{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:06:18Z","timestamp":1790139978192,"version":"4.0.1"},"reference-count":118,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","award":["#402440\/2021\u20138"],"award-info":[{"award-number":["#402440\/2021\u20138"]}],"id":[{"id":"https:\/\/ror.org\/03swz6y49","id-type":"ROR","asserted-by":"crossref"}]},{"award":["#402440\/2021\u20138"],"award-info":[{"award-number":["#402440\/2021\u20138"]}],"id":[{"id":"https:\/\/ror.org\/03swz6y49","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio Grande do Sul","award":["#24\/2551-0001395-4"],"award-info":[{"award-number":["#24\/2551-0001395-4"]}],"id":[{"id":"https:\/\/ror.org\/05k49za97","id-type":"ROR","asserted-by":"crossref"}]},{"award":["#24\/2551-0001395-4"],"award-info":[{"award-number":["#24\/2551-0001395-4"]}],"id":[{"id":"https:\/\/ror.org\/05k49za97","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Instituto Nacional de Ci\u00eancia e Tecnologia Sa\u00fade Cerebral","award":["#406020\/2022\u20131"],"award-info":[{"award-number":["#406020\/2022\u20131"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Methylmalonic and propionic acidemias are inherited disorders of propionyl-CoA catabolism characterized by deficient activity of L-methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. They lead to metabolite accumulation in tissues and biological fluids, including methylmalonic, propionic, 3-hydroxypropionic, 2-methylcitric and maleic acids. Affected patients develop multi-systemic symptoms, with predominant neurological manifestations. Although current therapy based on dietary protein restriction significantly decreases mortality and morbidity, it is still insufficient to prevent long-term complications in most patients. The pathogenesis of methylmalonic and propionic acidemias has been investigated in recent decades using chemically induced in vivo models, genetic animal models, in vitro models and tissues and biological fluids from patients. Although the precise mechanisms responsible for the clinical manifestations in these disorders remain under debate, biomarkers of mitochondrial dysfunction and oxidative stress have been consistently described in tissues from affected patients and genetic murine models. Notably, growing evidence indicates that the organic acids accumulating in these disorders, which are formed within mitochondria, compromise mitochondrial functions through multiple mechanisms, disrupting bioenergetics, quality control, calcium homeostasis and redox balance, ultimately leading to cell death. This review discusses pathomechanisms of mitotoxicity caused by the major organic acids accumulating in methylmalonic and propionic acidemias from observations taken from patients and animal models.<\/jats:p>","DOI":"10.3390\/ijms27188379","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:32:12Z","timestamp":1790083932000},"page":"8379","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Disturbances of Mitochondrial Functions and Oxidative Stress Induction in Methylmalonic and Propionic Acidemias: A Critical Role for Metabolite Accumulation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6512-0714","authenticated-orcid":false,"given":"Alexandre Umpierrez","family":"Amaral","sequence":"first","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Aten\u00e7\u00e3o Integral \u00e0 Sa\u00fade (UNICRUZ\/URI-Erechim\/UNIJU\u00cd), Universidade Regional Integrada do Alto Uruguai e das Miss\u00f5es, Erechim CEP 99709-910, RS, Brazil"},{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Biol\u00f3gicas: Bioqu\u00edmica, Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade, Universidade Federal do Rio Grande do Sul, Porto Alegre CEP 90035-003, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6372-1807","authenticated-orcid":false,"given":"Moacir","family":"Wajner","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Biol\u00f3gicas: Bioqu\u00edmica, Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade, Universidade Federal do Rio Grande do Sul, Porto Alegre CEP 90035-003, RS, Brazil"},{"name":"Servi\u00e7o de Gen\u00e9tica M\u00e9dica, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre CEP 90035-903, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Wallace, S.E., and Amemiya, A. (2022). Isolated Methylmalonic Acidemia. GeneReviews\u00ae, University of Washington."