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Red Blood Cell Metabolism in Patients with Propionic Acidemia separations Article Red Blood Cell Metabolism in Patients with Propionic Acidemia Micaela Kalani Roy 1, Francesca Isabelle Cendali 1, Gabrielle Ooyama 2,3, Fabia Gamboni 1, Holmes Morton 2,3,* and Angelo D’Alessandro 1,* 1 Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045, USA; [email protected] (M.K.R.); [email protected] (F.I.C.); [email protected] (F.G.) 2 Central Pennsylvania Clinic, A Medical Home for Special Children & Adults, Belleville, PA 17004, USA; [email protected] 3 Clinic for Special Children, Strasburg, PA 17579, USA * Correspondence: [email protected] (H.M.); [email protected] (A.D.); Tel.: +1-303-724-0096 (A.D.) Abstract: Propionic acidemia (PA) is a rare autosomal recessive disorder with an estimated incidence of 1:100,000 live births in the general population. Due in part to an insufficient understanding of the disease’s pathophysiology, PA is often associated with complications, and in severe cases can cause coma and death. Despite its association with hematologic disorders, PA’s effect on red blood cell metabolism has not been described. Mass spectrometry-based metabolomics analyses were performed on RBCs from healthy controls (n = 10) and PKD patients (n = 3). PA was associated with a significant decrease in the steady state level of glycolytic products and the apparent activation of the PPP. The PA samples showed decreases in succinate and increases in the downstream dicarboxylates of the TCA cycle. BCAAs were lowered in the PA samples and C3 carnitine, a direct metabolite of propionic acid, was increased. Trends in the markers of oxidative stress including hypoxanthine, Citation: Roy, M.K.; Cendali, F.I.; allantoate and spermidine were the opposite of those associated with elevated ROS burden. The Ooyama, G.; Gamboni, F.; Morton, H.; alteration of short chain fatty acids, the accumulation of some medium chain and long chain fatty D’Alessandro, A. Red Blood Cell acids, and decreased markers of lipid peroxidation in the PA samples contrasted with previous Metabolism in Patients with research. Despite limitations from a small cohort, this study provides the first investigation of RBC Propionic Acidemia. Separations 2021, metabolism in PA, paving the way for targeted investigations of the critical pathways found to be 8, 142. https://doi.org/10.3390/ dysregulated in the context of this disease. separations8090142 Keywords: erythrocyte; metabolism; mass spectrometry Academic Editor: Petr Bednar Received: 3 August 2021 Accepted: 20 August 2021 1. Introduction Published: 3 September 2021 Propionic acidemia (PA) is a rare, autosomal recessive disorder engendered by a Publisher’s Note: MDPI stays neutral dysfunctional propionyl-coA carboxylase (PCC) enzyme [1]. The impairment of PCC is with regard to jurisdictional claims in caused by mutations in PCCA or PCCB, genes which encode for the alpha and beta subunits published maps and institutional affil- of the 750 kDa heterododecamer [2,3]. PA has an estimated incidence of 1:100,000 live iations. births in the general population, and a higher prevalence in isolated populations like the Amish Mennonite community due to the founder effect [3,4]. Untreated, PA can lead to an accumulation of propionyl-CoA metabolites, causing hypotonia, seizures, dehydration, and in severe cases, coma and death. PCC catalyzes the carboxylation of propionyl-CoA to form methylmalonyl-CoA, Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. which in turn can be converted to succinyl-CoA and utilized in the tricarboxylic acid cycle This article is an open access article (TCA) [5]. This reaction represents a crucial step in the catalysis of isoleucine, valine, distributed under the terms and threonine and methionine for energy production. In PA patients, PCC dysfunction in- conditions of the Creative Commons hibits the conversion of propionyl-CoA to methylmalonyl-CoA, causing the accumulation Attribution (CC BY) license (https:// and alternative shunting of propionyl-CoA into propionic acid. In addition to impacting creativecommons.org/licenses/by/ energy metabolism by impairing the flow of amino acid catabolites into the TCA, the 4.0/). buildup of propionyl-CoA metabolites in PA has been shown to alter the activity of various Separations 2021, 8, 142. https://doi.org/10.3390/separations8090142 https://www.mdpi.com/journal/separations Separations 2021, 8, 142 2 of 12 metabolic processes [2,6]. Notably, propionyl-CoA buildup can impact key enzymes of energy metabolism, including succinate dehydrogenase (SDHG), a-ketoglutarate dehydro- genase (aKDHG), pyruvate dehydrogenase (PDH), and succinyl-CoA ligase [7–9]. Various studies have asserted that the impairment of essential