Mitochondrial Dysfunction in Cardiovascular Disease

Mitochondria lie at the heart of cellular energy production and metabolic regulation, and their impairment is increasingly recognised as a driver of cardiovascular pathology. In the arterial wall, endothelial cells exposed to dyslipidaemia or mechanical stress exhibit reduced mitochondrial respiration, increased leakage of electrons and excessive reactive oxygen species, which together promote inflammation and compromise vascular tone. In vascular smooth muscle cells, defects in mitochondrial dynamics and calcium handling can trigger abnormal proliferation and migration, contributing to plaque formation and vessel remodelling. In cardiac muscle, diminished oxidative phosphorylation and accumulation of mitochondrial DNA lesions impair contractile function and predispose to heart failure. Mounting evidence implicates disturbed mitophagy, altered mitochondrial biogenesis and unbalanced fission–fusion cycles as central features across atherosclerosis, hypertension and ischaemic injury. Restoration of mitochondrial quality control, enhancement of antioxidant defences and targeted modulation of metabolic sensors hold promise for novel cardioprotective strategies with global significance.

Research from Nature Portfolio

Investigations of mitochondria-directed pharmacology have demonstrated that conjugating natural compounds to mitochondrial targeting sequences can attenuate endothelial cell injury under oxidative challenge. One study introduced a mitochondria-localising derivative of the coumarin esculetin, which preserved nitric oxide bioavailability by activating an energy-sensing kinase and promoting mitochondrial biogenesis via upregulation of a deacetylase, ultimately reducing inflammatory plaque formation in experimental models. In parallel, work on the transcriptional coactivator PGC-1α has revealed its pivotal role in endothelial homeostasis: loss of this regulator exacerbates hypertension-induced dysfunction by suppressing endothelial nitric oxide synthase, whereas its overexpression protects vascular tone through a nuclear receptor-dependent mechanism that sustains eNOS expression and activity.

Research from all publishers

Recent reports have highlighted microRNA-mediated control of mitochondrial turnover as a novel therapeutic angle in atherosclerosis. Administration of a carbon monoxide-releasing molecule in cell and animal models reversed pro-atherogenic changes by downregulating a specific microRNA, restoring a mitochondrial biogenesis factor and normalising oxidative phosphorylation, thereby reducing reactive oxygen species and enhancing ATP generation in vascular cells. Complementing these findings, a comprehensive review has mapped the multifaceted contributions of mitochondrial dysfunction to plaque development, emphasising mitochondrial DNA mutations, dysregulated fission–fusion dynamics and inflammasome activation in arterial wall cells. This synthesis underscores the interdependence of metabolic derangement, oxidative stress and chronic inflammation, and advocates mitochondria-targeted antioxidants and modulators of mitophagy as promising interventions.

Mitochondrial Dysfunction in Cardiovascular Disease publication trend

The graph below shows the total number of articles in mitochondrial dysfunction in cardiovascular disease across all publications each year (not limited to Nature Index journals).

Technical terms

Reactive oxygen species (ROS): Electrically charged molecules formed during mitochondrial respiration that can damage DNA, lipids and proteins when not adequately neutralised.

Oxidative phosphorylation: The process by which mitochondria produce ATP by transferring electrons through a series of protein complexes to oxygen.

Endothelial dysfunction: Impaired ability of blood vessel lining cells to regulate vascular tone, inflammation and coagulation, often due to reduced nitric oxide availability.

AMP-activated protein kinase (AMPK): A cellular energy sensor that restores ATP levels by stimulating glucose uptake, fatty acid oxidation and mitochondrial biogenesis.

Sirtuin 3 (SIRT3): A mitochondrial deacetylase that enhances the function of key enzymes involved in antioxidant defence and energy metabolism.

PGC-1α: A transcriptional coactivator that orchestrates mitochondrial biogenesis and respiratory function in response to energetic demands.

References

1. Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: potential implications in atherosclerosis. Scientific Reports (2016).
2. PGC-1α dictates endothelial function through regulation of eNOS expression. Scientific Reports (2016).
3. CORM-A1 Alleviates Pro-Atherogenic Manifestations via miR-34a-5p Downregulation and an Improved Mitochondrial Function. Antioxidants (2023).
4. Mitochondrial Dysfunction in Vascular Wall Cells and Its Role in Atherosclerosis. International Journal of Molecular Sciences (2021).