Fig. 4: Oligodendroglial glucose starvation leads to a gradual myelin loss.
From: Oligodendroglial fatty acid metabolism as a central nervous system energy reserve
a, Targeting GLUT1 expression in oligodendrocytes. Plp-CreERT2::Slc2a1flox/flox mice received tamoxifen at age 2 months for phenotype analysis 5 months later. b, Western blot (WB) analysis of purified myelin membranes from whole-brain lysates. Note the decrease (quantified in c–e) of (oligodendroglial) GLUT1 (c), but not (neuronal) GLUT3 (d) or panglial MCT1 (e); CA2 (for control (CTR), N = 4; for icKO, N = 4; error bars: mean ± s.e.m., unpaired, two-tailed Student’s t-test). Rel., Relative. TUBA, α-tubulin. f, Electron micrographs of optic nerve cross-section from GLUT1 mutant icKO (N = 4; CTR: N = 4). Note the thinning of myelin in the absence of axonal degeneration. g, Scatter plot of calculated g-ratios (fiber diameter/axon diameter) from optic nerve EM data, with regression lines as a function of axon diameter. h, Myelin thinning in GLUT icKO mice (N = 4) compared with controls (N = 3). Error bars: mean ± s.e.m., unpaired, two-tailed Student’s t-test. i,j, Western blots of brain lysates from GLUT1 icKO mice (i) and quantification (j), normalized to protein input (fast green) (N = 4 for CTR and icKO; mean ± s.e.m., heteroscedastic for BDH1; Student’s t-test). k, Proposed working model of glycolytic oligodendrocytes with a myelin compartment that constitutes a lipid-based energy buffer. During normal myelin turnover, the degradation of myelin lipids in lysosomes liberates FAs for β-oxidation (β-Ox) in mitochondria (MT) and peroxisomes (PEX), leading to new myelin lipid synthesis. When glucose availability is reduced, as modeled in GLUT1 icKO mice, myelin synthesis drops and FA-derived acetyl-CoA begins, supporting mitochondrial respiration for oligodendroglial survival. This shift of normal myelin turnover to lipid-based ATP generation allows oligodendrocytes to share relatively more glucose-derived pyruvate/lactate with the axonal compartment to support ATP generation and prevent axon degeneration. Note that glucose is never absent in vivo and that myelin-associated peroxisomes14 are better positioned than mitochondria to support axons with the products of FA β-oxidation. Whether oligodendrocytes also use ketogenesis to metabolically support axons and other cells is not known.
