Mitochondrial Cardiomyopathy Research Articles

Complex I Inhibition Enhances Mitochondrial Calcium Uniporter Current

Ca2+ in the mitochondrial matrix regulates several physiological processes, from ATP synthesis to cell death. Most mitochondrial Ca2+ uptake occurs through the mitochondrial Ca2+ uniporter, a highly-selective ion channel embedded in the inner membrane. We recently demonstrated that both Ca2+ uptake and uniporter channel activity are increased in a mouse model of mitochondrial cardiomyopathies. In these diseases, which primarily present in infants and children, characteristic deficits in oxidative phosphorylation produce a signal that boosts mitochondrial Ca2+ levels. Here we investigated the mechanism for such enhancement. By selective pharmacological inhibition of individual electron transport chain complexes, we found that rotenone-induced complex I dysfunction increases mitochondrial Ca2+ uptake. Since Ca2+ transport is governed by both uniporter activity and the transmembrane voltage gradient (ΔΨ), we measured uniporter activity directly using whole-mitoplast patch-clamp. HEK293T cells were incubated with 0.1, 0.3 and 1 µM rotenone for 72 hr to chronically inhibit complex I. After such inhibition, we found that uniporter current density increased from −72 ± 6 pA/pF for control mitoplasts (0 nM rotenone) to −90 ± 6 pA/pF in 0.3 µM rotenone and −130 ± 20 pA/pF in 1 µM rotenone. Such an increase was not due to acute effects of rotenone on the uniporter channel itself, as it did not affect or only mildly inhibited current densities at these concentrations. Our data indicate that chronic inhibition of complex I produces a signal that increases the activity of MCU.

Mitochondrial Cardiomyopathy Caused by Elevated Reactive Oxygen Species and Impaired Cardiomyocyte Proliferation.

Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood. To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of Tfam (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication. Tfam inactivation by Nkx2.5Cre caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. Tfam inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic Tfam inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal Tfam inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal Tfam inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyte proliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of Tfam inactivation. Mitochondrial dysfunction caused by Tfam inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction.

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

Calcium (Ca2+) influx into the mitochondrial matrix stimulates ATP synthesis. Here, we investigate whether mitochondrial Ca2+ transport pathways are altered in the setting of deficient mitochondrial energy synthesis, as increased matrix Ca2+ may provide a stimulatory boost. We focused on mitochondrial cardiomyopathies, which feature such dysfunction of oxidative phosphorylation. We study a mouse model where the main transcription factor for mitochondrial DNA (transcription factor A, mitochondrial, Tfam) has been disrupted selectively in cardiomyocytes. By the second postnatal week (10–15day old mice), these mice have developed a dilated cardiomyopathy associated with impaired oxidative phosphorylation. We find evidence of increased mitochondrial Ca2+ during this period using imaging, electrophysiology, and biochemistry. The mitochondrial Ca2+ uniporter, the main portal for Ca2+ entry, displays enhanced activity, whereas the mitochondrial sodium-calcium (Na+-Ca2+) exchanger, the main portal for Ca2+ efflux, is inhibited. These changes in activity reflect changes in protein expression of the corresponding transporter subunits. While decreased transcription of Nclx, the gene encoding the Na+-Ca2+ exchanger, explains diminished Na+-Ca2+ exchange, the mechanism for enhanced uniporter expression appears to be post-transcriptional. Notably, such changes allow cardiac mitochondria from Tfam knockout animals to be far more sensitive to Ca2+-induced increases in respiration. In the absence of Ca2+, oxygen consumption declines to less than half of control values in these animals, but rebounds to control levels when incubated with Ca2+. Thus, we demonstrate a phenotype of enhanced mitochondrial Ca2+ in a mitochondrial cardiomyopathy model, and show that such Ca2+ accumulation is capable of rescuing deficits in energy synthesis capacity in vitro.

