Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mechanisms of disease

Anaplerosis in action

Nature Metabolism volume 5, pages 5–7 (2023)Cite this article

Subjects

Investigation of multi-omic changes and their effects on regulation of metabolic pathways confirm anaplerotic deficiencies in methylmalonic acidaemia, strengthening the need for future therapies aimed at replenishing intermediates of the tricarboxylic acid cycle.

Rare inborn errors of metabolism (IEMs), including organic acidaemias, are genetically inherited disorders most commonly caused by inactivating mutations in metabolic enzymes responsible for the oxidation of branched chain amino acids. One such IEM, methylmalonic acidaemia (MMA), results from mutations in methylmalonyl-CoA mutase (MMUT) or one of the enzymes that produce the cofactor 5′deoxyadenosylcobalamin (AdoCbl). MMA usually manifests within the first few days of life with severe, life-threatening pathophysiology affecting multiple organ systems that progresses over time. Treatment options are severely limited, in part because the connections between gene mutation(s) and the pleotropic effects of MMUT deficiency on metabolism remain unclear.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Dysregulation of anaplerosis and the TCA cycle in MMA.

References

  1. Morrow, G. 3rd & Barness, L. A. J. Pediatr. 74, 691–698 (1969).

    Article  CAS  Google Scholar 

  2. Forny, P. et al. Nat. Metab. https://doi.org/10.1038/s42255-022-00720-8 (2023).

    Article  Google Scholar 

  3. Knerr, I., Weinhold, N., Vockley, J. & Gibson, K. M. J. Inherit. Metab. Dis. 35, 29–40 (2012).

    Article  CAS  Google Scholar 

  4. Caterino, M. et al. Mol. Biosyst. 12, 566–574 (2016).

    Article  CAS  Google Scholar 

  5. Al-Dirbashi, O. et al. Sci. Rep. 9, 12366 (2019).

    Article  Google Scholar 

  6. Collado, M. S. et al. Mol. Genet. Metab. 130, 183–196 (2020).

    Article  CAS  Google Scholar 

  7. Schumann, A. et al. J. Inherit. Metab. Dis. 44, 1330–1342 (2021).

    Article  CAS  Google Scholar 

  8. Head, P. E. et al. Sci. Transl. Med. 14, eabn4772 (2022).

    Article  CAS  Google Scholar 

  9. Martini, W. Z. et al. Am. J. Physiol. Endocrinol. Metab. 284, E351–356 (2003).

    Article  CAS  Google Scholar 

  10. Brunengraber, H. & Roe, C. R. J. Inherit. Metab. Dis. 29, 327–331 (2006).

    Article  Google Scholar 

  11. Weidman, S. W. & Drysdale, G. R. Biochem. J. 177, 169–174 (1979).

    Article  CAS  Google Scholar 

  12. Chandler, R. J. et al. FASEB J. 23, 1252–1261 (2009).

    Article  CAS  Google Scholar 

  13. Manoli, I. et al. Proc. Natl Acad. Sci. USA 110, 13552–13557 (2013).

    Article  CAS  Google Scholar 

  14. Manoli, I. et al. JCI Insight 3, e124351 (2018).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. National Institute of General Medical Sciences, National Institutes of Health, Bethesda, MD, USA

    PamelaSara E. Head

  2. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    PamelaSara E. Head & Charles P. Venditti

Authors
  1. PamelaSara E. Head
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles P. Venditti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charles P. Venditti.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Head, P.E., Venditti, C.P. Anaplerosis in action. Nat Metab 5, 5–7 (2023). https://doi.org/10.1038/s42255-022-00724-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-022-00724-4

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing