The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia

You Wang^#^{1

2}, Suhong Zhu^#^{1

2}, Wentao He², Hannah Marchuk², Eva Richard³, Lourdes R Desviat³, Sarah P Young^{4

5}, Dwight Koeberl⁵, Takhar Kasumov⁶, Xiaoxin Chen^{7

8

9}, Guo-Fang Zhang^{10

11}

Affiliations

¹ School of Basic Medicine, Jining Medical University, Shandong, 272067, China.
² Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Carmichael Building 48-203, 300 North Duke Street, Durham, NC, 27701, USA.
³ Centro de Biología Molecular Severo Ochoa UAM-CSIC, CIBERER, IdiPaz, IUBM, Universidad Autónoma de Madrid, Madrid, Spain.
⁴ Biochemical Genetics Laboratory, Duke University Health System, Durham, NC, USA.
⁵ Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Duke University Medical Center, Durham, NC, 27710, USA.
⁶ Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH, USA.
⁷ Surgical Research Lab, Department of Surgery, Cooper University Hospital and Cooper Medical School of Rowan University, Camden, NJ, 08103, USA.
⁸ Coriell Institute for Medical Research, Camden, NJ, 08103, USA.
⁹ MD Anderson Cancer Center at Cooper, Camden, NJ, 08103, USA.
¹⁰ Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Carmichael Building 48-203, 300 North Duke Street, Durham, NC, 27701, USA. Guofang.zhang@duke.edu.
¹¹ Department of Medicine, Division of Endocrinology, Metabolism and Nutrition, Duke University Medical Center, Durham, NC, 27701, USA. Guofang.zhang@duke.edu.

^# Contributed equally.

PMID: 38992300
PMCID: PMC11702364 (available on 2025-12-01)
DOI: 10.1007/s00395-024-01066-w

The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia

You Wang et al. Basic Res Cardiol. 2024 Dec.

. 2024 Dec;119(6):1045-1062.

doi: 10.1007/s00395-024-01066-w. Epub 2024 Jul 11.

Authors

Affiliations

¹ School of Basic Medicine, Jining Medical University, Shandong, 272067, China.
² Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Carmichael Building 48-203, 300 North Duke Street, Durham, NC, 27701, USA.
³ Centro de Biología Molecular Severo Ochoa UAM-CSIC, CIBERER, IdiPaz, IUBM, Universidad Autónoma de Madrid, Madrid, Spain.
⁴ Biochemical Genetics Laboratory, Duke University Health System, Durham, NC, USA.
⁵ Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Duke University Medical Center, Durham, NC, 27710, USA.
⁶ Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH, USA.
⁷ Surgical Research Lab, Department of Surgery, Cooper University Hospital and Cooper Medical School of Rowan University, Camden, NJ, 08103, USA.
⁸ Coriell Institute for Medical Research, Camden, NJ, 08103, USA.
⁹ MD Anderson Cancer Center at Cooper, Camden, NJ, 08103, USA.
¹⁰ Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Carmichael Building 48-203, 300 North Duke Street, Durham, NC, 27701, USA. Guofang.zhang@duke.edu.
¹¹ Department of Medicine, Division of Endocrinology, Metabolism and Nutrition, Duke University Medical Center, Durham, NC, 27701, USA. Guofang.zhang@duke.edu.

^# Contributed equally.

PMID: 38992300
PMCID: PMC11702364 (available on 2025-12-01)
DOI: 10.1007/s00395-024-01066-w

Abstract

Propionic acidemia (PA), arising from PCCA or PCCB variants, manifests as life-threatening cardiomyopathy and arrhythmias, with unclear pathophysiology. In this work, propionyl-CoA metabolism in rodent hearts and human pluripotent stem cell-derived cardiomyocytes was investigated with stable isotope tracing analysis. Surprisingly, gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source. In a Pcca^-/-(A138T) mouse model and PA patients, accumulated propionyl-CoA and diminished acyl-CoA synthetase short-chain family member 3 impede hepatic propionate disposal, elevating circulating propionate. Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca^-/-(A138T) mice. Additionally, Pcca^-/-(A138T) mice exhibited mild diastolic dysfunction after the propionate challenge. These findings suggest that elevated circulating propionate may cause oxidative damage and functional impairment in the hearts of patients with PA.

Keywords: Cardiac complication; Human induced pluripotent stem cell-derived cardiomyocytes; Microbiome; Propionate; Propionic acidemia; Stable isotope-based metabolic flux.

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Conflict of interest statement

Declarations. Conflict of interest: The authors have declared that no conflict of interest exists.

References

1. AlGhamdi A, Alrifai MT, Al Hammad AI, Al Mutairi F, Alswaid A, Eyaid W, Alfadhel M (2018) Epilepsy in Propionic Acidemia: Case Series of 14 Saudi Patients. J Child Neurol 33:713–717 doi:10.1177/0883073818786157 - DOI - PubMed
1. Alvarez M, Ruiz-Sala P, Perez B, Desviat LR, 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 - DOI - PMC - PubMed
1. Amaral AU, Cecatto C, Castilho RF, Wajner M (2016) 2-Methylcitric acid impairs glutamate metabolism and induces permeability transition in brain mitochondria. J Neurochem 137:62–75 doi:10.1111/jnc.13544 - DOI - PubMed
1. Bartolomaeus H, Balogh A, Yakoub M, Homann S, Marko L, Hoges S, Tsvetkov D, Krannich A, Wundersitz S, Avery EG, Haase N, Kraker K, Hering L, Maase M, Kusche-Vihrog K, Grandoch M, Fielitz J, Kempa S, Gollasch M, Zhumadilov Z, Kozhakhmetov S, Kushugulova A, Eckardt KU, Dechend R, Rump LC, Forslund SK, Muller DN, Stegbauer J, Wilck N (2019) Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage. Circulation 139:1407–1421 doi:10.1161/CIRCULATIONAHA.118.036652 - DOI - PMC - PubMed
1. Baumgartner D, Scholl-Burgi S, Sass JO, Sperl W, Schweigmann U, Stein JI, Karall D (2007) Prolonged QTc intervals and decreased left ventricular contractility in patients with propionic acidemia. J Pediatr 150:192–197, 197 e191 doi:10.1016/j.jpeds.2006.11.043 - DOI - PubMed

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The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia

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The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia

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Abstract

Conflict of interest statement

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