Dominance of yeast aac2R96H and aac2R252G mutations, equivalent to pathological mutations in ant1, is due to gain of function

The mitochondrial ADP/ATP carrier is a nuclear encoded protein, which catalyzes the exchange of ATP generated in mitochondria with ADP produced in the cytosol. In humans, mutations in the major ADP/ATP carrier gene, ANT1, are involved in several degenerative mitochondrial pathologies, leading to instability of mitochondrial DNA. Recessive mutations have been associated with mitochondrial myopathy and cardiomyopathy whereas dominant mutations have been associated with autosomal dominant Progressive External Ophtalmoplegia (adPEO). Recently, two de novo dominant mutations, R80H and R235G, leading to extremely severe symptoms, have been identified. In order to evaluate if the dominance is due to haploinsufficiency or to a gain of function, the two mutations have been introduced in the equivalent positions of the AAC2 gene, the yeast orthologue of human ANT1, and their dominant effect has been studied in heteroallelic strains, containing both one copy of wild type AAC2 and one copy of mutant aac2 allele. Through phenotypic characterization of these yeast models we showed that the OXPHOS phenotypes in the heteroallelic strains were more affected than in the hemiallelic strain indicating that the dominant trait of the two mutations is due to gain of function.

MODELING THE DILATED CARDIOMYOPATHY WITH ATAXIA SYNDROME (DCMA), A PEDIATRIC MITOCHONDRIAL CARDIOMYOPATHY, USING CARDIOMYOCYTES DERIVED FROM INDUCED PLURIPOTENT STEM CELLS

Cardiomyopathy is a predominant and lethal feature of many inborn metabolic disorders but results from derangements in cellular energetics rather than ischemic myocardial injury. This fundamental difference is likely why standard heart failure medications appear to be ineffective. This problem is exemplified by the dilated cardiomyopathy with ataxia syndrome (DCMA). DCMA is related to Barth syndrome with abnormal cardiolipin and mitochondria causing heart failure, conduction defects and other systemic features. Isolated cases of DCMA have been identified worldwide but the largest known group of patients is found in the Hutterites of southern Alberta. No effective therapy exists and in our cohort there is 39% mortality in early childhood related to cardiac dysfunction despite recommended optimal medical therapy. The lack of useful drugs for mitochondrial cardiomyopathies means that there are few therapies available outside of mechanical circulatory support or heart transplantation. Since the rarity and heterogeneity of the pediatric cardiomyopathies preclude randomized drug trials, the use of patient cells and in vitro drug modeling represents the best possible option to identify effective therapeutics. Here, we describe the creation and characterization of cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) (as an in vitro model of DCMA) from 4 children with DCMA and varying severity of cardiac dysfunction. Purified peripheral blood mononuclear cells derived from 4 DCMA patients (Table 1) were reprogrammed into induced pluripotent stem cells (iPSCs) using Sendai virus and the 4 Yamanaka factors, and characterized using standard pluripotency tests. Our iPSCs expressed markers of pluripotency including SSEA4 and OCT4. The DCMA-derived iPSCs were sequenced to detect the DCMA related mutation in their genomic DNA. Results showed that the iPSCs carried the DNAJC19 mutation (rs137854888) responsible for the abnormal splicing causing the disease phenotype. These iPSCs were successfully differentiated into beating cardiomyocytes using a modified protocol and lactate as a sole carbon source to enrich purified iPSC-CMs. The resulting iPSC-CMs expressed the cardiac-specific markers TNNT2 and NKX2.5. We describe the development of iPSC-CMs for DCMA which represent a novel in vitro model for mitochondrial cardiomyopathy and provide a platform to study the efficacy of potential therapeutics and genome editing approaches.

P1-2 - Morphosis of Multi-Layered Mitochondria in the Myocardium of a Patient With Mitochondrial Cardiomyopathy Revealed by Electron Microscopy

P1-2 - Morphosis of Multi-Layered Mitochondria in the Myocardium of a Patient With Mitochondrial Cardiomyopathy Revealed by Electron Microscopy

Abstract 437: Mitochondrial Cardiomyopathies Feature Enhanced Mitochondrial Calcium Signaling

