TY - JOUR
T1 - A conditional mouse model of complex II deficiency manifesting as Leigh-like syndrome
AU - Khazal, Fatimah Al
AU - Holte, Molly Nelson
AU - Bolon, Brad
AU - White, Thomas A.
AU - LeBrasseur, Nathan
AU - Iii, L. James Maher
N1 - Funding Information:
National Cancer Institute Grant RO1 CA166025 (to L. J. M), and by the Robert and Arlene Kogod Center on Aging (Mayo Clinic). Funding of the Mayo Clinic Metabolomics Resource Core was by NIH National Institute of Diabetes and Digestive and Kidney Diseases Grant U24DK100469, and originated from the NIH Director's Common Fund. The authors declare no conflicts of interest.
Funding Information:
The authors acknowledge the European Conditional Mouse Mutagenesis Program (Wellcome Sanger Institute, Hinxton, United Kingdom) for providing the SDHC gene trap mouse line. The technical assistance of Jenny Pattengill and the Mayo Clinic Metabolomics Core Facility and the Mayo Clinic Mouse Histology Core Facility is acknowledged. This work was supported by generous funding from the Paradifference Foundation, U.S. National Institutes of Health (NIH)
Funding Information:
The authors acknowledge the European Conditional Mouse Mutagenesis Program (Wellcome Sanger Institute, Hinxton, United Kingdom) for providing the SDHC gene trap mouse line. The technical assistance of Jenny Pattengill and the Mayo Clinic Metabolomics Core Facility and the Mayo Clinic Mouse Histology Core Facility is acknowledged. This work was supported by generous funding from the Paradifference Foundation, U.S. National Institutes of Health (NIH) National Cancer Institute Grant RO1 CA166025 (to L. J. M), and by the Robert and Arlene Kogod Center on Aging (Mayo Clinic). Funding of the Mayo Clinic Metabolomics Resource Core was by NIH National Institute of Diabetes and Digestive and Kidney Diseases Grant U24DK100469, and originated from the NIH Director's Common Fund. The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB.
PY - 2019/12
Y1 - 2019/12
N2 - Leigh syndrome embodies degenerative disorders with a collection of symptoms secondary to inborn errors of metabolism. Combinations of hypomorphic and loss-of-function alleles in many genes have been shown to result in Leigh syndrome. Interestingly, deficiency for the tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH) can lead to Leigh-like syndrome in some circumstances and to cancer (paraganglioma, renal cell carcinoma, gastrointestinal stromal tumor) in others. In our experiments originally intended to create an inducible whole-body SDH-loss mouse model of tumorigenesis, we generated a condition reminiscent of Leigh-like syndrome that is lethal to mice within 4 wk. Remarkably, as has been shown for other mitochondrial diseases, chronic hypoxia offers substantial protection to mice from this condition after systemic SDH loss, allowing survival in the context of profoundly impaired oxidative metabolism.—Al Khazal, F., Holte, M. N., Bolon, B., White, T. A., LeBrasseur, N., Maher, L. J. III. A conditional mouse model of complex II deficiency manifesting as Leigh-like syndrome. FASEB J. 33, 13189–13201 (2019). www.fasebj.org.
AB - Leigh syndrome embodies degenerative disorders with a collection of symptoms secondary to inborn errors of metabolism. Combinations of hypomorphic and loss-of-function alleles in many genes have been shown to result in Leigh syndrome. Interestingly, deficiency for the tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH) can lead to Leigh-like syndrome in some circumstances and to cancer (paraganglioma, renal cell carcinoma, gastrointestinal stromal tumor) in others. In our experiments originally intended to create an inducible whole-body SDH-loss mouse model of tumorigenesis, we generated a condition reminiscent of Leigh-like syndrome that is lethal to mice within 4 wk. Remarkably, as has been shown for other mitochondrial diseases, chronic hypoxia offers substantial protection to mice from this condition after systemic SDH loss, allowing survival in the context of profoundly impaired oxidative metabolism.—Al Khazal, F., Holte, M. N., Bolon, B., White, T. A., LeBrasseur, N., Maher, L. J. III. A conditional mouse model of complex II deficiency manifesting as Leigh-like syndrome. FASEB J. 33, 13189–13201 (2019). www.fasebj.org.
KW - familial paraganglioma
KW - hypoxia
KW - mitochondrial disease
KW - succinate dehydrogenase
UR - http://www.scopus.com/inward/record.url?scp=85075960509&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075960509&partnerID=8YFLogxK
U2 - 10.1096/fj.201802655RR
DO - 10.1096/fj.201802655RR
M3 - Article
C2 - 31469588
AN - SCOPUS:85075960509
SN - 0892-6638
VL - 33
SP - 13189
EP - 13201
JO - FASEB Journal
JF - FASEB Journal
IS - 12
ER -