Abstract
Mice missing the Complex I subunit NADH:Ubiquinone Oxidoreductase Fe-S Protein 4 (NDUFS4) of the electron transport chain are a leading model of the severe mitochondrial disease Leigh syndrome. These mice have enabled a better understanding of mitochondrial dysfunction in human disease, as well as in the discovery of interventions that can potentially suppress mitochondrial disease manifestations. In addition, increasing evidence suggests significant overlap between interventions that increase survival in NDUFS4 knockout mice and that extend life span during normative aging. This chapter discusses the practical aspects of handling and studying these mice, which can be challenging due to their severe disease phenotype. Common procedures such as breeding, genotyping, weaning, or treating these transgenic mice are also discussed.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217. https://doi.org/10.1016/j.cell.2013.05.039
Srivastava S (2017) The mitochondrial basis of aging and age-related disorders. Genes (Basel) 8:398. https://doi.org/10.3390/genes8120398
Finsterer J (2004) Mitochondriopathies. Eur J Neurol 11:163–186. https://doi.org/10.1046/j.1351-5101.2003.00728.x
Breuer ME, Willems PH, Smeitink JA, Koopman WJ, Nooteboom M (2013) Cellular and animal models for mitochondrial complex I deficiency: a focus on the NDUFS4 subunit. IUBMB Life 65:202–208. https://doi.org/10.1002/iub.1127
Kruse SE, Watt WC, Marcinek DJ, Kapur RP, Schenkman KA, Palmiter RD (2008) Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab 7:312–320. https://doi.org/10.1016/j.cmet.2008.02.004
Johnson SC et al (2013) mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 342:1524–1528. https://doi.org/10.1126/science.1244360
Johnson SC et al (2015) Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice. Front Genet 6:247. https://doi.org/10.3389/fgene.2015.00247
Lee CF, Caudal A, Abell L, Nagana Gowda GA, Tian R (2019) Targeting NAD(+) metabolism as interventions for mitochondrial disease. Sci Rep 9:3073. https://doi.org/10.1038/s41598-019-39419-4
Ito TK et al (2017) Hepatic S6K1 partially regulates lifespan of mice with mitochondrial complex I deficiency. Front Genet 8:113. https://doi.org/10.3389/fgene.2017.00113
Jain IH et al (2016) Hypoxia as a therapy for mitochondrial disease. Science 352:54–61. https://doi.org/10.1126/science.aad9642
Sage-Schwaede A, Engelstad K, Salazar R, Curcio A, Khandji A, Garvin JH Jr, De Vivo DC (2019) Exploring mTOR inhibition as treatment for mitochondrial disease. Ann Clin Transl Neurol 6:1877–1881. https://doi.org/10.1002/acn3.50846
Johnson SC et al (2019) mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases. Kidney Int 95:455–466. https://doi.org/10.1016/j.kint.2018.08.038
Jin ZX, Wei W, Yang M, Du Y, Wan YH (2014) Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization. Cell Metab 20:483–498. https://doi.org/10.1016/j.cmet.2014.07.011
Acknowledgments
This work was supported by NIH grants R01NS098329 and P30AG013280 to MK. ASG was supported by a NIH Ruth L. Kirschstein grant (F32NS110109).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Grillo, A.S., Bitto, A., Kaeberlein, M. (2021). The NDUFS4 Knockout Mouse: A Dual Threat Model of Childhood Mitochondrial Disease and Normative Aging. In: Weissig, V., Edeas, M. (eds) Mitochondrial Medicine. Methods in Molecular Biology, vol 2277. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1270-5_10
Download citation
DOI: https://doi.org/10.1007/978-1-0716-1270-5_10
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-0716-1269-9
Online ISBN: 978-1-0716-1270-5
eBook Packages: Springer Protocols