},{"key":"ref_2","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Wallace, S.E., and Amemiya, A. (2024). Propionic Acidemia. GeneReviews\u00ae, University of Washington."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1007\/s10545-015-9839-3","article-title":"The Phenotypic Spectrum of Organic Acidurias and Urea Cycle Disorders. Part 1: The Initial Presentation","volume":"38","author":"Cazorla","year":"2015","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_4","first-page":"105","article-title":"Newborn Screening Programmes in Europe, Arguments and Efforts Regarding Harmonisation: Focus on Organic Acidurias","volume":"32","author":"Loeber","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s10238-016-0435-0","article-title":"\u201cClassical Organic Acidurias\u201d: Diagnosis and Pathogenesis","volume":"17","author":"Villani","year":"2017","journal-title":"Clin. Exp. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.pcl.2017.11.002","article-title":"Inborn Errors of Metabolism Overview","volume":"65","author":"Saudubray","year":"2018","journal-title":"Pediatr. Clin. N. Am."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1007\/s10545-017-0135-2","article-title":"Organic Acidurias in Adults: Late Complications and Management","volume":"41","author":"Tuncel","year":"2018","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1002\/jimd.12613","article-title":"Safety, Efficacy, and Timing of Transplantation(s) in Propionic and Methylmalonic Aciduria","volume":"46","author":"Chakrapani","year":"2023","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/1750-1172-8-148","article-title":"Long-Term Neurological Outcome of a Cohort of 80 Patients with Classical Organic Acidurias","volume":"8","author":"Nizon","year":"2013","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1007\/s00431-014-2359-6","article-title":"Propionic Acidemia in a Previously Healthy Adolescent with Acute Onset of Dilated Cardiomyopathy","volume":"173","author":"Laemmle","year":"2014","journal-title":"Eur. J. Pediatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1097\/PEC.0000000000001028","article-title":"Acute Illness Protocol for Organic Acidemias","volume":"33","author":"Aldubayan","year":"2017","journal-title":"Pediatr. Emerg. Care"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/s41556-018-0124-1","article-title":"The Multifaceted Contributions of Mitochondria to Cellular Metabolism","volume":"20","author":"Spinelli","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"102228","DOI":"10.1016\/j.molmet.2025.102228","article-title":"Three-Dimensional Network of Creatine Metabolism: From Intracellular Energy Shuttle to Systemic Metabolic Regulatory Switch","volume":"100","author":"Su","year":"2025","journal-title":"Mol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/s41580-018-0052-8","article-title":"The Machineries, Regulation and Cellular Functions of Mitochondrial Calcium","volume":"19","author":"Giorgi","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.tcb.2018.02.009","article-title":"Endoplasmic Reticulum\u2013Mitochondrial Contactology: Structure and Signaling Functions","volume":"28","author":"Weaver","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1038\/s41418-023-01187-0","article-title":"Identity, Structure, and Function of the Mitochondrial Permeability Transition Pore: Controversies, Consensus, Recent Advances, and Future Directions","volume":"30","author":"Bernardi","year":"2023","journal-title":"Cell Death Differ."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.mito.2013.01.003","article-title":"Mitochondrial Dysfunction and the Inflammatory Response","volume":"13","year":"2013","journal-title":"Mitochondrion"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11185","DOI":"10.1074\/jbc.M116.726968","article-title":"Compartment-Specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes","volume":"291","author":"Dey","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1161\/CIRCRESAHA.117.311401","article-title":"Reactive Oxygen Species in Metabolic and Inflammatory Signaling","volume":"122","author":"Forrester","year":"2018","journal-title":"Circ. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/s41580-020-0210-7","article-title":"The Cell Biology of Mitochondrial Membrane Dynamics","volume":"21","author":"Giacomello","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R170","DOI":"10.1016\/j.cub.2018.01.004","article-title":"Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance","volume":"28","author":"Pickles","year":"2018","journal-title":"Curr. