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

You Wang; Suhong Zhu; Wentao He; Hannah Marchuk; Eva Richard; Lourdes R Desviat; Sarah P Young; Dwight Koeberl; Takhar Kasumov; Xiaoxin Chen; Guo-Fang Zhang

doi:10.1007/s00395-024-01066-w

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

Basic Res Cardiol. 2024 Dec;119(6):1045-1062. doi: 10.1007/s00395-024-01066-w. Epub 2024 Jul 11.

Authors

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. [email protected].
¹¹ Department of Medicine, Division of Endocrinology, Metabolism and Nutrition, Duke University Medical Center, Durham, NC, 27701, USA. [email protected].

^# Contributed equally.

PMID: 38992300
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.

MeSH terms

Acyl Coenzyme A / metabolism
Animals
Disease Models, Animal
Female
Gastrointestinal Microbiome / drug effects
Humans
Liver* / metabolism
Male
Methylmalonyl-CoA Decarboxylase / genetics
Methylmalonyl-CoA Decarboxylase / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout*
Myocytes, Cardiac* / drug effects
Myocytes, Cardiac* / metabolism
Oxidative Stress* / drug effects
Propionates* / metabolism
Propionic Acidemia* / metabolism

Substances

Propionates
Methylmalonyl-CoA Decarboxylase
propionyl-coenzyme A
Acyl Coenzyme A

Abstract

MeSH terms

Substances

Grants and funding