Cardiac Complications in Inherited Mitochondrial Diseases

Heart Failure Reviews https://doi.org/10.1007/s10741-020-10009-1 Cardiac complications in inherited mitochondrial diseases Mohaddeseh Behjati1 & Mohammad Reza Sabri2 & Masood Etemadi Far3 & Majid Nejati4,5 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Maternally mitochondrial dysfunction includes a heterogeneous group of genetic disorders which leads to the impairment of the final common pathway of energy metabolism. Coronary heart disease and coronary venous disease are two important clinical manifestations of mitochondrial dysfunction due to abnormality in the setting of underlying pathways. Mitochondrial dysfunction can lead to cardiomyopathy, which is involved in the onset of acute cardiac and pulmonary failure. Mitochondrial diseases present other cardiac manifestations such as left ventricular noncompaction and cardiac conduction disease. Different clinical findings from mitochondrial dysfunction originate from different mtDNA mutations, and this variety of clinical symptoms poses a diagnostic challenge for cardiologists. Heart transplantation may be a good treatment, but it is not always possible, and other complications of the disease, such as mitochondrial encephalopathy, lactic acidosis, and stroke-like syndrome, should be considered. To diagnose and treat most mitochondrial disorders, careful cardiac, neurological, and molecular studies are needed. In this study, we looked at molecular genetics of MIDs and cardiac manifestations in patients with mitochondrial dysfunction. Keywords Mitochondrial dysfunction . mtDNA . Cardiac . Atrioventricular Abbreviations ND1 NADH-ubiquinone oxidoreductase chain 1 ANT Adenine nucleotide translocator NDUFAF1 NADH dehydrogenase [ubiquinone] 1 alpha BSCL2 Berardinelli-Seip congenital lipodystrophy subcomplex assembly factor 1 CMP Cardiomyopathy OXPHOS Oxidation-phosphorylation COX Cytochrome c oxidase ROS Reactiveoxygenspecies ECMP Encephalocardiomyopathy MELAS Mitochondrial encephalopathy lactic acidosis and stroke-like episodes Introduction MERRF Myoclonus epilepsy red ragged fibers MID Mitochondrial dysfunction Mitochondria are involved in various fundamental cellular pro- MRP Mitochondrial ribosomal protein cesses like apoptosis, calcium signaling, and generation of reac- MTO Mitochondrial tRNA translation optimization tive oxygen species (ROS), but the most principal action of mitochondria is the synthesis of adenosine triphosphate (ATP) through oxidative phosphorylation pathway. Electron transfer * Majid Nejati between respiratory chain enzymes occurs through an electro- [email protected] chemical slope in the inner mitochondrial membrane [1, 2]. 1 Echocardiography Research Center, Rajaie Cardiovascular Medical Defects in the oxidative phosphorylation pathway cause a and Research Center, Iran University of Medical Sciences, variety of diseases ranging from the involvement of one tissue Tehran, Iran to the involvement of multiple organs with high-energy de- 2 Pediatric Cardiovascular Research Center, Cardiovascular Research mands such as the heart and brain. Mutations or gene variation Institute, Isfahan University of Medical Sciences, Isfahan, Iran can play a role in the onset and severity of the disease [3, 4]. 3 Department of Neurosurgery, Isfahan University of Medical Mitochondrial DNA in neonatal heart cells has a simple, amor- Sciences, Isfahan, Iran phous and double-stranded structure. Branched forms appear in 4 Anatomical Sciences Research Center, Institute for Basic Sciences, adults as mitochondrial DNA copy number increases in early Kashan University of Medical Sciences, Kashan, Iran childhood [5]. Adult human mitochondrial DNA has a complex 5 Core Research Lab, Kashan University of Medical Sciences, organization with a large number of dimer molecules, four-way Kashan, Iran junction, and branching structures [6]. Heart Fail Rev In adults, mtDNA mutations are the most common cause of different from nuclear gene mutations. Mitochondrial gene mu- mitochondriopathy or mitochondrial dysfunction (MID). tations can be heterogeneous or homogeneous and cause a More than 300 mtDNA have been recognized so far. The disease phenotype when mutations exceed threshold levels. number of mtDNA molecules in the oocyte is remarkably Often, there is a correlation between the rate of mutation and diminished during the development of the female germ cells the expression of the disease phenotype, and sometimes differ- before re-amplification to final count (less than 100,000) [7]. ent mutations occur in different tissues [3]. Some pathways in The ratio of mutated to normal mtDNA can change over time, the pathogenesis of MID-induced cardiac disorders are also affecting the prevalence and severity of the disorder. Thus observed in the natural aging process