Neural-specific deletion of mitochondrial p32/C1qbp leads to leukoencephalopathy due to undifferentiated oligodendrocyte and axon degeneration

Abstract

Mitochondrial dysfunction is a critical step in the pathogenesis of many neurodegenerative diseases. The p32/ C1qbp gene functions as an essential RNA and protein chaperone in mitochondrial translation, and is indispensable for embryonic development. However, little is known about the consequences of mitochondrial dysfunction of p32 deletion in the brain development. Here, we found that mice lacking p32 in the central nervous system (p32cKO mice) showed white matter degeneration accompanied by progressive oligodendrocyte loss, axon degeneration and vacuolation in the mid brain and brain stem regions. Furthermore, p32cKO mice died within 8 weeks of birth. We also found that p32-deficient oligodendrocytes and neurons showed reduced oligodendrocyte differentiation and axon degeneration in primary culture. We show that mitochondrial disruption activates an adaptive program known as the integrated stress response (ISR). Mitochondrial respiratory chain function in oligodendrocytes and neurons is, therefore, essential for myelination and axon maintenance, respectively, suggesting that mitochondrial respiratory chain dysfunction in the central nervous system contributes to leukoencephalopathy.

Mitochondrial translation inhibition triggers ATF4 activation, leading to integrated stress response but not to mitochondrial unfolded protein response

“…Previously, we observed that knockout of the mitochondrial protein, p32/C1qbp, in mice caused the dysfunction of mitochondrial translation and ER stress induction, leading to induction of ISR genes [5,6]. As shown in Figure 2, eIF2α phosphorylation at Ser 51 , a well-established indicator of ER stress, was increased 2-4 h after CAP treatment MEF cells.…”

“…The reverse transcription (RT) product was then subjected to real-time PCR analysis with SYBR Premix ExTaq™ II and the StepOnePlus Real-Time PCR System (Applied Biosystems, Carlsbad, CA, U.S.A.). Total mRNA from wild type and homozygous p32loxP/loxP mice (nestin-Cre +/− , p32loxP/loxP) were previously described [6]. Mouse experiments and protocols were performed in accordance with the guidelines of the animal ethics committee of Kyushu University Graduate School of Medicine, Japan (#A29-052-0).…”

“…All experimental procedures confirmed to the Guide for the Care and Use of Laboratory Animals, eighth edition, updated by the U.S. National Research Council Committee in 2011 and approved by the guidelines by the Kyushu University Animal Care and Use Committee. p32cKO mice (nestin-Cre +/− , p32loxP/loxP) were generated as previously reported [6].…”

“…We have found that the endoplasmic reticulum (ER) stress response and the expression levels of mitokines such as Fgf21 and of integrated stress response (ISR) genes were significantly increased in these mice [5]. Neuron-specific deletion of p32 showed compromised mitochondrial respiration and shifted cellular metabolism toward glycolysis, leading to leukoencephalopathy and ER stress response [6]. However, the mechanism by which p32 knockout (KO) elicits these responses in mice is not clear.…”

YBEY is an essential biogenesis factor for mitochondrial ribosomes

“…One top-scoring YBEY partner was the putative RNA-binding protein p32/C1QBP, critically required for mitochondrial metabolism and associated with a variety of mitochondrial diseases and cancer (67)(68)(69)(70)(71)(72)(73)(74)(75)(76). The interaction between the two proteins was confirmed in cross-pulldown assays with the alternate use of YBEY-3×FLAG and p32-HA proteins as bait and prey (Supplementary Figure 8A).…”