4.7 Article

SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers

期刊

NEUROBIOLOGY OF DISEASE
卷 169, 期 -, 页码 -

出版社

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2022.105737

关键词

Alzheimer's disease; Insulin; Amino acids; mTOR; Tau

资金

  1. NIH/NIA [R01AG067048, 17-5]
  2. Alzheimer's and Related Diseases Research Award Fund [RF1 AG051085]
  3. University of Virginia's Brain Institute and Virginia Alzheimer's Disease Center Leadership Award
  4. Owens Family Foundation
  5. NIH/Office of the Director for funds [OD016446]
  6. Cure Alzheimer's Fund
  7. Alzheimer's Association [ZEN-16-363266]
  8. Virginia Chapter of the Lady's Auxiliary of the Fraternal Order of Eagles
  9. University of Virginia President's Fund for Excellence

向作者/读者索取更多资源

This study reveals a novel mechanism of mitochondrial DNA synthesis in Alzheimer's disease, where nutrient-stimulated lysosomal mTORC1 activity regulates mtDNA replication in neurons. The study also shows a link between tau and superoxide dismutase 1 (SOD1) to mitochondrial dysfunction and Alzheimer's disease.
Altered mitochondrial DNA (mtDNA) occurs in neurodegenerative disorders like Alzheimer's disease (AD); how mtDNA synthesis is linked to neurodegeneration is poorly understood. We previously discovered Nutrient-induced Mitochondrial Activity (NiMA), an inter-organelle signaling pathway where nutrient-stimulated lysosomal mTORC1 activity regulates mtDNA replication in neurons by a mechanism sensitive to amyloid-beta oligomers (A beta Os), a primary factor in AD pathogenesis (Norambuena et al., 2018). Using 5-ethynyl-2'-deoxyuridine (EdU) incorporation into mtDNA of cultured neurons, along with photoacoustic and mitochondrial metabolic imaging of cultured neurons and mouse brains, we show these effects being mediated by mTORC1-catalyzed T40 phosphorylation of superoxide dismutase 1 (SOD1). Mechanistically, tau, another key factor in AD pathogenesis and other tauopathies, reduced the lysosomal content of the tuberous sclerosis complex (TSC), thereby increasing NiMA and suppressing SOD1 activity and mtDNA synthesis. A beta Os inhibited these actions. Dysregulation of mtDNA synthesis was observed in fibroblasts derived from tuberous sclerosis (TS) patients, who lack functional TSC and elevated SOD1 activity was also observed in human AD brain. Together, these findings imply that tau and SOD1 couple nutrient availability to mtDNA replication, linking mitochondrial dysfunction to AD.

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