Proteolipid protein-deficient myelin promotes axonal mitochondrial dysfunction via altered metabolic coupling

Xinghua Yin, Grahame J. Kidd, Nobuhiko Ohno, Guy A. Perkins, Mark H. Ellisman, Chinthasagar Bastian, Sylvain Brunet, Selva Baltan, Bruce D. Trapp

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


Hereditary spastic paraplegia (HSP) is a neurological syndrome characterized by degeneration of central nervous system (CNS) axons. Mutated HSP proteins include myelin proteolipid protein (PLP) and axon-enriched proteins involved in mitochondrial function, smooth endoplasmic reticulum (SER) structure, and microtubule (MT) stability/function. We characterized axonal mitochondria, SER, and MTs in rodent optic nerves where PLP is replaced by the peripheral nerve myelin protein, P0 (P0-CNS mice). Mitochondrial pathology and degeneration were prominent in juxtaparanodal axoplasm at 1 mo of age. In wild-type (WT) optic nerve axons, 25% of mitochondria-SER associations occurred on extensions of the mitochondrial outer membrane. Mitochondria-SER associations were reduced by 86% in 1-mo-old P0-CNS juxtaparanodal axoplasm. 1-mo-old P0-CNS optic nerves were more sensitive to oxygen-glucose deprivation and contained less adenosine triphosphate (ATP) than WT nerves. MT pathology and paranodal axonal ovoids were prominent at 6 mo. These data support juxtaparanodal mitochondrial degeneration, reduced mitochondria-SER associations, and reduced ATP production as causes of axonal ovoid formation and axonal degeneration.

Original languageEnglish (US)
Pages (from-to)531-542
Number of pages12
JournalJournal of Cell Biology
Issue number4
StatePublished - 2016
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology


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