ReviewThe breathing heart — Mitochondrial respiratory chain dysfunction in cardiac disease
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
References (136)
- et al.
Uncoupling proteins in human heart
Lancet
(2004) - et al.
Uncoupling proteins and the control of mitochondrial reactive oxygen species production
Free Radic Biol Med
(2011) Uncoupling to survive? The role of mitochondrial inefficiency in ageing
Exp Gerontol
(2000)- et al.
Compromised respiratory adaptation and thermoregulation in aging and age-related diseases
Ageing Res Rev
(2010) - et al.
Assessing bioenergetic function in response to oxidative stress by metabolic profiling
Free Radic Biol Med
(2011) Genetic bases of mitochondrial respiratory chain disorders
Diabetes Metab
(4 2010)- et al.
Cardiomyopathies due to homoplasmic mitochondrial tRNA mutations: morphologic and molecular features
Hum Pathol
(7 2013) - et al.
Neonatal, lethal noncompaction of the left ventricular myocardium is allelic with Barth syndrome
Am J Hum Genet
(1997) - et al.
2011 consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology
Cardiovasc Pathol
(2012) Free radical theory of aging
Mutat Res DNAging Genet Instabil Aging
(1992)
The effect of UCP3 overexpression on mitochondrial ROS production in skeletal muscle of young versus aged mice
FEBS Lett
Electron transport chain dysfunction in neonatal pressure-overload hypertrophy precedes cardiomyocyte apoptosis independent of oxidative stress
J Thorac Cardiovasc Surg
Abnormal mitochondrial function in myocardium of dogs with chronic heart failure
J Mol Cell Cardiol
Abnormal mitochondrial respiration in failed human myocardium
J Mol Cell Cardiol
Mitochondrial DNA damage in iron overload
J Biol Chem
Mitochondrial dysfunction may explain the cardiomyopathy of chronic iron overload
Free Radic Biol Med
Mitochondrial involvement in chronic chagasic cardiomyopathy
Trans R Soc Trop Med Hyg
Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression
J Am Coll Cardiol
Mitochondrial DNA mutations and mitochondrial abnormalities in dilated cardiomyopathy
Am J Pathol
Increased reactive oxygen species production and functional alterations in antioxidant enzymes in human failing myocardium
J Card Fail
Targeting mitochondrial oxidative stress in heart failure: throttling the afterburner
J Am Coll Cardiol
Urinary biopyrrins levels are elevated in relation to severity of heart failure
J Am Coll Cardiol
Nitrite as a mediator of ischemic preconditioning and cytoprotection
Nitric Oxide Biol Chem
Mitochondrial complex II in the post-ischemic heart: oxidative injury and the role of protein S-glutathionylation
J Biol Chem
Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow
J Biol Chem
Effects of edaravone on reperfusion injury in patients with acute myocardial infarction
Am J Cardiol
AMPK signalling and the control of substrate use in the heart
Mol Cell Endocrinol
Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial
Lancet
Remote perconditioning reduces myocardial injury in adult valve replacement: a randomized controlled trial
J Surg Res
Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial
Lancet
Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial
Lancet
Mechanisms of nitrite reduction to nitric oxide in the heart and vessel wall
Nitric Oxide Biol Chem
Cardioprotection and mitochondrial S-nitrosation: effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury
J Mol Cell Cardiol
In vivo cardioprotection by S-nitroso-2-mercaptopropionyl glycine
J Mol Cell Cardiol
Reversible blockade of electron transport with amobarbital at the onset of reperfusion attenuates cardiac injury
Transl Res
Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise
Free Radic Biol Med
Dietary inorganic nitrate improves mitochondrial efficiency in humans
Cell Metab
The failing heart — an engine out of fuel
N Engl J Med
Mitochondrial proton and electron leaks
Essays Biochem
A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine
Annu Rev Genet
Nuclear genetic defects of oxidative phosphorylation
Hum Mol Genet
Mitochondrial respiratory-chain diseases
N Engl J Med
Cardiac involvement in mitochondrial DNA disease: clinical spectrum, diagnosis, and management
Eur Heart J
Decline in skeletal muscle mitochondrial function with aging in humans
Proc Natl Acad Sci U S A
Normal oxidative damage to mitochondrial and nuclear DNA is extensive
Proc Natl Acad Sci U S A
Mitochondrial decay in the aging rat heart: evidence for improvement by dietary supplementation with acetyl-l-carnitine and/or lipoic acid
Ann N Y Acad Sci
Mitochondria and the aging heart
J Geriatr Cardiol
Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster
Genetics
Extension of mouse lifespan by overexpression of catalase
Age
Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer
Aging Cell
Cited by (84)
The link between obesity and aging - insights into cardiac energy metabolism
2023, Mechanisms of Ageing and DevelopmentA study on the curative effect of nobiletin on paraquat induced toxicity in rat
2022, Journal of King Saud University - ScienceCitation Excerpt :Previous studies showed that intracellular ROS accumulation is the main reason for the damage of mitochondrial ETC (Cheraghi et al., 2019). Once the transmission of the mitochondrial ETC is blocked, ATPs' synthesis is affected, and this condition is due to mitochondrial damage (Schwarz et al., 2014). The previous investigation revealed the mitochondrial role in PQ intoxication (Huang et al., 2016) because PQ inhibits complexes' activities in mitochondria (Choi et al., 2008).
Comprehensive non-invasive assessment of electrocardiographic abnormalities and cardiac arrhythmias in patients with genetically confirmed mitochondrial diseases
2021, Journal of ElectrocardiologyCitation Excerpt :Until now, no results of Tp-e and Tp-e/QT ratio intervals in patients with MitD are present in available literature. The reason of observed in our research alternations of ventricular repolarization and dispersion seems to be dysfunction in aerobic metabolism of cardiomyocytes and theirs injury expressed by elevated levels of troponin T. [4,5] This is only speculation because we did not demonstrated correlations between disease duration or cardiac biomarkers levels and QTc, QTd, Tp-e or Tp-e/QT interval ratio. It should be added that abnormalities of ventricular repolarization, as well as arrhythmias, might also be caused by myocardial inhomogeneity due to latent perfusion deficits causing areas of myocardial injuries.
Flavonoids extracted from mulberry (Morus alba L.) leaf improve skeletal muscle mitochondrial function by activating AMPK in type 2 diabetes
2020, Journal of EthnopharmacologyCitation Excerpt :When certain causes lead to obstacles in the electron transport process of respiratory chain, MMP will be decreased. Further oxidative phosphorylation and ATP synthesis of cells are reduced, resulting in mitochondrial Ca2+ release, ROS production, and release of cytochrome C and other mitochondrial contents (Schwarz et al., 2014). Among them, COX is the terminal compound enzyme of mitochondrial respiratory chain electron transfer and the COXIV is a subunit of COX (Klinge, 2008).