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JCI Insight. 2018 Dec 6;3(23). pii: 124351. doi: 10.1172/jci.insight.124351.

FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia.

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Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Kidney Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Sherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, Sherbrooke, Quebec, Canada.
Péléforo Gbon Coulibaly University, Korhogo, Ivory Coast.
Office of Research Services, NIH, Bethesda, Maryland, USA.
Ultrastructural Pathology Section, Center for Cancer Research, NIH, Bethesda, Maryland, USA.
Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Neurology, Columbia University Medical Center, New York, New York, USA.
Division of Medical Genetics, Stanford University, Stanford, California, USA.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Hayward Genetics Center, Tulane University Medical School, New Orleans, Louisiana, USA.
Department of Pediatric Metabolic Medicine, Great Ormond Street Hospital for Children Foundation Trust, Institute of Child Health, UCL, London, United Kingdom.
Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.
Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.


Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.


Gene therapy; Genetics; Intermediary metabolism; Metabolism; Mitochondria

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