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The Interplay among Subunit Composition, Cardiolipin Content, and Aggregation State of Bovine Heart Cytochrome c Oxidase.

ABSTRACT: Mitochondrial cytochrome c oxidase (CcO) is a multisubunit integral membrane complex consisting of 13 dissimilar subunits, as well as three to four tightly bound molecules of cardiolipin (CL). The monomeric unit of CcO is able to form a dimer and participate in the formation of supercomplexes in the inner mitochondrial membrane. The structural and functional integrity of the enzyme is crucially dependent on the full subunit complement and the presence of unperturbed bound CL. A direct consequence of subunit loss, CL removal, or its oxidative modification is the destabilization of the quaternary structure, loss of the activity, and the inability to dimerize. Thus, the intimate interplay between individual components of the complex is imperative for regulation of the CcO aggregation state. While it appears that the aggregation state of CcO might affect its conformational stability, the functional role of the aggregation remains unclear as both monomeric and dimeric forms of CcO seem to be fully active. Here, we review the current status of our knowledge with regard to the role of dimerization in the function and stability of CcO and factors, such as subunit composition, amphiphilic environment represented by phospholipids/detergents, and posttranslational modifications that play a role in the regulation of the CcO aggregation state.

SUBMITTER: Sedlak E

PROVIDER: S-EPMC7761698 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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The Interplay among Subunit Composition, Cardiolipin Content, and Aggregation State of Bovine Heart Cytochrome <i>c</i> Oxidase.

Sedlák Erik E Kožár Tibor T Musatov Andrey A

Cells 20201203 12

Mitochondrial cytochrome <i>c</i> oxidase (CcO) is a multisubunit integral membrane complex consisting of 13 dissimilar subunits, as well as three to four tightly bound molecules of cardiolipin (CL). The monomeric unit of CcO is able to form a dimer and participate in the formation of supercomplexes in the inner mitochondrial membrane. The structural and functional integrity of the enzyme is crucially dependent on the full subunit complement and the presence of unperturbed bound CL. A direct con ...[more]

PMID: 33287231

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Project description:BACKGROUND:Treatment 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). METHODS:Fifty-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. RESULTS:Gene 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. CONCLUSION:In 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.

Dataset Information

The Interplay among Subunit Composition, Cardiolipin Content, and Aggregation State of Bovine Heart Cytochrome c Oxidase.

Publications

The Interplay among Subunit Composition, Cardiolipin Content, and Aggregation State of Bovine Heart Cytochrome <i>c</i> Oxidase.

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