Hormesis underlies the adaptive response in methylmalonic acidemia (MMA)

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 the chronic and acute settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepato-renal 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 responded abberrantly to fasting when compared to controls. RNA expression was studied in livers from the following 4 conditions: heterozygote Mut +/-;TgINS-MCK-Mut mice at baseline and after 12 hrs of fasting, mutant Mut -/- ;TgINS-MCK-Mut mice at baseline and after 8-12 hrs of fasting. Four mice in each genotype group and fed or fasting state were sacrificed for liver and RNA extraction. All the mice used in this study were males, at 4 months of age. After organ removal, livers were snap frozen in liquid nitrogen.