De novo serine synthesis is protective in mitochondrial dysfunction Jackson CB1, Marmyleva A1, Mito T1, Forsström S1, Euro L1, Tatsuta T2, Langer T2, Wang L3, Zamboni N4, Carroll CJ1, Suomalainen A1
1.Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Finland; 2. Max Planck Institute for Biology of Ageing, Cologne, Germany;3. Department of Anatomy, Swedish University of Agricultural Sciences, Uppsala, Sweden; 4. Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Switzerland;
Dominant mutations in mitochondrial DNA (mtDNA) replicase Twinkle cause adult-onset mitochondrial myopathy, with accumulation of mtDNA deletions and progressive respiratory chain deficiency. In response to the mtDNA replication stalling, these mice undergo dramatic metabolic changes in the affected tissue, with increased de novo serine biosynthesis with subsequent induction of mitochondrial folate cycle, imbalanced one-carbon and methyl cycles, transsulfuration pathway and purine synthesis, and late-onset upregulation of mitochondrial heat—shock proteins. Whether these metabolic and chaperone pathways, together called integrated mitochondrial stress response (ISRmt), impact each other and disease progression is unclear. To understand the role of glucose-driven de novo serine biosynthesis in mitochondrial myopathy, we pharmacologically inhibited the rate-limiting enzyme in this pathway, phosphoglycerate dehydrogenase (PHGDH). This inhibition increased mTOR activity and eIF2α phosphorylation, and induced ISRmt, demonstrating that serine biosynthesis is protective adaptation. Although increased whole-cellular purine intermediates, found in the diseased muscle, were not significantly affected, mtDNA deletion amounts were marginally increased. Serine-driven phospholipid synthesis, however, was impaired in the inhibitor-treated mice. Pharmacological and genetic in vitro experiments further confirmed that inhibiting de novo serine synthesis resulted in decreased oxidative capacity, and long-term inhibition compromised cell viability upon mitochondrial dysfunction. In conclusion, similar to cancer metabolism, the postmitotic skeletal muscle with mitochondrial dysfunction diverts glycolytic flux to de novo serine synthesis, which contributes to remodelled biosynthetic pathways including mitochondrial folate metabolism, increased amino acid and lipid synthesis and modified cellular redox environment via increased glutathione synthesis. These changes delay disease progression and are therefore protective for disease, suggesting that activating PHGDH might be a therapeutic strategy.
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