Fig. 3: FA β-oxidation in oligodendrocytes supports axonal energy metabolism and function.
From: Oligodendroglial fatty acid metabolism as a central nervous system energy reserve
a, Stimulating (Stim.) and recording (Rec.) CAPs from isolated optic nerves and monitoring axonal ATP by ratiometric FRET analysis. b, Top, typical CAP at 10 mM glucose with the CAPA shaded in red below. Bottom, recording of a stable CAPA, normalized to 1.0 (at 10 mM glucose, normoxia, low spiking rate (1 per 30 s)). Note a 5-min glucose withdrawal step to deplete astroglial glycogen. a.u., arbitrary units. c, Ratiometric FRET analysis using transgenically expressed5 ATP sensor ATeam1.03YEMK (Ex and Em depict maximum excitation and emission wavelength respectively). d, Optic nerves, maintained functionally stable at 2 mM glucose and low spiking activity (0.2 Hz), exposed to 4-Br (25 µM; N = n = 5), an inhibitor of mitochondrial FA β-oxidation. Note the progressive decline of optic nerve conductivity (N = n = 7). e, Optic nerves exposed to Etox (5 µM, N = 6, n = 6), an inhibitor of long-chain FA uptake into mitochondria. Note the faster declining CAPA (N = n = 7). f, Same as in d, demonstrating a progressive loss of axonal ATP. Note the faster and stronger effect on the axonal ATP levels (N = n = 4) compared with controls (N = n = 5). g, Axonal ATP in Etox-treated nerves (N = n = 3) and controls (N = n = 5) as before. h, Optic nerves stimulated as before but in the presence of Thio (5 µM, N = 5, n = 5), an inhibitor of peroxisomal β-oxidation (N = n = 7). Note the difference to cell survival which is independent of peroxisomal β-oxidation (in Fig. 1i). i, Axonal ATP in Thio-treated nerves (N = n = 5) and controls (N = n = 5) as before. j, Optic nerves from Cnp-Cre+/-::Mfp2flox/flox mice, lacking peroxisomal β-oxidation in oligodendrocytes27 and controls, at 2.7 mM glucose with increasing stimulation frequency (N = n = 7 each). Stronger CAPA decline in mutant nerves (7 Hz) confirms the role of oligodendrocytes in metabolic support. k, Optic nerves from Cnp-Cre+/−::Tfebflox/flox mice (N = n = 9) and controls (N = n = 6), showing that FA mobilization does not depend on de novo autophagy induction. All mice are aged 2 months (from both sexes). Bar graphs are mean ± s.e.m. (unpaired, two-tailed Student’s t-test) of data recorded in the last 5 min at each frequency. Controls are shared across d, e and h.