Mitochondrial diseases often feature early onset of dilated cardiomyopathy, due to the large energetic demand placed by the heart. Among regulators of mitochondrial respiration, we focus on calcium, which potently stimulates ATP synthesis. We assessed the hypothesis that cells boost mitochondrial calcium to stimulate respiration as this declines in mitochondrial cardiomyopathies. To this end, we studied mice that develop a neonatal, severe cardiomyopathy caused by cardiac-specific knockout (KO) of mitochondrial transcription factor A ( Tfam ). Such deletion impairs transcription of mitochondrial DNA, which encodes multiple subunits of the electron transport chain (ETC). Tfam KO mice exhibited a dilated cardiomyopathy, with decreased fractional shortening and increased LV diameters, and had marked inhibition of multiple ETC complexes. We determined that Tfam KO mitochondria took up calcium twice as fast as mitochondria from littermate controls, while calcium efflux was approximately 70% slower. Whole-mitoplast voltage clamp revealed that the enhanced calcium uptake was due to an increase in the current carried by the uniporter. Furthermore, the larger uniporter current reflected increased amounts of uniporter subunit proteins. This occurred despite a reduction in the transcripts of genes encoding these subunits, suggesting a post-translational mechanism for the enhanced uniporter stability. Finally, we found that the rate of ADP-stimulated oxygen consumption in calcium-free solution was 50% less in the Tfam KO mitochondria compared to controls, but increased substantially more, nearly to control levels, when calcium was present (2.5-fold increase for KO versus 1.7-fold for control). In conclusion, enhanced mitochondrial calcium signaling in a mitochondrial cardiomyopathy model may serve to compensate for energetic failure.

Ultrastructural aspects of vacuolar degeneration of cardiomyocytes in human endomyocardial biopsies.

Vacuolar degeneration of cardiomyocytes is a histological finding commonly encountered during routine light microscopic examination of human endomyocardial biopsy specimens. The vacuoles appear as intracellular clear areas lacking myofibers. By itself, this finding has little diagnostic value, but may have important clinical implications when the vacuolar contents are of etiological significance (e.g., accumulation of abnormal metabolites), and the clinical importance is increased when the disease is treatable. Thanks to its great resolving power, electron microscopy can often reveal the contents of the vacuoles and lead to a correct diagnosis. It can be used to differentially diagnose lysosomal storage diseases such as Fabry, Danon, and Pompe disease, doxorubicin cardiomyopathy, mitochondrial cardiomyopathy, autophagic degeneration, and accumulation of subcellular organelles (mitochondria, lipofuscin, glycogen granules, endoplasmic reticulum, etc.) as a nonspecific finding in failing cardiomyocytes. Nonetheless, undiagnosed cases certainly remain. It is strongly recommended that small pieces of tissue samples be fixed for electron microscopy at every endomyocardial biopsy procedure, and electron microscopic examination should be performed when a marked vacuolar degeneration is found.

Molecular mechanisms in cardiomyopathy.

Cardiomyopathies represent a heterogeneous group of diseases that negatively affect heart function. Primary cardiomyopathies specifically target the myocardium, and may arise from genetic [hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), mitochondrial cardiomyopathy] or genetic and acquired [dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM)] etiology. Modern genomics has identified mutations that are common in these populations, while invitro and invivo experimentation with these mutations have provided invaluable insight into the molecular mechanisms native to these diseases. For example, increased myosin heavy chain (MHC) binding and ATP utilization lead to the hypercontractile sarcomere in HCM, while abnormal protein-protein interaction and impaired Ca2+ flux underlie the relaxed sarcomere of DCM. Furthermore, expanded access to genetic testing has facilitated identification of potential risk factors that appear through inheritance and manifest sometimes only in the advanced stages of the disease. In this review, we discuss the genetic and molecular abnormalities unique to and shared between these primary cardiomyopathies and discuss some of the important advances made using more traditional basic science experimentation.

Progress in Molecular Genetic Study of Mitochondrial Cardiomyopathy.

Mitochondria plays a key role in providing ATP for the energy-consuming cardiac tissues. Mitochondrial cardiomyopathy is a myocardial condition characterized by abnormal heart structure and/or function secondary to genetic defects involving the mitochondrial respiratory chain. The typical cardiac manifestations of mitochondrial cardiomyopathy include hypertrophic and dilated cardiomyopathy,while left ventricular myocardial noncompaction is less common. Recent research has suggested that most mitochondrial diseases result from mitochondrial DNA mutation,which can be found in genes that encode ancillary proteins needed for genetic transcription (tRNA),in genes that encode subunits of the electron transport chain complexes,or in genes that control the activities of the mitochondria called D-loop zone. However,the exact physiological mechanisms remain unclear. This review summarizes the recent advances in the molecular mechanism of mitochondrial cardiomyopathy.

Advances in Diagnosis and Management of Mitochondrial Cardiomyopathy.

