Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis

Neurodegenerative diseases and other age -related disorders are closely associated with mitochondrial dysfunction. We previously showed that mice with neuron -speci fic de ficiency of mitochondrial translation exhibit leukoencephalopathy because of demyelination. Reduced cholesterol metabolism has been associated with demyelinating diseases of the brain such as Alzheimer 's disease. However, the molecular mechanisms involved and relevance to the pathogenesis remained unknown. In this study, we show that inhibition of mitochondrial translation signi ficantly reduced expression of the cholesterol synthase genes and degraded their sterol -regulated transcription factor, sterol regulatory element -binding protein 2 (Srebp2). Furthermore, the phosphorylation of Pyk2 and Gsk3 beta was increased in the white matter of p32cKO mice. We observed that Pyk2 inhibitors reduced the phosphorylation of Gsk3 beta and that GSK3 beta inhibitors suppressed degradation of the transcription factor Srebp2. The Pyk2 -Gsk3 beta axis is involved in the ubiquitination of Srebp2 and reduced expression of cholesterol gene. These results suggest that inhibition of mitochondrial translation may be a causative mechanism of neurodegenerative diseases of aging. Improving the mitochondrial translation or effectiveness of Gsk3 beta inhibitors is a potential therapeutic strategy for leukoencephalopathy.