The results of a recent study suggest an intriguing link between mitochondrial genetics and health. This study used C57BL-nuclear-genome matched conplastic mice, where one strain carries mitochondria from the C57BL background (BL6C57) and the other strain carries the mitochondria from the NZ background (BL6NZB). The authors reported that mice carrying NZB mitochondrial DNA (mtDNA) are healthier and show significant differences in longevity despite sharing the same nuclear genome as the BL6C57 mice. Since the mtDNA of NZB and C57BL6 mice vary by only a few mutations, their findings suggest that small changes in mitochondirla genetics can cause large difference in health and longevity. They reported that these differences correlated with a number of changes that are consistent with the activation of axes of the mitochondrial unfolded protein response (UPRmt) identified in the Germain's lab. One axis is regulated by SIRT3 and FOXO3a, both key regulators of aging. Another axis is regulated by the estrogen receptor alpha (ER?). We also recently reported that small differences in mtDNA sequence can lead to differential activation of the axes of the UPRmt and also that their activation varies between males and females. Our central hypothesis is that the differences between the conplastic mice are due to the ability mtDNA of the BL6NZB to activate the UPRmt and will differ not only between males and females. To test this hypothesis, we propose the following three aims:
Specific aim 1 : Assess the activation of the UPRmt in tissues in the BL6C57 males and females versus BL6NZB males and females congenic mice.
Specific aim 2 : Test whether deleting key genes of each UPRmt nodes abolishes the health benefit of the BL6NZB conplastic mice.
Specific aim 3 : Assess whether interventions known to increase SIRT3, FOXO3a or ER? improve the health and longevity of BL6C57 conplastic mice.

Public Health Relevance

Studies have now established that mitochondrial genetics have major impact on health and diseases. This application focuses on the mitochondrial unfolded protein response as a mechanism explaining these observations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG059635-01
Application #
9575200
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Fridell, Yih-Woei
Project Start
2018-08-01
Project End
2023-04-30
Budget Start
2018-08-01
Budget End
2019-04-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029