Propionic acidemia (PA) is a rare, autosomal recessive disorder engendered by a dysfunctional propionyl-CoA carboxylase (PCC) enzyme [1]. PA has an estimated incidence of 1:100,000 live births in the general population, and a higher prevalence in isolated populations like the Amish Mennonite community [2,3].

PCC is a key enzyme of glycolysis­, a cellular process involved in the breakdown of glucose in the body [4]. In patients with PA, PCC function is impaired, and glucose cannot fully be converted into its byproducts. Moreover, the impairment of PCC causes an accumulation of propionyl-CoA and related molecules, which can alter the activity of various metabolic processes and contribute to symptoms of the disease [5,6].

Red blood cells (RBC) are the most abundant cell type in the body and are critical in oxygen exchange and physiological equilibrium [7,8]. Although PA has been correlated with RBC disorders including pancytopenia and anemia, the effects of PA on RBCs have not been fully described [5,9]. In this study, we used metabolomics—a technology that gives a broad window into metabolic processes through quantifying molecules of metabolism—to better understand the effects of PA on RBC metabolism. Because metabolic analysis of blood is a common tool in diagnosing and treating disease, our study aims to expand the current understanding of PA with the goal of informing diagnosis and patient care [10].

RBC are the only cells that perform the essential task of transporting oxygen throughout the body and to the tissues. As a result, they are exposed to greater oxidant challenge than any other cell in the human body. Our results show that this increased oxidant stress results in overactivations of the main antioxidant pathway—the pentose phosphate pathway—in RBCs from patients with PA. Our analyses also identified increases in the levels of markers of mitochondrial metabolism. Since mature RBCs lack organelles, including nuclei and mitochondria, these results may have indicate an increase in the production and circulation of organelle-containing immature RBCs in these patients. 

Although this study is limited by its small cohort, it provides foundational information for future studies on the metabolic effects of PA. By describing the dysregulation of metabolic pathways including glycolysis, the PPP, purine, and carboxylate metabolism, we hope to pave the way for continued research on RBC metabolism in PA patients.

1. Pena, L.; Franks, J.; Chapman, K.A.; Gropman, A.; Ah Mew, N.; Chakrapani, A.; Island, E.; MacLeod, E.; Stagni, K, Matern, D.; et al. Natural history of propionic acidemia. Mol. Genet. Metab. 2012, 105, 5–9.
2. Baumgartner, M.R.; Hörster, F.; Dionisi-Vici, C.; Haliloglu, G.; Karall, D.; Chapman, K.A.; Huemer, M.; Hochuli, M.; Assoun, M.; Ballhausen, D.; et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J. Rare Dis. 2014, 9, 130.
3. Hannah, W.B.; Dempsey, K.J.; Schillaci, L.-A.P.; Zacharias, M.; McCandless, S.E.; Wynshaw-Boris, A.; Konczal, L.L.; Bedoyan, J.K. Life-threatening presentations of propionic acidemia due to the Amish PCCB founder variant. Mol. Genet. Metab. Rep. 2019, 21, 100537.
4. Davis, E.J.; Spydevold, O.; Bremer, J. Pyruvate carboxylase and propionyl-CoA carboxylase as anaplerotic enzymes in skeletal muscle mitochondria. Eur. J. Biochem. 1980, 110, 255–262.
5. Wongkittichote, P.; Mew, N.A.; Chapman, K.A. Propionyl-CoA Carboxylase—A Review. Mol. Genet. Metab. 2017, 122, 145–152.
6. Lagerwaard, B.; Pougovkina, O.; Bekebrede, A.F.; Brinke, H.T.; Wanders, R.J.; Nieuwenhuizen, A.G.; Keijer, J.; de Boer, V.C.J. Increased protein propionylation contributes to mitochondrial dysfunction in liver cells and fibroblasts, but not in myotubes. J. Inherit. Metab. Dis. 2021, 44, 438–449.
7. Bianconi, E.; Piovesan, A.; Facchin, F.; Beraudi, A.; Casadei, R.; Frabetti, F.; Vitale, L.; Pelleri, M.C.; Tassani, S.; Piva, F.; et al. An estimation of the number of cells in the human body. Ann. Hum. Biol. 2013, 40, 463–471.
8. Nemkov, T.; Reisz, J.A.; Xia, Y.; Zimring, J.C.; D’Alessandro, A. Red blood cells as an organ? How deep omics characterization of the most abundant cell in the human body highlights other systemic metabolic functions beyond oxygen transport. Expert Rev. Proteom. 2018, 15, 855–864.
9. Stork, L.C.; Ambruso, D.R.; Wallner, S.F.; Sambrano, J.E.; Moscinski, L.C.; Wilson, H.L.; McCabe, E.R.B. Pancytopenia in propionic acidemia: Hematologic evaluation and studies of hematopoiesis in vitro. Pediatr. Res. 1986, 20, 783–788.
10. D’Alessandro, A.; Giardina, B.; Gevi, F.; Timperio, A.M.; Zolla, L. Clinical Metabolomics: The next stage of clinical biochemistry. Blood Transfus. 2012, 10, s19–s24.

From the Fall 2021 OAA Newsletter