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41392-026-02813-2","article-title":"Mitochondrial Quality Control in Health and Disease: Mechanisms and Therapeutic Targets","volume":"11","author":"Creus","year":"2026","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1038\/s42255-026-01563-3","article-title":"Mitochondrial Quality Control in Human Ageing and Longevity","volume":"8","author":"Picca","year":"2026","journal-title":"Nat. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1042\/BJ20060221","article-title":"Secondary Mitochondrial Dysfunction in Propionic Aciduria: A Pathogenic Role for Endogenous Mitochondrial Toxins","volume":"398","author":"Schwab","year":"2006","journal-title":"Biochem. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1002\/jimd.12419","article-title":"Mitochondrial Damage in Renal Epithelial Cells Is Potentiated by Protein Exposure in Propionic Aciduria","volume":"44","author":"Schumann","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1096\/fj.08-121848","article-title":"Mitochondrial Dysfunction in Mut Methylmalonic Acidemia","volume":"23","author":"Chandler","year":"2009","journal-title":"FASEB J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1620\/tjem.137.329","article-title":"Comparison of Cytosolic and Mitochondrial Enzyme Alterations in the Livers of Propionic or Methylmalonic Acidemia: A Reduction of Cytochrome Oxidase Activity","volume":"137","author":"Hayasaka","year":"1982","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"309","DOI":"10.3109\/01913123.2014.921657","article-title":"Abnormal Hepatocellular Mitochondria in Methylmalonic Acidemia","volume":"38","author":"Wilnai","year":"2014","journal-title":"Ultrastruct. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1111\/cge.12426","article-title":"Methylmalonic Aciduria CblB Type: Characterization of Two Novel Mutations and Mitochondrial Dysfunction Studies","volume":"87","author":"Brasil","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13552","DOI":"10.1073\/pnas.1302764110","article-title":"Targeting Proximal Tubule Mitochondrial Dysfunction Attenuates the Renal Disease of Methylmalonic Acidemia","volume":"110","author":"Manoli","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/s41467-020-14729-8","article-title":"Impaired Mitophagy Links Mitochondrial Disease to Epithelial Stress in Methylmalonyl-CoA Mutase Deficiency","volume":"11","author":"Luciani","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_32","first-page":"34","article-title":"Clinical Experience with N-Carbamylglutamate in a Single-Centre Cohort of Patients with Propionic and Methylmalonic Aciduria","volume":"8","author":"Burlina","year":"2016","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"104924","DOI":"10.1016\/j.jaccas.2025.104924","article-title":"Ventricular Fibrillation and Cardiomyopathy in Propionic Acidemia","volume":"30","author":"Edgardo","year":"2025","journal-title":"JACC Case Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7653716","DOI":"10.1155\/2020\/7653716","article-title":"Propionic and Methylmalonic Acidemias: Initial Clinical and Biochemical Presentation","volume":"2020","author":"Mobarak","year":"2020","journal-title":"Int. J. Pediatr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1515\/jpem-2012-0148","article-title":"Citric Acid as the Last Therapeutic Approach in an Acute Life-Threatening Metabolic Decompensation of Propionic Acidaemia","volume":"26","author":"Siekmeyer","year":"2013","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Walther, B.K., Murray, B.M., Pandiyan, P., Ray, R., Yeoh, L., and Kritzer, A. (2026). Mitochondrial Dysfunction in Propionic Acidemia: A Case-Report and Review of the Literature. JIMD Rep., 67.","DOI":"10.1002\/jmd2.70073"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/s40268-023-00449-z","article-title":"Real-World Experience of Carglumic Acid for Methylmalonic and Propionic Acidurias: An Interim Analysis of the Multicentre Observational PROTECT Study","volume":"24","author":"Yap","year":"2024","journal-title":"Drugs R D"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1111\/j.1442-200X.2011.03412.x","article-title":"Neonatal Lactic Acidosis with Methylmalonic Aciduria Due to Novel Mutations in the SUCLG1 Gene","volume":"53","author":"Sakamoto","year":"2011","journal-title":"Pediatr. Int."