Elsevier

Mitochondrion

Volume 10, Issue 2, March 2010, Pages 143-150
Mitochondrion

Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation

https://doi.org/10.1016/j.mito.2009.12.141Get rights and content

Abstract

Demyelination occurs in multiple inherited mitochondrial diseases. We studied which genes were induced as a consequence of differentiation in rodent and human oligodendroglia. Cholesterol, myelin and mitochondrial genes were significantly increased with oligodendroglial differentiation. Mitochondrial DNA content per cell and acetyl CoA-related transcripts increased significantly; thus, the large buildup of cholesterol necessary for myelination appears to require mitochondrial production of acetyl-CoA. Oligodendroglia were treated with low doses of the mitochondrial inhibitor rotenone to test the dependence of differentiation on mitochondrial function. Undifferentiated cells were resistant to rotenone, whereas differentiating cells were much more sensitive. Very low doses of rotenone that did not affect viability or ATP synthesis still inhibited differentiation, as measured by reduced levels of the myelin transcripts 2′,3′-Cyclic Nucleotide-3′-Phosphodiesterase and Myelin Basic Protein. Thus, mitochondrial transcripts and mtDNA are amplified during oligodendroglial differentiation, and differentiating oligodendroglia are especially sensitive to mitochondrial inhibition, suggesting mechanisms for demyelination observed in mitochondrial disease.

Introduction

Oligodendrocytes are responsible for myelination of the axons in the Central Nervous System (CNS). Axons are initially unmyelinated and become myelinated during development. Myelination buffers the dissipation of the action potential along the axons, and provides trophic support for neurons. Oligodendroglial precursor cells grow into immature/galactosylceramide-positive oligodendrocytes, and finally into mature, myelin-producing oligodendrocytes (Baumann and Pham-Dinh, 2001).

Crosstalk between neurons, astrocytes and oligodendrocytes is necessary for proper oligodendrocyte differentiation and myelination. Growth factors such as PDGF, FGF-2, IGF-1, NT-3 and CNTF, released by neurons and astrocytes, function to promote oligodendrocyte differentiation. Neuregulin promotes differentiation via interaction with the ErbB receptor on oligodendrocytes (reviewed in (Simons and Trajkovic, 2006)). The interaction between F3/contactin and notch also promotes oligodendrocyte maturation (Hu et al., 2003). The electrical activity of neurons and the release of leukemia inhibitory factor from astrocytes have been shown to be important for initiating myelination (Ishibashi et al., 2006).

Demyelination occurs in multiple mitochondrial diseases, including Leber’s Hereditary Optic Neuropathy (Kovacs et al., 2005), Friedreich’s ataxia (Carelli et al., 2002), MELAS (Rusanen et al., 1995), Charcot-Marie Tooth 2a, caused by a defect in mitofusin 2 (Niemann et al., 2006), and Dominant Optic Atrophy, caused by a defect in opa1 (Johnston et al., 1979). Demyelination also occurs in Periventricular Leukomalacia (PVL), as a consequence of hypoxia/ischemia (Volpe, 2008). Consistent with the observation of demyelination in the mitochondrial genetic diseases named above, a recent microarray study of five mitochondrial diseases produced the unexpected result of significant down-regulation of several transcripts involved in myelination (Cortopassi et al., 2006). These results suggest that mitochondrial functions might be required for proper oligodendrocyte differentiation and myelination. To test this idea, we microarrayed undifferentiated and differentiated rat and human oligodendroglia. We also tested the effects of mitochondrial inhibition on oligodendroglial differentiation and found differentiating cells to be particularly sensitive to rotenone.

Section snippets

Materials and methods

Biochemical reagents were purchased from Sigma (St. Louis, MO), Invitrogen (Carlsbad, CA) or Bio-Rad (Hercules, CA). Microarray chips and reagents were purchased from Affymetrix (Santa Clara, CA).

Microarray analysis

We carried out four independent microarray comparisons of undifferentiated to differentiated oligodendroglia, two from primary rat cells and two from human cells lines (HOG and MO3.13), using 4–9 chips per group. We then counted those genes that were significantly altered in the same direction in at least three of the four groups. These included 559 activated and 535 inhibited genes. Thus, differentiation induced and inhibited similar numbers of transcripts (Supplementary Fig. 1).

Oligodendroglial differentiation induces mitochondrial transcripts and inhibits cell cycle transcripts

We carried out

Oligodendroglial differentiation induces cholesterologenic and mitochondrial transcripts

We microarrayed and performed gene ontology analysis on oligodendroglial precursor cells and differentiated oligodendroglia. A strong and significant induction of cholesterol-related, mitochondrial and myelination transcripts was observed with differentiation, demonstrating an intense activation of the cholesterol pathway and a requirement for mitochondrial functions. In contrast, many important cell proliferation genes, including DNA ligase 1, Cyclins B1 and D1 and cell division cycle 20 and

Acknowledgements

This work was supported by grants from the USPHSEY12245, AG11967, AG16719, AG23311 (to G.A.C.), NS25044 (to D.P.) and National Multiple Sclerosis Society award RG3419A1/1T (to T.I.). We thank J. Nielsen and L. Hudson for sharing microarray data.

References (46)

  • D. Pleasure et al.

    Sterol synthesis by myelinating cultures of mouse spinal cord

    Brain Res.

    (1976)
  • H. Schulz

    Beta oxidation of fatty acids

    Biochim. Biophys. Acta

    (1991)
  • J.M. Silva et al.

    Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia

    Neurobiol. Dis.

    (2009)
  • J.E. Vance et al.

    The synthesis and transport of lipids for axonal growth and nerve regeneration

    Biochim. Biophys. Acta

    (2000)
  • L. Atorino et al.

    Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia

    J. Cell Biol.

    (2003)
  • N. Baumann et al.

    Biology of oligodendrocyte and myelin in the mammalian central nervous system

    Physiol. Rev.

    (2001)
  • O.A. Bizzozero et al.

    Effect of ATP depletion on the palmitoylation of myelin proteolipid protein in young and adult rats

    J. Neurochem.

    (1999)
  • I. Bjorkhem et al.

    Brain cholesterol: long secret life behind a barrier

    Arterioscler. Thromb. Vasc. Biol.

    (2004)
  • M. Buntinx et al.

    Characterization of three human oligodendroglial cell lines as a model to study oligodendrocyte injury: morphology and oligodendrocyte-specific gene expression

    J. Neurocytol.

    (2003)
  • W. Deng et al.

    Calcium-permeable AMPA/kainate receptors mediate toxicity and preconditioning by oxygen-glucose deprivation in oligodendrocyte precursors

    Proc. Natl. Acad. Sci. USA

    (2003)
  • W. Deng et al.

    Oligodendrocyte excitotoxicity determined by local glutamate accumulation and mitochondrial function

    J. Neurochem.

    (2006)
  • W. Deng et al.

    Progress in periventricular leukomalacia

    Arch. Neurol.

    (2008)
  • S. Draghici et al.

    Onto-Tools, the toolkit of the modern biologist: Onto-Express, Onto-Compare, Onto-Design and Onto-Translate

    Nucleic Acids Res.

    (2003)
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