Mitochondrial cardiomyopathy (MCM) is a series of myocardial conditions characterized by abnormal heart-muscle structure,function,or both,secondary to genetic defects involving the mitochondrial respiratory chain,in the absence of concomitant coronary artery disease,hypertension,valvular disease,or congenital heart disease. MCM patients typically have hypertrophic or dilated cardiomyopathy. Arrhythmias and left ventricular myocardial noncompaction are less common,and heart failure may occur as the first symptom in some patients. Since MCM patients often have symptoms of multiple organ involvement,the symptoms are not specific and the diagnosis can be difficult. Thus,awareness of this disease must be increased in clinical settings. Treatments for MCM are mostly supportive and nonspecific. In this review,we summarize new advances in the diagnosis and management of MCM,with an improve the clinical management of this disease.

Co segregation of the m.1555A>G mutation in the MT-RNR1 gene and mutations in MT-ATP6 gene in a family with dilated mitochondrial cardiomyopathy and hearing loss: A whole mitochondrial genome screening

Mitochondrial disease refers to a heterogeneous group of disorders resulting in defective cellular energy production due to dysfunction of the mitochondrial respiratory chain, which is responsible for the generation of most cellular energy. Because cardiac muscles are one of the high energy demanding tissues, mitochondrial cardiomyopathies is one of the most frequent mitochondria disorders. Mitochondrial cardiomyopathy has been associated with several point mutations of mtDNA in both genes encoded mitochondrial proteins and mitochondrial tRNA and rRNA.We reported here the first description of mutations in MT-ATP6 gene in two patients with clinical features of dilated mitochondrial cardiomyopathy. The mutational analysis of the whole mitochondrial DNA revealed the presence of m.1555A>G mutation in MT-RNR1 gene associated to the m.8527A>G (p.M>V) and the m.8392C>T (p.136P>S) variations in the mitochondrial MT-ATP6 gene in patient1 and his family members with variable phenotype including hearing impairment. The second patient with isolated mitochondrial cardiomyopathy presented the m.8605C>T (p.27P>S) mutation in the MT-ATP6 gene. The three mutations p.M1V, p.P27S and p.P136S detected in MT-ATP6 affected well conserved residues of the mitochondrial protein ATPase 6. In addition, the substitution of proline residue at position 27 and 136 effect hydrophobicity and structure flexibility conformation of the protein.

A Case of Mitochondrial Cardiomyopathy Initially Diagnosed as Angina Pectoris with Hypertrophic Cardiomyopathy whose Electrocardiography Gradually Changed to Typical Mitochondrial Disease

A Case of Mitochondrial Cardiomyopathy Initially Diagnosed as Angina Pectoris with Hypertrophic Cardiomyopathy whose Electrocardiography Gradually Changed to Typical Mitochondrial Disease

Recurrent De Novo Dominant Mutations in SLC25A4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number

Mutations in SLC25A4 encoding the mitochondrial ADP/ATP carrier AAC1 are well-recognized causes of mitochondrial disease. Several heterozygous SLC25A4 mutations cause adult-onset autosomal-dominant progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions, whereas recessive SLC25A4 mutations cause childhood-onset mitochondrial myopathy and cardiomyopathy. Here, we describe the identification by whole-exome sequencing of seven probands harboring dominant, de novo SLC25A4 mutations. All affected individuals presented at birth, were ventilator dependent and, where tested, revealed severe combined mitochondrial respiratory chain deficiencies associated with a marked loss of mitochondrial DNA copy number in skeletal muscle. Strikingly, an identical c.239G>A (p.Arg80His) mutation was present in four of the seven subjects, and the other three case subjects harbored the same c.703C>G (p.Arg235Gly) mutation. Analysis of skeletal muscle revealed a marked decrease of AAC1 protein levels and loss of respiratory chain complexes containing mitochondrial DNA-encoded subunits. We show that both recombinant AAC1 mutant proteins are severely impaired in ADP/ATP transport, affecting most likely the substrate binding and mechanics of the carrier, respectively. This highly reduced capacity for transport probably affects mitochondrial DNA maintenance and in turn respiration, causing a severe energy crisis. The confirmation of the pathogenicity of these de novo SLC25A4 mutations highlights a third distinct clinical phenotype associated with mutation of this gene and demonstrates that early-onset mitochondrial disease can be caused by recurrent de novo mutations, which has significant implications for the application and analysis of whole-exome sequencing data in mitochondrial disease.

Mitochondrial Cardiomyopathies.