},{"key":"ref_39","first-page":"831","article-title":"Multi-Slice Proton MR Spectroscopy and Diffusion-Weighted Imaging in Methylmalonic Acidemia: Report of Two Cases and Review of the Literature","volume":"22","author":"Trinh","year":"2001","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.radcr.2022.12.037","article-title":"Multimodal MR Imaging in Acute Exacerbation of Methylmalonic Acidemia","volume":"18","author":"Saito","year":"2023","journal-title":"Radiol. Case Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/0009-9120(91)80007-P","article-title":"Lactic Acidosis and Mitochondrial Disorders","volume":"24","author":"Kerr","year":"1991","journal-title":"Clin. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1093\/brain\/awh259","article-title":"Mitochondrial Disorders","volume":"127","author":"Zeviani","year":"2004","journal-title":"Brain"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Stanescu, S., Belanger-Quintana, A., Fern\u00e1ndez-Felix, B.M., Ruiz-Sala, P., Alcaide, P., Arrieta, F., and Mart\u00ednez-Pardo, M. (2022). Plasma CoQ10 Status in Patients with Propionic Acidaemia and Possible Benefit of Treatment with Ubiquinol. Antioxidants, 11.","DOI":"10.3390\/antiox11081588"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.mito.2014.07.001","article-title":"Successful Reversal of Propionic Acidaemia Associated Cardiomyopathy: Evidence for Low Myocardial Coenzyme Q10 Status and Secondary Mitochondrial Dysfunction as an Underlying Pathophysiological Mechanism","volume":"17","author":"Baruteau","year":"2014","journal-title":"Mitochondrion"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.ymgme.2005.04.004","article-title":"Clinical, Pathological, and Biochemical Studies in a Patient with Propionic Acidemia and Fatal Cardiomyopathy","volume":"85","author":"Mardach","year":"2005","journal-title":"Mol. Genet. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1203\/PDR.0b013e3181a7c270","article-title":"Multiple OXPHOS Deficiency in the Liver, Kidney, Heart, and Skeletal Muscle of Patients With Methylmalonic Aciduria and Propionic Aciduria","volume":"66","author":"Valayannopoulos","year":"2009","journal-title":"Pediatr. Res."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"\u00c1lvarez, M., Ruiz-Sala, P., P\u00e9rez, B., Desviat, L.R., and Richard, E. (2023). Dysregulated Cell Homeostasis and MiRNAs in Human IPSC-Derived Cardiomyocytes from a Propionic Acidemia Patient with Cardiomyopathy. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032182"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s00018-025-05661-5","article-title":"Metabolic Flux Analysis in HiPSC-CMs Reveals Insights into Cardiac Dysfunction in Propionic Acidemia","volume":"82","author":"Richard","year":"2025","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1007\/s10545-009-1150-8","article-title":"Coenzyme Q 10 Is Decreased in Fibroblasts of Patients with Methylmalonic Aciduria but Not in Mevalonic Aciduria","volume":"32","author":"Haas","year":"2009","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7677","DOI":"10.1038\/s41598-023-34373-8","article-title":"The Impact of Metabolic Stressors on Mitochondrial Homeostasis in a Renal Epithelial Cell Model of Methylmalonic Aciduria","volume":"13","author":"Schumann","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"32933","DOI":"10.1038\/s41598-025-20600-x","article-title":"Effects of Anserine on Oxidative Stress and on Cell Barrier Integrity in Methylmalonic Aciduria","volume":"15","author":"Fleming","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/s42003-025-07828-z","article-title":"Mitochondrial Dysfunction Drives a Neuronal Exhaustion Phenotype in Methylmalonic Aciduria","volume":"8","author":"Denley","year":"2025","journal-title":"Commun. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1002\/jimd.12231","article-title":"Cardiometabolic Risk Factor Clustering in Patients with Deficient Branched-chain Amino Acid Catabolism: A Case-control Study","volume":"43","author":"Gancheva","year":"2020","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_54","first-page":"1","article-title":"In Vivo Evidence of Mitochondrial Dysfunction and Altered Redox Homeostasis in a Genetic Mouse Model of Propionic Acidemia: Implications for the Pathophysiology of This Disorder","volume":"96","author":"Guenzel","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"124351","DOI":"10.1172\/jci.insight.124351","article-title":"FGF21 Underlies a Hormetic Response to Metabolic Stress in Methylmalonic Acidemia","volume":"3","author":"Manoli","year":"2018","journal-title":"JCI Insight"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.ymgme.2019.10.007","article-title":"Tricarboxylic Acid Cycle Enzyme Activities in a Mouse Model of Methylmalonic Aciduria","volume":"128","author":"Wongkittichote","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"30478","DOI":"10.1038\/s41598-024-79572-z","article-title":"Renal Phenotyping in a Hypomorphic Murine Model of Propionic Aciduria Reveals Common Pathomechanisms in Organic Acidurias","volume":"14","author":"Schumann","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"117357","DOI":"10.1016\/j.celrep.2026.117357","article-title":"Loss of Pyruvate Carboxylase Suppresses Lethality in Propionic Acidemia","volume":"45","author":"Encarnacion","year":"2026","journal-title":"Cell Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s10545-017-0111-x","article-title":"Propionyl-CoA Carboxylase Pcca-1 and Pccb-1 Gene Deletions in Caenorhabditis Elegans Globally Impair Mitochondrial Energy Metabolism","volume":"41","author":"Chapman","year":"2018","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"165586","DOI":"10.1016\/j.bbadis.2019.165586","article-title":"Intracellular Calcium Mishandling Leads to Cardiac Dysfunction and Ventricular Arrhythmias in a Mouse Model of Propionic Acidemia","volume":"1866","author":"Tamayo","year":"2020","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Alonso-Barroso, E., P\u00e9rez, B., Desviat, L.R., and Richard, E. (2021). Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031161"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e70319","DOI":"10.1002\/mco2.70319","article-title":"Mitochondrial Quality Control in Health and Disease","volume":"6","author":"Ye","year":"2025","journal-title":"MedComm"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Zhang, M., Jin, H., Lv, S., Li, Y., and Li, Y. (2025). Mitochondrial Quality Control and Cell Death. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262211084"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1089\/ars.2012.4729","article-title":"Mitochondria as a Source of Reactive Oxygen and Nitrogen Species: From Molecular Mechanisms to Human Health","volume":"18","author":"Figueira","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/1873-3468.12964","article-title":"Role of Mitochondrial ROS in the Brain: From Physiology to Neurodegeneration","volume":"592","author":"Angelova","year":"2018","journal-title":"FEBS Lett."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ijdevneu.2010.01.002","article-title":"Reduction of Lipid and Protein Damage in Patients with Disorders of Propionate Metabolism under Treatment: A Possible Protective Role of l-carnitine Supplementation","volume":"28","author":"Ribas","year":"2010","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3941","DOI":"10.1073\/pnas.0813409106","article-title":"Inherited Disorders Affecting Mitochondrial Function Are Associated with Glutathione Deficiency and Hypocitrullinemia","volume":"106","author":"Atkuri","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1515\/jpem-2025-0184","article-title":"Oxidative Stress in Branched-Chain Organic Acidemias Using Thiol-Disulfide Homeostasis","volume":"38","author":"Keskin","year":"2025","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s10571-011-9736-8","article-title":"Oxidative Stress Parameters in Urine from Patients with Disorders of Propionate Metabolism: A Beneficial Effect of l-Carnitine Supplementation","volume":"32","author":"Ribas","year":"2012","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ymgme.2009.06.007","article-title":"Profiling of Oxidative Stress in Patients with Inborn Errors of Metabolism","volume":"98","author":"Parikh","year":"2009","journal-title":"Mol. Genet. Metab."