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FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia
Irini Manoli, … , Randy J. Chandler, Charles P. Venditti
Irini Manoli, … , Randy J. Chandler, Charles P. Venditti
Published December 6, 2018
Citation Information: JCI Insight. 2018;3(23):e124351. https://doi.org/10.1172/jci.insight.124351.
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Research Article Genetics Metabolism

FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia

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Abstract

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.

Authors

Irini Manoli, Justin R. Sysol, Madeline W. Epping, Lina Li, Cindy Wang, Jennifer L. Sloan, Alexandra Pass, Jack Gagné, Yiouli P. Ktena, Lingli Li, Niraj S. Trivedi, Bazoumana Ouattara, Patricia M. Zerfas, Victoria Hoffmann, Mones Abu-Asab, Maria G. Tsokos, David E. Kleiner, Caterina Garone, Kristina Cusmano-Ozog, Gregory M. Enns, Hilary J. Vernon, Hans C. Andersson, Stephanie Grunewald, Abdel G. Elkahloun, Christiane L. Girard, Jurgen Schnermann, Salvatore DiMauro, Eva Andres-Mateos, Luk H. Vandenberghe, Randy J. Chandler, Charles P. Venditti

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Figure 2

Hepatic ultrastructural changes in Mut–/–;TgINS-MCK-Mut animals replicate the pathology seen in MMA patients.

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Hepatic ultrastructural changes in Mut–/–;TgINS-MCK-Mut animals replicat...
(A) Electron microscopy of mutant mouse liver tissue showed lipid droplets (white asterisk, middle) and wide-spread large, abnormally shaped mitochondria with cristae rarefication and decreased matrix density in mutant animals (white arrows, middle and right), as opposed to their heterozygote littermates reared on the same diet (left) (scale bars: 1 μm). Many formed ring-shaped structures and appeared to be engulfing other cellular components (arrow with two heads, middle inset). (B) Ultrastructure of explanted livers from patients undergoing a liver transplantation procedure showed mitochondria with reduced matrix density and shortened, disorganized cristae and, in some cases, complex cytoplasmic inclusions of varying density engulfed by membranes, suggestive of autophagic vacuoles. Representative structural changes and a graphic of the observed pathology in the mitochondrial ultrastructure (left) and cellular autophagic vacuoles/inclusions (right) are depicted.

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