Acetyl‐CoA production from pyruvate is not necessary for preservation of myelin

Abstract

Oligodendrocytes and Schwann cells not only form myelin in the central and peripheral nervous system, but also provide metabolic and trophic support to the axons they ensheathe. Acetyl-CoA is potentially a key molecule in Schwann cells and oligodendrocytes because it is at the crossroads of cellular lipid biosynthesis and energy generation. The main route for acetyl-CoA production is the oxidation of pyruvate by the pyruvate dehydrogenase complex (PDC). PDC deficiency in humans results in neurodegeneration and developmental impairments in both white and gray matter structures. To address the importance of PDC in myelinating glia, we deleted Pdha1 gene specifically in oligodendrocytes and Schwann cells. Surprisingly, sciatic and optic nerve morphology and the motor performance of Pdha1f/Y ; CnpCre/+ mice are undistinguishable from those of controls at 1 month of age. In addition, myelin is stably maintained for at least 10 months. However, Pdha1f/Y ; CnpCre/+ mice showed reduced fiber density and signs of axonal degeneration in both sciatic and optic nerves from 6 months of age. In contrast, 10 month-old mice bearing a floxed Pdha1 gene with either P0-Cre (expressed only by Schwann cells) or NG2-CreER (expressed in oligodendrocyte precursor cells) do not show any sign of axonal pathology or alterations in myelin structure or thickness. This indicates that the axonopathy is specific to the Pdha1f/Y ; CnpCre/+ mice. Taken together, these results suggest that acetyl-CoA derived from pyruvate is not necessary for myelin maintenance and, thus, myelin-forming cells are not likely to contribute to the pathophysiology of PDC deficiency.

Prohibitin 1 is essential to preserve mitochondria and myelin integrity in Schwann cells.

“…This could suggest that mitochondrial energy production is necessary for proper myelination. However, SCs can tolerate a signi cant reduction in ATP levels without any noticeable effect in myelin formation or maintenance, as described by our group when Pdha1 (which codes for an essential subunit of the pyruvate dehydrogenase complex, a mitochondrial enzyme) was deleted in SCs 43 . Ablation of the mitochondrial network regulator Gdap1 in SCs leads to an age-related hypomyelinating peripheral neuropathy, recapitulating aspects of the Charcot-Marie-Tooth disease seen in patients with mutated Gdap1 44 .…”

“…Mice were euthanized at the indicated ages and sciatic, tibial, femoral motor and saphenous nerves were dissected and processed as previously reported 43 . For g-ratio analyses, four images per nerve were acquired using the 100X objective and axon and ber diameters were calculated using a semi-automated protocol in the Leica QWin software (Leica Microsystem).…”

“…Electrophysiological analyses were performed as described 43 , and distal amplitude and average nerve conduction velocity are reported.…”

Myelin Fat Facts: An Overview of Lipids and Fatty Acid Metabolism

“…In addition (3), myelin defects occurred with pyruvate dehydrogenase deficiency, an enzyme required for the synthesis of acetyl-coA from glycolytic sources [117,118]. However, a recent study reported that myelination is normal in animals with ablated pyruvate dehydrogenase in myelinating cells, indicating that oligodendrocytes and Schwann cells metabolism do not rely essential on glycolytic sources for the generation of acetyl-CoA [119]. The elongation of long chain fatty acids (over 16 carbons) into VLCFA (over 20 carbons) occurs in the endoplasmic reticulum.…”

YAP and TAZ Regulate Cc2d1b and Purβ in Schwann Cells

“…Immunohistochemistry, immunocytochemistry and immunoblotting were performed as described (Della-Flora Nunes et al, 2017). Ten microgram of protein was used for western blot.…”