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Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency. 2023
Patrick Forny, and
Ximena Bonilla, and
David Lamparter, and
Wenguang Shao, and
Tanja Plessl, and
Caroline Frei, and
Anna Bingisser, and
Sandra Goetze, and
Audrey van Drogen, and
Keith Harshman, and
Patrick G A Pedrioli, and
Cedric Howald, and
Martin Poms, and
Florian Traversi, and
Céline Bürer, and
Sarah Cherkaoui, and
Raphael J Morscher, and
Luke Simmons, and
Merima Forny, and
Ioannis Xenarios, and
Ruedi Aebersold, and
Nicola Zamboni, and
Gunnar Rätsch, and
Emmanouil T Dermitzakis, and
Bernd Wollscheid, and
Matthias R Baumgartner, and
D Sean Froese
Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
Methylmalonic aciduria (MMA) is an inborn error of metabolism with multiple monogenic causes and a poorly understood pathogenesis, leading to the absence of effective causal treatments. Here we employ multi-layered omics profiling combined with biochemical and clinical features of individuals with MMA to reveal a molecular diagnosis for 177 out of 210 (84%) cases, the majority (148) of whom display pathogenic variants in methylmalonyl-CoA mutase (MMUT). Stratification of these data layers by disease severity shows dysregulation of the tricarboxylic acid cycle and its replenishment (anaplerosis) by glutamine. The relevance of these disturbances is evidenced by multi-organ metabolomics of a hemizygous Mmut mouse model as well as through identification of physical interactions between MMUT and glutamine anaplerotic enzymes. Using stable-isotope tracing, we find that treatment with dimethyl-oxoglutarate restores deficient tricarboxylic acid cycling. Our work highlights glutamine anaplerosis as a potential therapeutic intervention point in MMA.
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