TY - JOUR
T1 - Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice
AU - McElroy, Gregory S.
AU - Chakrabarty, Ram P.
AU - D’Alessandro, Karis B.
AU - Vasan, Karthik
AU - Tan, Jerica
AU - Stoolman, Joshua S.
AU - Weinberg, Samuel E.
AU - Steinert, Elizabeth M.
AU - Reyfman, Paul A.
AU - Singer, Benjamin D.
AU - Ladiges, Warren C.
AU - Gao, Lin
AU - Lopéz-Barneo, José
AU - Budinger, G. R.Scott
AU - Chandel, Navdeep S.
N1 - Funding Information:
We thank the following core facilities at Northwestern: Pulmonary NextGen Sequencing Core, RHLCCC Metabolomics Core, RHLCCC Flow Cytometry Core Facility. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the RHLCC. We thank the Center for Comparative Medicine staff. We thank Elizabeth Bartom for the use of the Ceto pipeline. We thank the following members of the Northwestern University Department of Medicine, Division of Pulmonary and Critical Care for technical support and data analysis, Jennifer Yuan-Shih Hu, Luzivette Robles Cardona, Kathryn Helmin Nikita Joshi, Francisco J Gonzalez-Gonzalez, Satoshi Watanabe, Luisa Morales-Nebreda, Ziyan Lu, Hiam Abdala-Valencia, and Peng Gao. Funding for this project was provided by the following NIH grants: NIH2PO1HL071643-11A1, NIH1R35CA197532-01 to N.S.C.; NIH1PO1AG049665-01 to G.R.S.B and N.S.C.; NIH/NCI T32CA09560 to G.S.M.; NHLBI F32HL136111 to P.A.R.; P.A.R. was supported by an American Thoracic Society/Boehringer Ingelheim Partner grant; R.P.C was supported by a Northwestern University Pulmonary and Critical Care Department Cugell predoctoral fellowship. ,
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Aging in mammals leads to reduction in genes encoding the 45-subunit mitochondrial electron transport chain complex I. It has been hypothesized that normal aging and age-related diseases such as Parkinson’s disease are in part due to modest decrease in expression of mitochondrial complex I subunits. By contrast, diminishing expression of mitochondrial complex I genes in lower organisms increases lifespan. Furthermore, metformin, a putative complex I inhibitor, increases healthspan in mice and humans. In the present study, we investigated whether loss of one allele of Ndufs2, the catalytic subunit of mitochondrial complex I, impacts healthspan and lifespan in mice. Our results indicate that Ndufs2 hemizygous mice (Ndufs2+/−) show no overt impairment in aging-related motor function, learning, tissue histology, organismal metabolism, or sensitivity to metformin in a C57BL6/J background. Despite a significant reduction of Ndufs2 mRNA, the mice do not demonstrate a significant decrease in complex I function. However, there are detectable transcriptomic changes in individual cell types and tissues due to loss of one allele of Ndufs2. Our data indicate that a 50% decline in mRNA of the core mitochondrial complex I subunit Ndufs2 is neither beneficial nor detrimental to healthspan.
AB - Aging in mammals leads to reduction in genes encoding the 45-subunit mitochondrial electron transport chain complex I. It has been hypothesized that normal aging and age-related diseases such as Parkinson’s disease are in part due to modest decrease in expression of mitochondrial complex I subunits. By contrast, diminishing expression of mitochondrial complex I genes in lower organisms increases lifespan. Furthermore, metformin, a putative complex I inhibitor, increases healthspan in mice and humans. In the present study, we investigated whether loss of one allele of Ndufs2, the catalytic subunit of mitochondrial complex I, impacts healthspan and lifespan in mice. Our results indicate that Ndufs2 hemizygous mice (Ndufs2+/−) show no overt impairment in aging-related motor function, learning, tissue histology, organismal metabolism, or sensitivity to metformin in a C57BL6/J background. Despite a significant reduction of Ndufs2 mRNA, the mice do not demonstrate a significant decrease in complex I function. However, there are detectable transcriptomic changes in individual cell types and tissues due to loss of one allele of Ndufs2. Our data indicate that a 50% decline in mRNA of the core mitochondrial complex I subunit Ndufs2 is neither beneficial nor detrimental to healthspan.
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U2 - 10.1038/s41598-022-09074-3
DO - 10.1038/s41598-022-09074-3
M3 - Article
C2 - 35338200
AN - SCOPUS:85127303428
VL - 12
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 5196
ER -