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1159\/000511590","article-title":"Determination of Cytokines and Oxidative Stress Biomarkers in Cognitive Impairment Induced by Methylmalonic Acidemia","volume":"28","author":"Li","year":"2021","journal-title":"Neuroimmunomodulation"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s11011-024-01475-9","article-title":"Neurodegenerative Biomarkers and Inflammation in Patients with Propionic and Methylmalonic Acidemias: Effect of L-Carnitine Treatment","volume":"40","author":"Becker","year":"2024","journal-title":"Metab. Brain Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1007\/s10545-012-9545-3","article-title":"Functional Characterization of Novel Genotypes and Cellular Oxidative Stress Studies in Propionic Acidemia","volume":"36","author":"Abia","year":"2013","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/path.2248","article-title":"Methylmalonic Acidaemia Leads to Increased Production of Reactive Oxygen Species and Induction of Apoptosis through the Mitochondrial\/Caspase Pathway","volume":"213","author":"Richard","year":"2007","journal-title":"J. Pathol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Abd Elbaky, M.A., Shehata, M., Abdelkhalek, K., Girgis, M.Y., and Elmonem, M.A. (2026). Fibroblast Growth Factor 21 and Growth Differentiation Factor 15 as Biomarkers for Oxidative Stress in Children with Methylmalonic Acidemia. BMC Pediatr., 26.","DOI":"10.1186\/s12887-026-06719-4"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e63893","DOI":"10.1002\/ajmg.a.63893","article-title":"Evidence That Long-Term Treatment Prevents Tissue Oxidative Damage in Patients With Inherited Disorders of the Propionate Pathway","volume":"197","author":"Becker","year":"2025","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1007\/s00395-024-01066-w","article-title":"The Attenuated Hepatic Clearance of Propionate Increases Cardiac Oxidative Stress in Propionic Acidemia","volume":"119","author":"Wang","year":"2024","journal-title":"Basic Res. Cardiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/S0197-0186(01)00130-9","article-title":"Inhibition of the Mitochondrial Respiratory Chain Complex Activities in Rat Cerebral Cortex by Methylmalonic Acid","volume":"40","author":"Brusque","year":"2002","journal-title":"Neurochem. Int."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ijdevneu.2005.10.005","article-title":"Differential Inhibitory Effects of Methylmalonic Acid on Respiratory Chain Complex Activities in Rat Tissues","volume":"24","author":"Pettenuzzo","year":"2006","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"14674","DOI":"10.1074\/jbc.M200997200","article-title":"Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity","volume":"277","author":"Okun","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/BF00711328","article-title":"Inhibition of Succinate Dehydrogenase and \u0392-hydroxybutyrate Dehydrogenase Activities by Methylmalonate in Brain and Liver of Developing Rats","volume":"16","author":"Dutra","year":"1993","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.neuroscience.2015.09.043","article-title":"The Effect of WIN 55,212-2 Suggests a Cannabinoid-Sensitive Component in the Early Toxicity Induced by Organic Acids Accumulating in Glutaric Acidemia Type I and in Related Disorders of Propionate Metabolism in Rat Brain Synaptosomes","volume":"310","author":"Serratos","year":"2015","journal-title":"Neuroscience"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s11064-025-04364-4","article-title":"Costunolide Ameliorates the Methylmalonic Acidemia Via the PINK1\/Parkin Pathway","volume":"50","author":"Lu","year":"2025","journal-title":"Neurochem. Res."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Proctor, E.C., Turton, N., Boan, E.J., Bennett, E., Philips, S., Heaton, R.A., and Hargreaves, I.P. (2020). The Effect of Methylmalonic Acid Treatment on Human Neuronal Cell Coenzyme Q10 Status and Mitochondrial Function. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239137"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1046\/j.1528-1157.2003.42902.x","article-title":"Intrastriatal Methylmalonic Acid Administration Induces Convulsions and TBARS Production, and Alters Na+, K+ -ATPase Activity in the Rat Striatum and Cerebral Cortex","volume":"44","author":"Malfatti","year":"2003","journal-title":"Epilepsia"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1097\/00001756-200007140-00052","article-title":"Methylmalonate Administration Decreases Na+,K+-ATPase Activity in Cerebral Cortex of Rats","volume":"11","author":"Wyse","year":"2000","journal-title":"Neuroreport"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1002\/jnr.23020","article-title":"Methylmalonate Impairs Mitochondrial Respiration Supported by NADH-linked Substrates: Involvement of Mitochondrial Glutamate Metabolism","volume":"90","author":"Melo","year":"2012","journal-title":"J. Neurosci. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1007\/s10545-007-0798-1","article-title":"Methylmalonate Inhibits Succinate-supported Oxygen Consumption by Interfering with Mitochondrial Succinate Uptake","volume":"31","author":"Mirandola","year":"2008","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2608","DOI":"10.1021\/acschemneuro.1c00119","article-title":"Methylmalonic Acid Compromises Respiration and Reduces the Expression of Differentiation Markers of SH-SY5Y Human Neuroblastoma Cells","volume":"12","author":"Silva","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1007\/s10571-022-01236-1","article-title":"Methylmalonic Acid Impairs Cell Respiration and Glutamate Uptake in C6 Rat Glioma Cells: Implications for Methylmalonic Acidemia","volume":"43","author":"Costa","year":"2023","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.neuint.2004.03.006","article-title":"Inhibition of Mitochondrial Creatine Kinase Activity from Rat Cerebral Cortex by Methylmalonic Acid","volume":"45","author":"Schuck","year":"2004","journal-title":"Neurochem. Int."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0306-4522(97)00594-0","article-title":"Methylmalonate Toxicity in Primary Neuronal Cultures","volume":"86","author":"McLaughlin","year":"1998","journal-title":"Neuroscience"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1097\/00001756-199806010-00009","article-title":"Inhibition of Na+, K+-ATPase from Rat Brain Cortex by Propionic Acid","volume":"9","author":"Wyse","year":"1998","journal-title":"NeuroReport"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s11010-019-03534-7","article-title":"Experimental Evidence That Maleic Acid Markedly Compromises Glutamate Oxidation through Inhibition of Glutamate Dehydrogenase and \u03b1-Ketoglutarate Dehydrogenase Activities in Kidney of Developing Rats","volume":"458","author":"Roginski","year":"2019","journal-title":"Mol. Cell. Biochem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s10863-022-09945-4","article-title":"Disruption of Mitochondrial Functions Involving Mitochondrial Permeability Transition Pore Opening Caused by Maleic Acid in Rat Kidney","volume":"54","author":"Roginski","year":"2022","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"165682","DOI":"10.1016\/j.bbadis.2020.165682","article-title":"Disturbance of Bioenergetics and Calcium Homeostasis Provoked by Metabolites Accumulating in Propionic Acidemia in Heart Mitochondria of Developing Rats","volume":"1866","author":"Roginski","year":"2020","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/jnc.13544","article-title":"2-Methylcitric Acid Impairs Glutamate Metabolism and Induces Permeability Transition in Brain Mitochondria","volume":"137","author":"Amaral","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1111\/j.1471-4159.2004.02565.x","article-title":"Mitochondrial Permeability Transition in Neuronal Damage Promoted by Ca2+ and Respiratory Chain Complex II Inhibition","volume":"90","author":"Maciel","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"13248","DOI":"10.1038\/s41598-023-40130-8","article-title":"Propionic Acid Induces Alterations in Mitochondrial Morphology and Dynamics in SH-SY5Y Cells","volume":"13","author":"Buchanan","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.neuro.2019.09.009","article-title":"Propionic Acid Induces Mitochondrial Dysfunction and Affects Gene Expression for Mitochondria Biogenesis and Neuronal Differentiation in SH-SY5Y Cell Line","volume":"75","author":"Kim","year":"2019","journal-title":"Neurotoxicology"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Jung, M., Choi, H., Kim, J., and Mun, J.Y. (2020). Correlative Light and Transmission Electron Microscopy Showed Details of Mitophagy by Mitochondria Quality Control in Propionic Acid Treated SH-SY5Y Cell. Materials, 13.","DOI":"10.3390\/ma13194336"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1097\/00001756-200002280-00023","article-title":"Propionic and L-Methylmalonic Acids Induce Oxidative Stress in Brain of Young Rats","volume":"11","author":"Fontella","year":"2000","journal-title":"NeuroReport"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1007\/s10571-011-9675-4","article-title":"Experimental Evidence That Methylmalonic Acid Provokes Oxidative Damage and Compromises Antioxidant Defenses in Nerve Terminal and Striatum of Young Rats","volume":"31","author":"Fernandes","year":"2011","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.neulet.2004.11.038","article-title":"Involvement of NO in the Convulsive Behavior and Oxidative Damage Induced by the Intrastriatal Injection of Methylmalonate","volume":"376","author":"Royes","year":"2005","journal-title":"Neurosci. Lett."