Mitochondria are found in all nucleated human cells and perform various essential functions, including the generation of cellular energy. Mitochondria are under dual genome control. Only a small fraction of their proteins are encoded by mitochondrial DNA (mtDNA), whereas more than 99% of them are encoded by nuclear DNA (nDNA). Mutations in mtDNA or mitochondria-related nDNA genes result in mitochondrial dysfunction leading to insufficient energy production required to meet the needs for various organs, particularly those with high energy requirements, including the central nervous system, skeletal and cardiac muscles, kidneys, liver, and endocrine system. Because cardiac muscles are one of the high energy demanding tissues, cardiac involvement occurs in mitochondrial diseases with cardiomyopathies being one of the most frequent cardiac manifestations found in these disorders. Cardiomyopathy is estimated to occur in 20–40% of children with mitochondrial diseases. Mitochondrial cardiomyopathies can vary in severity from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death. Hypertrophic cardiomyopathy is the most common type; however, mitochondrial cardiomyopathies might also present as dilated, restrictive, left ventricular non-compaction, and histiocytoid cardiomyopathies. Cardiomyopathies are frequent manifestations of mitochondrial diseases associated with defects in electron transport chain complexes subunits and their assembly factors, mitochondrial transfer RNAs, ribosomal RNAs, ribosomal proteins, translation factors, mtDNA maintenance, and coenzyme Q10 synthesis. Other mitochondrial diseases with cardiomyopathies include Barth syndrome, Sengers syndrome, TMEM70-related mitochondrial complex V deficiency, and Friedreich ataxia.

Abstract 375: MCL-1 Regulates Mitochondrial Dynamics and Mitophagy

The anti-apoptotic BCL-2 family protein Myeloid Cell Leukemia-1 (MCL-1) is essential for maintaining mitochondrial integrity and cardiac function in the adult heart. Recently, we reported that cardiac-specific deletion of MCL-1 in mice leads to rapid mitochondrial dysfunction, hypertrophy, and lethal cardiomyopathy. Surprisingly, MCL-1 ablation does not result in apoptotic cell death, but rather cells show signs of mitochondrial deterioration and necrotic cell death. This suggests that in addition to its anti-apoptotic role, MCL-1 has unidentified roles in maintaining mitochondrial function in cardiac myocytes. MCL-1 exists in two distinct locations in myocytes: one form is localized to the outer mitochondrial membrane (MCL-1 OM ) and a shorter cleaved form exists in the mitochondrial matrix (MCL-1 Matrix ). Interestingly, overexpression of MCL-1 WT or MCL-1 OM , but not MCL-1 Matrix , leads to translocation of Drp1 to mitochondria, which correlates with fission and perinuclear aggregation of mitochondria. We also found that Drp1 co-immunoprecipitates with MCL-1 in heart lysates and that MCL-1-deficient hearts lack mitochondrial Drp1. Additionally, the interaction between Drp1 and MCL-1 and mitochondrial fission increase in response to serum starvation in neonatal myocytes. This suggests that MCL-1 OM recruits Drp1 to mitochondria to induce fission. Since there is a strong link between mitochondrial fission and degradation, we examined the effect of MCL-1 on mitophagy. Parkin is an E3 ubiquitin ligase that plays an important role in mitophagy. MEFs, which lack detectable Parkin, do not efficiently clear their depolarized mitochondria in response to FCCP treatment. However, overexpression of Parkin or MCL-1 increased the efficiency of mitophagy in MEFs in response to FCCP treatment. MCL-1-mediated mitophagy is abrogated in autophagy-deficient Atg5 -/- MEFs, confirming that the clearance occurs via enhanced autophagy. Thus, our data suggest that MCL-1 OM has dual actions in coordinating Drp1-mediated fission and mitophagy, which allows for more efficient removal of damaged mitochondria.

Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt.

The mitochondrial matrix protease CLPP plays a central role in the activation of the mitochondrial unfolded protein response (UPR(mt)) in Caenorhabditis elegans Far less is known about mammalian UPR(mt) signaling, although similar roles were assumed for central players, including CLPP To better understand the mammalian UPR(mt) signaling, we deleted CLPP in hearts of DARS2-deficient animals that show robust induction of UPR(mt) due to strong dysregulation of mitochondrial translation. Remarkably, our results clearly show that mammalian CLPP is neither required for, nor it regulates the UPR(mt) in mammals. Surprisingly, we demonstrate that a strong mitochondrial cardiomyopathy and diminished respiration due to DARS2 deficiency can be alleviated by the loss of CLPP, leading to an increased de novo synthesis of individual OXPHOS subunits. These results question our current understanding of the UPR(mt) signaling in mammals, while introducing CLPP as a possible novel target for therapeutic intervention in mitochondrial diseases.

