Cyclophilin D–dependent oligodendrocyte mitochondrial ion leak contributes to neonatal white matter injury
Zoya Niatsetskaya, Sergey Sosunov, Anna Stepanova, James Goldman, Alexander Galkin, Maria Neginskaya, Evgeny Pavlov, Vadim Ten
Zoya Niatsetskaya, Sergey Sosunov, Anna Stepanova, James Goldman, Alexander Galkin, Maria Neginskaya, Evgeny Pavlov, Vadim Ten
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Research Article Development Neuroscience

Cyclophilin D–dependent oligodendrocyte mitochondrial ion leak contributes to neonatal white matter injury

Abstract

Postnatal failure of oligodendrocyte maturation has been proposed as a cellular mechanism of diffuse white matter injury (WMI) in premature infants. However, the molecular mechanisms for oligodendrocyte maturational failure remain unclear. In neonatal mice and cultured differentiating oligodendrocytes, sublethal intermittent hypoxic (IH) stress activated cyclophilin D–dependent mitochondrial proton leak and uncoupled mitochondrial respiration, leading to transient bioenergetic stress. This was associated with development of diffuse WMI: poor oligodendrocyte maturation, diffuse axonal hypomyelination, and permanent sensorimotor deficit. In normoxic mice and oligodendrocytes, exposure to a mitochondrial uncoupler recapitulated the phenotype of WMI, supporting the detrimental role of mitochondrial uncoupling in the pathogenesis of WMI. Compared with WT mice, cyclophilin D–knockout littermates did not develop bioenergetic stress in response to IH challenge and fully preserved oligodendrocyte maturation, axonal myelination, and neurofunction. Our study identified the cyclophilin D–dependent mitochondrial proton leak and uncoupling as a potentially novel subcellular mechanism for the maturational failure of oligodendrocytes and offers a potential therapeutic target for prevention of diffuse WMI in premature infants experiencing chronic IH stress.

Authors

Zoya Niatsetskaya, Sergey Sosunov, Anna Stepanova, James Goldman, Alexander Galkin, Maria Neginskaya, Evgeny Pavlov, Vadim Ten

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Figure 8

CypD-KO mice are protected against WMI.

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CypD-KO mice are protected against WMI. (A) Sensorimotor performance of ...
(A) Sensorimotor performance of WT and CypD–/– mice after IH exposure in comparison with normoxic controls (combined genotypes). Kruskal-Wallis and Dunn’s post hoc tests. (B and C) Sensorimotor performance of adult control, WT, and CypD–/– mice exposed to IH stress in their neonatal age. One-way ANOVA, Dunnett’s post hoc test (B) and Kruskal-Wallis and Dunn’s post hoc tests (C). (D) Western blot analysis of phosphorylated (activated) AMPK in WT and CypD–/– mice and cerebral ATP content in CypD–/– control and IH mice. Unpaired t test. (E) Representative images of electron microscopy of corpus callosum in adult mice of different genotype exposed to neonatal IH stress compared with control (WT). Scale bar: 500 nm. (F) Analysis of axonal g-ratio estimated using electron microscopy images of corpus callosum in adult mice. One-way ANOVA, Dunnett’s post hoc test.