Review
The breathing heart — Mitochondrial respiratory chain dysfunction in cardiac disease

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Abstract

The relentlessly beating heart has the greatest oxygen consumption of any organ in the body at rest reflecting its huge metabolic turnover and energetic demands. The vast majority of its energy is produced and cycled in form of ATP which stems mainly from oxidative phosphorylation occurring at the respiratory chain in the mitochondria. Apart from energy production, the respiratory chain is also the main source of reactive oxygen species and plays a pivotal role in the regulation of oxidative stress. Dysfunction of the respiratory chain is therefore found in most common heart conditions. The pathophysiology of mitochondrial respiratory chain dysfunction in hereditary cardiac mitochondrial disease, the ageing heart, in LV hypertrophy and heart failure, and in ischaemia–reperfusion injury is reviewed. We introduce the practising clinician to the complex physiology of the respiratory chain, highlight its impact on common cardiac disorders and review translational pharmacological and non-pharmacological treatment strategies.

Introduction

Approximately 25% of a human myocardial cell is made up of mitochondria. Mitochondria are cellular factories converting substrates from diet into usable energy for many intracellular processes including mechanical contraction of myofilaments. The ultimate substrate used by most enzymes to convert chemically stored energy into conformational changes and finally mechanical motion is adenosine-triphosphate (ATP). The heart has a voracious requirement for energy — indeed the human heart cycles approximately 6 kg of ATP per day [1]. The majority of this ATP is generated in mitochondria at the respiratory chain by oxidative phosphorylation, and as a byproduct the respiratory chain generates reactive oxygen species (ROS). Under physiological conditions ROS plays an important role in intracellular signalling, but in pathological states increased ROS production can become detrimental to the cardiomyocyte. Associated with energy balance are other mitochondrial key roles, namely regulation of calcium homeostasis and apoptotic signalling. It is beyond the scope of this review to discuss in detail the latter two important processes.

It is not surprising that mitochondrial diseases preferentially affect tissues with high energy turnover such as the heart. Impaired oxidative phosphorylation and defective electron transport chain (ETC) function are central to most cardiac conditions associated with mitochondrial dysfunction. Their malfunction has been implicated in hereditary mitochondrial cardiomyopathies, in the ageing heart, cardiac hypertrophy, heart failure, and in ischaemia–reperfusion injury.

Section snippets

Physiology of respiratory chain

Mitochondria generate adenosine triphosphate (ATP), by means of the electron transport chain (ETC) and the oxidative phosphorylation system (OXPHOS). The proteins involved in this process are located in the mitochondrial inner membrane (MIM) and collectively referred to as the respiratory chain (RC), Fig. 1. Acetyl CoA generated from glycolysis and from fatty acid beta oxidation (FAO) enters the Tricarboxylic acid cycle (TCA). The TCA cycle, glycolysis and FAO all generate high energy electrons

Hereditary cardiomyopathies

The RC system is made up of about 100 different proteins. Only 13 of these are encoded by mitochondrial DNA [(mtDNA) with a maternal pattern of inheritance [8]], the remainder being encoded by nuclear DNA (nDNA), following a Mendelian inheritance pattern [9]. All complexes of the ETC, except complex II which is encoded exclusively by mtDNA, have a double genetic origin (mtDNA and nDNA). Moreover it is hypothesised that several hundred nuclear genes are also needed for various functions of the

Ageing heart

In 1956 Harman suggested mitochondria as the main source of ROS and its causative role in age related changes [16]. Short et al. have confirmed that in human mtDNA abundance and ATP production declines with advancing age, whereas the level of oxidative mtDNA lesions increases [17]. mtDNA is not protected by histones unlike nDNA and has less effective repair mechanisms [18]. All of these factors contribute to a gradual increase in mtDNA mutation rates with age. This affects the expression and

LV hypertrophy and heart failure

Changes in mitochondrial energetic profile are a hallmark of hypertrophied and failing hearts. Increased oxidative stress activates a variety of hypertrophy signalling kinases and transcription factors [30], [31]. Initially a pressure overload induced LV hypertrophy leads to a shift of fatty acid oxidation towards more efficient glucose oxidation. However it also leads to reduction of maximal OXPHOS capacity with decreased activities of respiratory chain complexes and increase of electron leak

Ischaemia reperfusion injury — ‘to breathe or not to breathe?’

Final infarct size is due to injury conferred during ischaemia and also the injury incurred as a result of ischaemia reperfusion injury (IRI). The damage occurring on reperfusion is largely determined by a massive burst of ROS production originating from ischaemically damaged mitochondria. During ischaemia intracellular ATP levels and pH drop due to impaired OXPHOS and a switch to anaerobic glycolysis with lactic acid production. The intracellular proton accumulation activates the Na/H

Other potential therapeutic interventions targeting the respiratory chain

Ischaemia–reperfusion injury is a classic example where modulation of respiratory chain function has been extensively investigated in an experimental setting and currently significant efforts are undertaken to translate these results into human applications. However as described in the previous sections, respiratory chain dysfunction occurs in almost every pathology involving the working heart. Therefore it is not surprising that attempts to modify the electron transport chain in order to

Future directions

A wealth of evidence is currently available to confirm the major role of mitochondrial respiratory dysfunction in metabolic disorders of the heart. An exciting novel approach to identify new cardioprotective agents is the use of high-throughput tests measuring cellular respiration following various stressors by screening blindly thousands of small molecules from commercially available chemical compound libraries [130], [131]. Identified candidates are then subjected to more rigorous bench

Summary

Cardiac function is dependent on mitochondrial aerobic energy delivery by oxidative phosphorylation. However the respiratory chain complex is important not only in aerobic energy delivery, but also in regulation of oxidative stress and cell signalling. There is growing body of evidence suggesting pivotal role of respiratory chain dysfunction in pathogenesis of common cardiac conditions such as heart failure or ischaemia reperfusion injury. Understanding the molecular biology of these conditions

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