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Mitohormesis in Mice via Sustained Basal Activation of Mitochondrial and Antioxidant Signaling.

Cell metabolism | 2018

Transient mitochondrial stress can promote beneficial physiological responses and longevity, termed "mitohormesis." To interrogate mitohormetic pathways in mammals, we generated mice in which mitochondrial superoxide dismutase 2 (SOD2) can be knocked down in an inducible and reversible manner (iSOD2-KD mice). Depleting SOD2 only during embryonic development did not cause post-natal lethality, allowing us to probe adaptive responses to mitochondrial oxidant stress in adult mice. Liver from adapted mice had increased mitochondrial biogenesis and antioxidant gene expression and fewer reactive oxygen species. Gene expression analysis implicated non-canonical activation of the Nrf2 antioxidant and PPARγ/PGC-1α mitochondrial signaling pathways in this response. Transient SOD2 knockdown in embryonic fibroblasts from iSOD2-KD mice also resulted in adaptive mitochondrial changes, enhanced antioxidant capacity, and resistance to a subsequent oxidant challenge. We propose that mitohormesis in response to mitochondrial oxidative stress in mice involves sustained activation of mitochondrial and antioxidant signaling pathways to establish a heightened basal antioxidant state.

Pubmed ID: 30122556 RIS Download

Associated grants

  • Agency: NINDS NIH HHS, United States
    Id: F32 NS077723
  • Agency: NIEHS NIH HHS, United States
    Id: R21 ES025636
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM067543
  • Agency: NIA NIH HHS, United States
    Id: F32 AG052995
  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK034989
  • Agency: NIEHS NIH HHS, United States
    Id: R33 ES025636
  • Agency: NCI NIH HHS, United States
    Id: P30 CA014195

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