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Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

ABSTRACT: Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

PROVIDER: PRJNA780798 | ENA |

REPOSITORIES: ENA

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Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Project description:Maintenance of energetic homeostasis during periods of limited supply requires metabolic adaptation. Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria (MMAuria), present unique challenges to this homeostasis by disrupting energetic pathways. To better understand the systemic and cellular responses to long-term energy shortage, we investigated a hemizygous mouse model of MMAuria that has a knock-in (ki) missense allele combined with a knock-out (ko) allele (Mmut-ko/ki) and shows typical clinical features including reduced growth. We found that Mmut-ko/ki (mutant) mice, compared to their Mmut-ki/wt (control) littermates, have reduced body mass along with a relative reduction in lean mass but increase in fat mass. White adipose tissue appears histologically normal, but brown adipose tissue show a process of whitening, in line with their lower body surface temperature and lesser ability to cope with cold challenge. Ad libitum fed mice show constitutive hypometabolism: they have reduced food intake, reduced energy expenditure, and reduced plasma glucose, but elevated lactate and fibroblast growth factor 21 (Fgf21). Together, these changes culminate in a loss of metabolic flexibility in mutant mice. This is manifested in lesser ability to regulate energy sources when switching from the fed to fasted state, and in a delayed glucose clearance in response to exogenous glucose and insulin. Liver investigations find multi-metabolite accumulation and suggest upregulation of peroxisome proliferator-activated receptor (Ppar)- and Fgf21-controlled metabolic pathways, including beta-oxidation, and downregulation of oxidative phosphorylation, as molecular consequences. Altogether, this study identifies a multi-faceted metabolic response to chronic energy shortage in MMAuria and suggests hypometabolism combined with dysregulated adaptive capability to be underlying features.

2023-06-26 | GSE188931 | GEO

Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria.

Project description:Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria, present unique challenges to energetic homeostasis by disrupting energy-producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut)-type methylmalonic aciduria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared with littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator-activated receptor and Fgf21-controlled pathways. Together, these shed light on the mechanisms and adaptations behind energy imbalance in methylmalonic aciduria and provide insight into metabolic responses to chronic energy shortage, which may have important implications for disease understanding and patient management.

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Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria

Project description:Methylmalonic aciduria (MMA) is an inborn error of metabolism resulting in loss of function of the enzyme methylmalonyl-CoA mutase (MMUT). Despite acute and persistent neurological symptoms, the pathogenesis of MMA in the central nervous system is poorly understood, which has contributed to a dearth of effective brain specific treatments. Here we utilised patient-derived induced pluripotent stem cells and in vitro differentiation to generate a human neuronal model of MMA. We reveal strong evidence of mitochondrial dysfunction caused by deficiency of MMUT in patient neurons. By employing patch-clamp electrophysiology, targeted metabolomics, and bulk transcriptomics, we further expose an altered state of excitability, which we suggest may be connected to metabolic rewiring which is exacerbated by application of 2-dimethyloxoglutarate. Our work provides first evidence of mitochondrial driven neuronal dysfunction in MMA, which through our comprehensive characterisation of this paradigmatic model, enables first steps to identifying effective therapies.

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Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria

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