Defective vascular smooth muscle cell tafazzin impairs mitochondrial function and promotes atherosclerosis in preclinical models

Cindy Dong, Alison Finigan, Nichola Figg, Benjamin Jenkins, Albert Koulman, Suvagata R. Chowdhury, Anne-Marie Tricolici, Jordi Lambert, Sebnem Oc, Helle F. Jørgensen, Julien Prudent, Michael P. Murphy, Martin Bennett and Emma Yu ()
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Cindy Dong: University of Cambridge, Section of Cardiorespiratory Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute
Alison Finigan: University of Cambridge, Section of Cardiorespiratory Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute
Nichola Figg: University of Cambridge, Section of Cardiorespiratory Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute
Benjamin Jenkins: University of Cambridge, Core Metabolomics and Lipidomics Laboratory, Wellcome-MRC Institute of Metabolic Science Metabolic Research Laboratories
Albert Koulman: University of Cambridge, Core Metabolomics and Lipidomics Laboratory, Wellcome-MRC Institute of Metabolic Science Metabolic Research Laboratories
Suvagata R. Chowdhury: University of Cambridge, Medical Research Council Mitochondrial Biology Unit
Anne-Marie Tricolici: University of Cambridge, Section of Cardiorespiratory Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute
Jordi Lambert: University of Cambridge, Section of Cardiorespiratory Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute
Sebnem Oc: University of Cambridge, Section of Cardiorespiratory Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute
Helle F. Jørgensen: University of Cambridge, Section of Cardiorespiratory Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute
Julien Prudent: University of Cambridge, Medical Research Council Mitochondrial Biology Unit
Michael P. Murphy: University of Cambridge, Medical Research Council Mitochondrial Biology Unit
Martin Bennett: University of Cambridge, Section of Cardiorespiratory Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute
Emma Yu: University of Cambridge, Section of Cardiorespiratory Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Atherosclerotic lesions show significant mitochondrial dysfunction but the underlying mechanisms and consequences remain unknown. Cardiolipin is a phospholipid found exclusively in the mitochondrial inner membrane, the site of oxidative phosphorylation. Tafazzin is a trans-acylase that acylates immature monolysocardiolipin to mature cardiolipin. Tafazzin mutations can result in Barth’s Syndrome, which is characterised by dilated cardiomyopathy, skeletal myopathy and impaired growth. However, a role for tafazzin in atherosclerosis development has not been previously identified. Here we show that tafazzin expression is decreased in atherosclerotic lesions and specifically in plaque vascular smooth muscle cells (VSMCs). MicroRNA 125a-5p expression is increased in plaques, downregulates tafazzin expression and is induced by oxidised low-density lipoprotein in a NFκB-dependent manner. Silencing tafazzin or overexpression of mutant tafazzin decreases VSMC cardiolipin content and mitochondrial respiration, and promotes apoptosis and atherosclerosis. In contrast tafazzin overexpression increases respiration, protects against apoptosis and increases features of plaque stability. Tafazzin therefore has important effects on VSMC mitochondrial function and atherosclerosis, and is a potential therapeutic target in atherosclerotic disease.

Date: 2025
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DOI: 10.1038/s41467-025-65873-y

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