Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice

Gregory S. McElroy; Ram P. Chakrabarty; Karis B. D’Alessandro; Karthik Vasan; Jerica Tan; Joshua S. Stoolman; Samuel E. Weinberg; Elizabeth M. Steinert; Paul A. Reyfman; Benjamin D. Singer; Warren C. Ladiges; Lin Gao; José Lopéz-Barneo; G. R.Scott Budinger; Navdeep S. Chandel

doi:10.1038/s41598-022-09074-3

Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice

Gregory S. McElroy, Ram P. Chakrabarty, Karis B. D’Alessandro, Karthik Vasan, Jerica Tan, Joshua S. Stoolman, Samuel E. Weinberg, Elizabeth M. Steinert, Paul A. Reyfman, Benjamin D. Singer, Warren C. Ladiges, Lin Gao, José Lopéz-Barneo, G. R.Scott Budinger, Navdeep S. Chandel^*

^*Corresponding author for this work

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

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.

Original language	English (US)
Article number	5196
Journal	Scientific reports
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41598-022-09074-3
State	Published - Dec 2022

Funding

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. ,

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McElroy, G. S., Chakrabarty, R. P., D’Alessandro, K. B., Vasan, K., Tan, J., Stoolman, J. S., Weinberg, S. E., Steinert, E. M., Reyfman, P. A., Singer, B. D., Ladiges, W. C., Gao, L., Lopéz-Barneo, J., Budinger, G. R. S., & Chandel, N. S. (2022). Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice. Scientific reports, 12(1), Article 5196. https://doi.org/10.1038/s41598-022-09074-3

@article{6cf9676cc8634a60a511a89dbeb23360,

title = "Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice",

abstract = "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{\textquoteright}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.",

author = "McElroy, {Gregory S.} and Chakrabarty, {Ram P.} and D{\textquoteright}Alessandro, {Karis B.} and Karthik Vasan and Jerica Tan and Stoolman, {Joshua S.} and Weinberg, {Samuel E.} and Steinert, {Elizabeth M.} and Reyfman, {Paul A.} and Singer, {Benjamin D.} and Ladiges, {Warren C.} and Lin Gao and Jos{\'e} Lop{\'e}z-Barneo and Budinger, {G. R.Scott} and Chandel, {Navdeep S.}",

note = "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: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41598-022-09074-3",

language = "English (US)",

volume = "12",

journal = "Scientific reports",

issn = "2045-2322",

publisher = "Nature Research",

number = "1",

}

McElroy, GS, Chakrabarty, RP, D’Alessandro, KB, Vasan, K, Tan, J, Stoolman, JS, Weinberg, SE, Steinert, EM, Reyfman, PA, Singer, BD, Ladiges, WC, Gao, L, Lopéz-Barneo, J, Budinger, GRS & Chandel, NS 2022, 'Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice', Scientific reports, vol. 12, no. 1, 5196. https://doi.org/10.1038/s41598-022-09074-3

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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UR - http://www.scopus.com/inward/citedby.url?scp=85127303428&partnerID=8YFLogxK

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DO - 10.1038/s41598-022-09074-3

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AN - SCOPUS:85127303428

SN - 2045-2322

VL - 12

JO - Scientific reports

JF - Scientific reports

IS - 1

M1 - 5196

ER -

Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice

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