Mitochondrial diseases with the main manifestations of cardiomyopathy and respiratory muscle damage

Objective The 3243A>G mutation in mitochondrial DNA is a common cause of the classical mitochondrial diseases characterized by neuro-muscular disorders.This study reports a rare case with the main manifestations of mitochondrial disease in children of mitochondrial cardiomyopathy and respiratory muscle damage. Methods The clinical characteristics, diagnosis and treatment, biochemical, pathological and genetic features of a 10-year-old girl were studied. Results The girl was admitted because of heart failure and respiratory failure at the age of 10.Ragged red fibers in skeletal muscles had been noticed.On her mitochondrial gene, 3243A>G mutation, Leu tRNA (UUR), was detected.The mutation rate in the peripheral blood cells was 94%.After the treatment with a high dose of creatine phosphate sodium, coenzyme Q10 and L-carnitine with assisted ventilation, the patient improved rapidly.The child was followed up for 2 years without recurrence.Meanwhile the growth, development and daily life were normal. Conclusions Cardiac and respiratory muscle impairments that appeared at the same time as the first manifestations of the children's mitochondrial disease is not common, and it is rare to have cardiomyopathy based mitochondrial gene 3243A>G mutation is seldom seen clinically.Skeletal muscle biopsy and genetic test is the key for accurate diagnosis.Improving mitochondrial metabolism and assisted ventilation appear to be helpful treatments. Key words: Cardiomyopathy; Mitochondrial disease; Ragged red fiber; Mitochondrial gene; 3243A>G

Mitochondrial dysfunction bridges negative affective disorders and cardiomyopathy in socially isolated rats: Pros and cons of fluoxetine

Objectives Depression is tightly associated with cardiovascular comorbidity and accounts for high financial and social burden worldwide. Mitochondrial dysfunction contributes to the pathophysiology of depression and cardiovascular disorders; its contribution to depression-cardiovascular comorbidity has not yet been investigated. Methods Adolescent rats were subjected to 4 weeks of isolation (social isolation stress or SIS) or social conditions (control), and then they were divided into treatment (fluoxetine, 7.5 mg/kg/day for 21 days) and non-treatment groups. After different housing conditions and treatment, animals were evaluated by behavioural tests (n = 6–8) and mitochondrial assessments (n = 3) of brain and cardiac tissues. Results We found that juvenile SIS induced behavioural abnormalities and mitochondrial dysfunction in adulthood. We showed that juvenile SIS was associated with impaired respiratory chain complex, which leads to reactive oxygen species formation, oxidative damage and ATP abatement in both brain and heart. Administration of FLX (7.5 mg/kg/day) during the isolation period attenuated the effects of SIS on the brain mitochondria and behavioural abnormalities, but had little or no effect on SIS-induced mitochondrial dysfunction in cardiac tissue. Conclusions This suggests that juvenile SIS predisposes the co-occurrence of depression and cardiovascular disease through mitochondrial dysfunction and that therapeutic effect of fluoxetine is partly mediated by its effect on mitochondrial function.

MELAS syndrome and cardiomyopathy: linking mitochondrial function to heart failure pathogenesis.

Heart failure remains an important clinical burden, and mitochondrial dysfunction plays a key role in its pathogenesis. The heart has a high metabolic demand, and mitochondrial function is a key determinant of myocardial performance. In mitochondrial disorders, hypertrophic remodeling is the early pattern of cardiomyopathy with progression to dilated cardiomyopathy, conduction defects and ventricular pre-excitation occurring in a significant proportion of patients. Cardiac dysfunction occurs in approximately a third of patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, a stereotypical example of a mitochondrial disorder leading to a cardiomyopathy. We performed unique comparative ultrastructural and gene expression in a MELAS heart compared with non-failing controls. Our results showed a remarkable increase in mitochondrial inclusions and increased abnormal mitochondria in MELAS cardiomyopathy coupled with variable sarcomere thickening, heterogeneous distribution of affected cardiomyocytes and a greater elevation in the expression of disease markers. Investigation and management of patients with mitochondrial cardiomyopathy should follow the well-described contemporary heart failure clinical practice guidelines and include an important role of medical and device therapies. Directed metabolic therapy is lacking, but current research strategies are dedicated toward improving mitochondrial function in patients with mitochondrial disorders.