Abstract
Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon-glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon-glia metabolic coupling serves a physiological function.
| Original language | English |
|---|---|
| Pages (from-to) | 517-521 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 485 |
| Issue number | 7399 |
| DOIs | |
| State | Published - May 24 2012 |
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Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. / Fünfschilling, Ursula; Supplie, Lotti M.; Mahad, Don; Boretius, Susann; Saab, Aiman S.; Edgar, Julia; Brinkmann, Bastian G.; Kassmann, Celia M.; Tzvetanova, Iva D.; Möbius, Wiebke; Diaz, Francisca; Meijer, Dies; Suter, Ueli; Hamprecht, Bernd; Sereda, Michael W.; Moraes, Carlos T; Frahm, Jens; Goebbels, Sandra; Nave, Klaus Armin.
In: Nature, Vol. 485, No. 7399, 24.05.2012, p. 517-521.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity
AU - Fünfschilling, Ursula
AU - Supplie, Lotti M.
AU - Mahad, Don
AU - Boretius, Susann
AU - Saab, Aiman S.
AU - Edgar, Julia
AU - Brinkmann, Bastian G.
AU - Kassmann, Celia M.
AU - Tzvetanova, Iva D.
AU - Möbius, Wiebke
AU - Diaz, Francisca
AU - Meijer, Dies
AU - Suter, Ueli
AU - Hamprecht, Bernd
AU - Sereda, Michael W.
AU - Moraes, Carlos T
AU - Frahm, Jens
AU - Goebbels, Sandra
AU - Nave, Klaus Armin
PY - 2012/5/24
Y1 - 2012/5/24
N2 - Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon-glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon-glia metabolic coupling serves a physiological function.
AB - Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon-glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon-glia metabolic coupling serves a physiological function.
UR - http://www.scopus.com/inward/record.url?scp=84861429431&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861429431&partnerID=8YFLogxK
U2 - 10.1038/nature11007
DO - 10.1038/nature11007
M3 - Article
C2 - 22622581
AN - SCOPUS:84861429431
VL - 485
SP - 517
EP - 521
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7399
ER -