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Cyclophilin D-dependent oligodendrocyte mitochondrial ion leak contributes to neonatal white matter injury
Zoya Niatsetskaya1, Sergey Sosunov1, Anna Stepanova1
1Department of Pediatrics and.
Insights
Intermittent hypoxia causes white matter injury in premature infants by impairing oligodendrocyte maturation via mitochondrial dysfunction. Blocking this mitochondrial pathway protects against injury and preserves neurofunction.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Postnatal failure of oligodendrocyte maturation is linked to diffuse white matter injury (WMI) in premature infants.
- The molecular pathways driving this maturational failure remain largely unknown.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying oligodendrocyte maturational failure induced by intermittent hypoxia (IH).
- To investigate the role of mitochondrial function and cyclophilin D in the pathogenesis of IH-induced WMI.
Main Methods:
- Utilized neonatal mouse models and primary cultured oligodendrocytes exposed to IH.
- Assessed mitochondrial respiration, bioenergetic stress, oligodendrocyte maturation, myelination, and sensorimotor deficits.
- Employed cyclophilin D-knockout mice to evaluate its specific role.
Main Results:
- Sublethal IH stress induced cyclophilin D-dependent mitochondrial proton leak and uncoupled respiration, causing bioenergetic stress.
- This mitochondrial dysfunction correlated with impaired oligodendrocyte maturation, hypomyelination, and sensorimotor deficits.
- Mitochondrial uncouplers mimicked WMI phenotypes, and cyclophilin D knockout prevented IH-induced WMI.
Conclusions:
- Identified cyclophilin D-dependent mitochondrial proton leak as a key mechanism for IH-induced oligodendrocyte maturational failure.
- Mitochondrial uncoupling plays a critical role in the pathogenesis of diffuse WMI.
- This pathway represents a potential therapeutic target for preventing WMI in premature infants exposed to chronic IH stress.
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.