TCA enzymes leads to secondary mitochondrial dysfunction and increased oxidative stress in individuals with PA [10,11]. Although the current understanding of PA has deepened over past decades, leading to improved management of the condition, major complications still arise in many cases of PA [12]. The state of preventative and interventional treatments for PA remains inadequate in mitigating these complications. Thus, fully understanding the effects of PA on system- wide processes is essential in developing new interventions for the disease. Very few comprehensive metabolomics studies have been published on samples from patients with this condition, exclusively testing plasma, urine, whole blood from dried blood spots or fibroblasts [13–15]. Moreover, to our knowledge there have been no metabolomic studies on the red blood cells (RBCs) of individuals afflicted by this disease. RBCs are the most abundant cell type in the body, and are critical in gas exchange and systemic homeostasis [16,17]. Metabolic analysis of blood is at the core of clinical chemistry, routinely informing medical efforts to diagnose and treat disease [18]. Because pancy- topenia and anemia are associated with PA, investigating the disease-specific impacts on RBC metabolism is essential for fully understanding the pathophysiology of this disor- der [2,19]. In order to characterize the metabolic effects of PA on red cells, we performed a comprehensive metabolomic analysis on RBC samples from PA patients. 2. Materials and Methods 2.1. Sample Collection and Processing Samples were collected through venipuncture from 10 healthy controls and 3 patients with PA at the Central Pennsylvania Clinic under institutionally reviewed Protocol No. 2014-12 and upon signing of informed consent. The three PA patients included a 24- yo who has had 3 episodes of life-threatening cardiomyopathy and two children, 4 and 6 years of age, who have mildly depressed left ventricular ejection fractions 50–55% (nl 65–70%) and both have increased end diastolic volumes and mildly increased beta-naturetic peptides. RBCs were separated from whole blood through centrifugation for 10 min at 4 ◦C and 2000× g. 2.2. Mass Spectrometry-Based Metabolomics RBCs were extracted for metabolomic analysis as previously described [20–22]. Sam- ◦ ples were resuspended at −4 C in ice-cold lysis buffer (5:3:2 MeOH: ACN: H2O) at a 1:10 RBC:buffer ratio. Next, the samples were vortexed vigorously for 30 min at 4 ◦C. Solids were separated from the extract with centrifugation for 10 min at 18,213 rcf and 4 ◦C and discarded. The supernatant was analyzed with ultra-high-pressure liquid chromatography coupled to mass spectrometry at a flow rate of 450 µL/min using 5 min gradients as pre- viously described (UHPLC-MS—Vanquish and Q Exactive, Thermo Fisher, San Jose, CA, USA) [23]. After untargeted acquisition, metabolite peaks were manually validated using the software Maven (Princeton University, Princeton, NJ, USA) and the KEGG database. Peak quality was determined by assessing 13C abundance, blanks, and technical mixes. Statistical analyses, including principal component analysis (PCA), hierarchical clustering analysis, t-test and determination of variable importance in projection (VIP) for metabolites with the highest loading weights on PC1 were performed through MetaboAnalyst 5.0, as in previous studies [22–25]. 3. Results 3.1. PA RBCs Show A Unique Metabolic Signature When Compared with Controls Metabolomics analyses were performed on RBC samples from PA patients and com- pared with unaffected controls (Figure1A; Supplementary Table S1). Distinct metabolic phenotypes between the two groups were confirmed by principal component analysis Separations 2021, 8, x FOR PEER REVIEW 3 of 12 3. Results Separations 2021, 8, 142 3.1. PA RBCs Show A Unique Metabolic Signature When Compared with Controls3 of 12 Metabolomics analyses were performed on RBC samples from PA patients and com- pared with unaffected controls (Figure 1A; Supplementary Table S1). Distinct metabolic phenotypes between the two groups were confirmed by principal component analysis (PCA—Figure1(PCA—FigureB), which discriminated 1B), which thediscriminated two groups the across two PC1,groups which across explained PC1, which explained 32.6% of the total32.6% variance. of the total A variable variance. importance A variable in importance projection in analysis projection (VIP) analysis and hier- (VIP) and hierar- archal clusteringchal analysis clustering (HCA) analysis were (HCA) performed were performed on the data on to the identify data to theidentify metabolic the metabolic path- pathways mostways affected most in affected RBCs from in RBCs PA patientsfrom PA compared patients compared to controls
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