Does MRNA Upregulation of Cytochrome C Oxidase Subunit 4 Isoform 2 Sustain Atrial Fibrillation?

Objectives: Pathogenesis of atrial fibrillation (AF) remains poorly understood. Success of cardiosurgical ablation procedures are under debate. Optimized techniques require good indicators for enduring therapy. Deficit in the mitochondrial energy metabolism contributes to the progression of AF. In this case, the activity of respiratory chain alters and myocardial oxygen extraction increases resulting in a state of relative hypoxia. Cytochrome-c-oxidase (EC 1.9.3.1., CytOx), complex IV of the respiratory chain, catalyzes the rate-limiting step of respiratory chain. Subunit 4 of the enzyme represents a key regulatory subunit involved in regulating oxidative phosphorylation. Expression of isoform 4–2 is induced by HIF 1α and is dependent on cellular oxygen content for carrying out optimal efficiency of respiration at low oxygen levels. Here, we addressed the question whether AF is induced or accompanied by elevated expression levels of isoform 4–2 of the cytochrome-c oxidase.

Methods: Technique: RNA extraction, cDNA synthesis, real time PCR. (1) Experimental approach: Examination a HeLa-cell-line cell culture under normoxia and under conditions of oxygen deprivation. (2) Clinical approach: Myocardial biopsies of the right atrium of 42 cardiac surgery patients were examined. Eleven patients had permanent AF, whereas 31 patients served as control (SR). The mRNA expressions of isoform 4–1 and 4–2 of the CytOx were quantified. To evaluate the hypoxic response, mRNA expressions of HIF-1α and VEGF-B were examined.

Result: In cell culture, it became apparent that an extended hypoxia resulted in an increased expression of isoform 4–2 (p = 0.037). In biopsies, isoform 4–2/4–1 ratio revealed permanent AF with an elevated expression of isoform 4–2 (p = 0.007) and decreased expression of isoform 4–1 mRNA (p = 0.006). Isoform 4–2 quantity was independent of the extent of the coronary artery vessel disease. We suggest statin therapy and consequential change in lipid metabolism lead to the alterations in isoform 4–2 expression. Supposedly, regression analysis indicates likelihood of increased left atrial diameter and AF with an increased isoform 4–2 expression.

Conclusion: An elevated hypoxic CytOx subunit 4–2 isoform expression in myocardial tissue (less HIF-1α, increase of VEGF-B) may serve as a compensatory mechanism to adapt mitochondrial energy metabolism and limitation of ROS production. Shift in isoform expression pattern may represent a repair and/or regeneration mechanism in AF.

Publication History

Article published online:
19 February 2021