title: Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation.
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.
authors.affiliation: Molecular Biosciences, One Shields Avenue, University of California, Davis, CA 95616, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Schoenfeld
authors.forename: Alice
authors.initials: A
authors.lastname: Wong
authors.forename: Jillian
authors.initials: J
authors.lastname: Silva
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Aki
authors.initials: A
authors.lastname: Itoh
authors.forename: Makoto
authors.initials: M
authors.lastname: Horiuchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Itoh
authors.forename: David
authors.initials: D
authors.lastname: Pleasure
authors.forename: Gino
authors.initials: G
authors.lastname: Cortopassi
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D002454:Cell Differentiation; D050259:Genes, Mitochondrial; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008928:Mitochondria / Q000502:physiology*; D009836:Oligodendroglia / Q000502:physiology*; D012402:Rotenone / Q000494:pharmacology; D015533:Transcriptional Activation; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D014475:Uncoupling Agents; D012402:Rotenone; D000105:Acetyl Coenzyme A