). Mice were treated with XJB-5–131 antioxidant (treatment for 50 weeks) (p < 0...
Figure 7
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(C) Representative Nissl stained images of the STR or CBL as described in (Figure 1).
Figure 7
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See also Figure S6F.
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