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.pbb.2005.12.017","article-title":"Effectiveness of Creatine Monohydrate on Seizures and Oxidative Damage Induced by Methylmalonate","volume":"83","author":"Royes","year":"2006","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"233","DOI":"10.3109\/10715762.2012.762771","article-title":"Acute Renal Failure Potentiates Methylmalonate-Induced Oxidative Stress in Brain and Kidney of Rats","volume":"47","author":"Schuck","year":"2013","journal-title":"Free Radic. Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s11010-014-1996-4","article-title":"Methylmalonic Acid Administration Induces DNA Damage in Rat Brain and Kidney","volume":"391","author":"Andrade","year":"2014","journal-title":"Mol. Cell. Biochem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1093\/jnen\/nlw121","article-title":"Methylmalonate Induces Inflammatory and Apoptotic Potential: A Link to Glial Activation and Neurological Dysfunction","volume":"76","author":"Gabbi","year":"2017","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/S0091-3057(02)00856-0","article-title":"Ascorbic Acid Prevents Cognitive Deficits Caused by Chronic Administration of Propionic Acid to Rats in the Water Maze","volume":"73","author":"Pettenuzzo","year":"2002","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.neulet.2006.08.075","article-title":"Propionic Acid Induces Convulsions and Protein Carbonylation in Rats","volume":"408","author":"Rigo","year":"2006","journal-title":"Neurosci. Lett."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.mrgentox.2010.07.008","article-title":"Prevention by L-Carnitine of DNA Damage Induced by Propionic and l-Methylmalonic Acids in Human Peripheral Leukocytes in Vitro","volume":"702","author":"Ribas","year":"2010","journal-title":"Mutat. Res.\/Genet. Toxicol. Environ. Mutagen."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"dos Reis, B.G., Lopes, F.F., Tedesco, L.M.B., de Moura Sarmento, S.M., Manfredini, V., and Vargas, C.R. (2026). Protective in Vitro Effects of Antioxidants against DNA Damage Induced by Metabolites Accumulated in Propionic and Methylmalonic Acidemias. Naunyn. Schmiedebergs. Arch. Pharmacol.","DOI":"10.1007\/s00210-026-05636-8"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/s41392-024-01839-8","article-title":"Mitochondrial Dysfunction: Mechanisms and Advances in Therapy","volume":"9","author":"Zong","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ymgme.2020.05.003","article-title":"Biochemical and Anaplerotic Applications of in Vitro Models of Propionic Acidemia and Methylmalonic Acidemia Using Patient-Derived Primary Hepatocytes","volume":"130","author":"Collado","year":"2020","journal-title":"Mol. Genet. Metab."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/s42255-022-00720-8","article-title":"Integrated Multi-Omics Reveals Anaplerotic Rewiring in Methylmalonyl-CoA Mutase Deficiency","volume":"5","author":"Forny","year":"2023","journal-title":"Nat. Metab."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.ymgme.2017.07.009","article-title":"Treatment with Antioxidants Ameliorates Oxidative Damage in a Mouse Model of Propionic Acidemia","volume":"122","author":"Murphy","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.bbrc.2014.08.091","article-title":"Antioxidants Successfully Reduce ROS Production in Propionic Acidemia Fibroblasts","volume":"452","author":"Ugarte","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ymgme.2017.07.003","article-title":"Anaplerotic Therapy in Propionic Acidemia","volume":"122","author":"Longo","year":"2017","journal-title":"Mol. Genet. Metab."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8379\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T04:44:30Z","timestamp":1790138670000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8379"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,20]]},"references-count":118,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27188379"],"URL":"https:\/\/doi.org\/10.3390\/ijms27188379","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,20]]}}}