Format

Send to

Choose Destination
Cell Metab. 2018 Nov 6;28(5):776-786.e5. doi: 10.1016/j.cmet.2018.07.011. Epub 2018 Aug 16.

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

Author information

1
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
2
Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA; Yale School of Nursing, Yale School of Medicine, New Haven, CT 06520, USA.
3
Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
4
Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Chemistry, Appalachian State University, Boone, NC 28608, USA.
5
Salk Institute for Biological Studies, 10010 N Torrey Pines Road, La Jolla, CA 92037, USA.
6
Salk Institute for Biological Studies, 10010 N Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: gshadel@salk.edu.

Abstract

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.

KEYWORDS:

NRF2; PPARγ; hormesis; mitochondria; mtDNA; oxidative stress; reactive oxygen species; signaling; superoxide dismutase

PMID:
30122556
PMCID:
PMC6221994
DOI:
10.1016/j.cmet.2018.07.011
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center