by increased cardiac mi- inter-genetic shifts in mtDNA mutation with subsequent var- tochondrial ROS and decreased mitochondrial and nuclear iation in clinical disease severity are due to this germ cell DNA integrity [19, 20]. bottleneck [8]. Due to the deficiency of DNA repair mecha- nisms and proximity to the OXPHOS system, 10–17-fold mitochondrial mutations higher than nuclear DNA mutations Mitochondrial genetics result in MIDs [9, 10]. Cellular OXPHOS dysfunction due to primary genetic de- Mitochondria have been implicated in important cellular pro- fects (mitochondrial or nuclear DNA) leads to MIDs [11]. The cesses such as apoptosis and calcium signaling, but cellular precise extent and range of MIDs in the general population respiration and adenosine triphosphate (ATP) synthesis is their have yet to be determined [12]. The actual prevalence of these main function. ATP production is accomplished by the elec- defects is underestimated, probably due to regional referral trons transmission between the respiratory chain enzymatic patterns. In the general population, there is a 1/300 G complexes and transfer of proton into the mitochondrial inner m.3243A>G mutation [13]. Diseases related to mtDNA mu- membrane and the creation of an electrochemical gradient. As tation appear to be more common than previously thought well as 13 import polypeptides of the OXPHOS enzyme com- (about 1/5000) because many people may have low mutation- plexes, the mitochondrial genome encodes 22 transfer RNA al burden and are asymptomatic [14]. In a broad spectrum of (mt-tRNA) and two ribosomal RNA (mt-rRNA). Other struc- MIDs, point mutations in mitochondrial DNA have been iden- tural and functional proteins of mitochondria are expressed by tified. Increasing the mutant mtDNA ratio (60–90%) affects the nucleus genome. The mitochondrial genome has unique the MID and its onset and severity. A small fraction of the features and complex inheritance. The maternal inheritance of mitochondrial genome (< 1%) is mutated in the general mitochondrial DNA differs from that of the Mendelian model populatio. [15]. There are different phenotypes of MID, but of nuclear DNA mutations. There are several copies of mtDNA one of their main features is heterogeneity due to the presence in each cell, and a small percentage of them may have a muta- of both normal and mutant mtDNA in the cell population [16]. tion. The rate and threshold of mtDNA mutation may affect In cardiac muscle cells, mitochondrial number, topological clinical disease incidence and extent [21]. The identification arrangement, and replication mode are linked together [8]. of pathogenic mtDNA mutations, that commonly result in iso- By now, more than 250 pathogenic mtDNA mutations have lated organ phenotypes such as cardiomyopathy (CMP), re- been identified which many are associated with cardiac mani- veals the fact that other genetic (e.g., expression of festations. Maternally transmitted MIDs comprise a heteroge- aminoacyl-tRNA synthetase) or environmental factors can neous group of genetic disorders that disrupt the pathway of the modulate the phenotype [22, 23]. Since the inheritance of hu- final metabolism of energy production. The major components man mitochondrial diseases is purely from the mother’sside, of the respiratory chain are affected by mitochondrial DNA the presence of the disease in maternal relatives increases the mutations, which include most for a majority of mitochondrial suspicion of mitochondrial disease, so diagnosis through genet- DNA deletion syndromes. Clinical presentations of MIDs are ic counseling is quite different from nuclear genetic diseases varied from oligo-symptomatic (migraine, type 2 diabetes [24]. Depending on the type of mutation, the probability of mellitus (DM)) to very complex syndrome [10]. In summary, transfer from mother to child varies. Large and single deletions clinical phenotype of MIDs include mitochondrial encephalop- are less likely to be transmitted, while point mutations are more athy, lactic acidosis and stroke-like episodes (MELAS), myoc- likely to be inherited from mothers. The number of mtDNA in lonus, epilepsy, red ragged fibers (MERRF), Leber hereditary each oocyte decreases greatly during the development of female optic neuritis with acute or sub-acute visual loss), Leigh (sub- germ cells. The variation in the severity of hereditary diseases acute necrotizing encephalopathy and basal ganglion lesions), can partly be explained by this “genetic bottleneck” and change mitochondrial myopathy-cardiomyopathy, Wolfram syndrome in the rate of mtDNA mutation across generations [25]. The (diabetes insidious, optic atrophy, and deafness), and Pearson’s percentage of mutations in the mitochondrial genome is higher marrow pancreas

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