Myocardial insufficiency is related to reduced subunit 4 content of cytochrome c oxidase

Abstract

BackgroundTreatment of heart failure remains one of the most challenging task for intensive care medicine, cardiology and cardiac surgery. New options and better indicators are always required. Understanding the basic mechanisms underlying heart failure promote the development of adjusted therapy e.g. assist devices and monitoring of recovery. If cardiac failure is related to compromised cellular respiration of the heart, remains unclear. Myocardial respiration depends on Cytochrome c- Oxidase (CytOx) activity representing the rate limiting step for the mitochondrial respiratory chain. The enzymatic activity as well as mRNA expression of enzyme’s mitochondrial encoded catalytic subunit 2, nuclear encoded regulatory subunit 4 and protein contents were studied in biopsies of cardiac patients suffering from myocardial insufficiency and dilated cardiomyopathy (DCM).MethodsFifty-four patients were enrolled in the study and underwent coronary angiography. Thirty male patients (mean age: 45 +/− 15 yrs.) had a reduced ejection fraction (EF) 35 ± 12% below 45% and a left ventricular end diastolic diameter (LVEDD) of 71 ± 10 mm bigger than 56 mm. They were diagnosed as having idiopathic dilated cardiomyopathy (DCM) without coronary heart disease and NYHA-class 3 and 4. Additionally, 24 male patients (mean age: 52 +/− 11 yrs.) after exclusion of secondary cardiomyopathies, coronary artery or valve disease, served as control (EF: 68 ± 7, LVEDD: 51 ± 7 mm). Total RNA was extracted from two biopsies of each person. Real-time PCR analysis was performed with specific primers followed by a melt curve analysis. Corresponding protein expression in the tissue was studied with immune-histochemistry while enzymatic activity was evaluated by spectroscopy.ResultsGene and protein expression analysis of patients showed a significant decrease of subunit 4 (1.1 vs. 0.6, p < 0.001; 7.7 ± 3.1% vs. 2.8 ± 1.4%, p < 0.0001) but no differences in subunit 2. Correlations were found between reduced subunit 2 expression, low EF (r = 0.766, p < 0.00045) and increased LVEDD (r = 0.492, p < 0.0068). In case of DCM less subunit 4 expression and reduced shortening fraction (r = 0.524, p < 0.017) was found, but enzymatic activity was higher (0.08 ± 0.06 vs. 0.26 ± 0.08 U/mg, p < 0.001) although myocardial oxygen consumption continued to the same extent.ConclusionIn case of myocardial insufficiency and DCM, decreased expression of COX 4 results in an impaired CytOx activity. Higher enzymatic activity but equal oxygen consumption contribute to the pathophysiology of the myocardial insufficiency and appears as an indicator of oxidative stress. This kind of dysregulation should be in the focus for the development of diagnostic and therapy procedures.

MicroRNA-26a/b-5p promotes myocardial infarction-induced cell death by downregulating cytochrome c oxidase 5a

“…Ischemic stress induces Cox3 upregulation, Cox1 downregulation, impaired Cox oxidative activity, and apoptosis in monkey models of MI 37 . In human myocardial insufficiency and dilated cardiomyopathy, decreased Cox4 results in impaired Cox oxidative activity 38 . Thus, several studies have reported associations between Cox5a and hypoxic environments and between other Cox subunits and heart disease.…”

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“…In heart failure, higher enzymatic activity with maintained oxygen consumption contributes to the physiopathology of myocardial insufficiency and appears to be an indicator of oxidative stress [ 162 ]. In 2021, Ortega-Gomez et al [ 51 ] developed a plasmonic tip biosensor for the detection of reduced cytochrome c, which is a multifunctional enzyme with a crucial role in electron transfer in the mitochondrial transport chain.…”

The regulatory mechanism between lysosomes and mitochondria in the aetiology of cardiovascular diseases

“…Cytochrome C is a key electron carrier for mitochondrial electron transport to cytochrome C oxidase, and its release from the mitochondria into the cellular cytoplasm triggers cellular apoptosis. It has also been found that lack of cytochrome C oxidase activity leads to myocardial insufficiency and dysfunction via reduction in mitochondrial respiration 20 . Any specific mutations in mtDNAs encoding OXPHOS, rRNAs or tRNAs required for mitochondrial protein synthesis are also involved in cardiovascular diseases 21,22 .…”

“…It has also been found that lack of cytochrome C oxidase activity leads to myocardial insufficiency and dysfunction via reduction in mitochondrial respiration. 20 Any specific mutations in mtDNAs encoding OXPHOS, rRNAs or tRNAs required for mitochondrial protein synthesis are also involved in cardiovascular diseases. 21,22 Mitochondrial dysfunctions because of other factors, including mitochondrial structural disorganization, enlargement or through changes of membrane potential can trigger the mitochondrial degradation mechanism.…”