Mitochondria and arrhythmias

Yang, Kai-Chien; Bonini, Marcelo G.; Dudley, Samuel C.

doi:10.1016/j.freeradbiomed.2014.03.033

Cited by 113 publications

(111 citation statements)

References 208 publications

(258 reference statements)

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“…Mitochondria are the major source of ATP that provides the energy to support myocardial contraction and maintenance of ionic homeostasis and cellular integrity (21,22,61). Under physiological conditions, Ͼ90% of energy production required for heart function comes from mitochondria and is dependent on activity of the multisubunit complexes forming the ETC (complexes I-IV) that generates the proton-motive force driving ATP synthesis through complex V. The activities of the ETC and ATP synthesis are tightly regulated to match ATP supply and demand in the heart during physiological workload (22).…”

Section: Discussionmentioning

confidence: 99%

“…Although the pathophysiology of AF has been well characterized, the underlying mechanisms that contribute to the progression of AF in human atria have not been fully defined (33,35,57,58,60). Mitochondria, occupying 30% of cardiomyocyte volume, are critical for maintaining normal energetics of the heart, a highly aerobic organ dependent on oxidative phosphorylation (OXPHOS) for maintenance of its normal electrical and mechanical function (1,61). Imbalance in the production of high-energy phosphate compounds and metabolic oscillations with supply-demand mismatch in adenosine 5=-triphosphate (ATP) can affect cardiac electrical activity through impact on ion channels (5a, 11, 15, 27), oxidative stress, and regulation of cell death/survival signaling (12,17,56,59), which increases predisposition to arrhythmogenesis.…”

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confidence: 99%

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Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation

Emelyanova

Ashary

Cosic

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation. Am J Physiol Heart Circ Physiol 311: H54 -H63, 2016. First published May 6, 2016 doi:10.1152/ajpheart.00699.2015Mitochondria are critical for maintaining normal cardiac function, and a deficit in mitochondrial energetics can lead to the development of the substrate that promotes atrial fibrillation (AF) and its progression. However, the link between mitochondrial dysfunction and AF in humans is still not fully defined. The aim of this study was to elucidate differences in the functional activity of mitochondrial oxidative phosphorylation (OXPHOS) complexes and oxidative stress in right atrial tissue from patients without (non-AF) and with AF (AF) who were undergoing open-heart surgery and were not significantly different for age, sex, major comorbidities, and medications. The overall functional activity of the electron transport chain (ETC), NADH:O2 oxidoreductase activity, was reduced by 30% in atrial tissue from AF compared with non-AF patients. This was predominantly due to a selective reduction in complex I (0.06 Ϯ 0.007 vs. 0.09 Ϯ 0.006 nmol·min Ϫ1 ·citrate synthase activity Ϫ1 , P ϭ 0.02) and II (0.11 Ϯ 0.012 vs. 0.16 Ϯ 0.012 nmol·min Ϫ1 ·citrate synthase activity Ϫ1 , P ϭ 0.003) functional activity in AF patients. Conversely, complex V activity was significantly increased in AF patients (0.21 Ϯ 0.027 vs. 0.12 Ϯ 0.01 nmol·min Ϫ1 ·citrate synthase activity Ϫ1 , P ϭ 0.005). In addition, AF patients exhibited a higher oxidative stress with increased production of mitochondrial superoxide (73 Ϯ 17 vs. 11 Ϯ 2 arbitrary units, P ϭ 0.03) and 4-hydroxynonenal level (77.64 Ϯ 30.2 vs. 9.83 Ϯ 2.83 ng·mg Ϫ1 protein, P ϭ 0.048). Our findings suggest that AF is associated with selective downregulation of ETC activity and increased oxidative stress that can contribute to the progression of the substrate for AF. atrial fibrillation; humans; mitochondria; electron transport chain complexes; oxidative phosphorylation; oxidative stress; superoxide; 4-hydroxynonenal protein adducts NEW & NOTEWORTHYThe study provides evidence of a selective downregulation of mitochondrial electron transport chain functional activity predominantly affecting complexes I and II and associated increase ATRIAL FIBRILLATION (AF), a rapid irregular rhythm of the atria, is associated with electrical, functional, and structural changes in the atria that promote the substrate for its recurrence and progression (36, 53, 60). The incidence and prevalence of AF increase with advancing age and aging-associated diseases such as hypertension, ischemic heart disease, and heart failure (2, 40) and contribute to increased morbidity, particularly an increased risk for stroke, heart failure, and death (25,52). Although the pathophysiology of AF has been well characterized, the underlying mechanisms that contribute to the progression of AF in human atria have not been fully defined (33,35,57,58,60). Mitochondria, occupying 30% ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation

Emelyanova

Ashary

Cosic

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…Indeed, in CMs, a complex network involving plasmalemma, SR receptors (namely, Rya, but also IP3 receptors), and mitochondria is responsible for fine-tuning cytosolic Ca 2þ (72)(73)(74). In this interplay, the mitochondria serve as an efficient dynamic buffer of the Ca 2þ released during contraction.…”

Section: Discussionmentioning

confidence: 99%

Biochemical and Electrophysiological Modification of Amyloid Transthyretin on Cardiomyocytes

Sartiani

Bucciantini

Spinelli

et al. 2016

Biophysical Journal

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Transthyretin (TTR) amyloidoses are familial or sporadic degenerative conditions that often feature heavy cardiac involvement. Presently, no effective pharmacological therapy for TTR amyloidoses is available, mostly due to a substantial lack of knowledge about both the molecular mechanisms of TTR aggregation in tissue and the ensuing functional and viability modifications that occur in aggregate-exposed cells. TTR amyloidoses are of particular interest regarding the relation between functional and viability impairment in aggregate-exposed excitable cells such as peripheral neurons and cardiomyocytes. In particular, the latter cells provide an opportunity to investigate in parallel the electrophysiological and biochemical modifications that take place when the cells are exposed for various lengths of time to variously aggregated wild-type TTR, a condition that characterizes senile systemic amyloidosis. In this study, we investigated biochemical and electrophysiological modifications in cardiomyocytes exposed to amyloid oligomers or fibrils of wild-type TTR or to its T4-stabilized form, which resists tetramer disassembly, misfolding, and aggregation. Amyloid TTR cytotoxicity results in mitochondrial potential modification, oxidative stress, deregulation of cytoplasmic Ca 2þ levels, and Ca 2þ cycling. The altered intracellular Ca 2þ cycling causes a prolongation of the action potential, as determined by whole-cell recordings of action potentials on isolated mouse ventricular myocytes, which may contribute to the development of cellular arrhythmias and conduction alterations often seen in patients with TTR amyloidosis. Our data add information about the biochemical, functional, and viability alterations that occur in cardiomyocytes exposed to aggregated TTR, and provide clues as to the molecular and physiological basis of heart dysfunction in sporadic senile systemic amyloidosis and familial amyloid cardiomyopathy forms of TTR amyloidoses.

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“…3f). Mounting evidence suggests that mitochondria are the primary source of ROS [39], and reduced activities of the mitochondrial respiratory chain complexes can result in the overproduction of mitochondrial ROS (mtROS) at the expense of ATP production [40]. Moreover, excessive mtROS production can promote oxidative stress and cause oxidative damage in tissues [41].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Dihydromyricetin Attenuates Dexamethasone-Induced Muscle Atrophy by Improving Mitochondrial Function via the PGC-1α Pathway

Huang¹,

Chen²,

Ren³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Skeletal muscle atrophy is an important health issue and can impose tremendous economic burdens on healthcare systems. Glucocorticoids (GCs) are well-known factors that result in muscle atrophy observed in numerous pathological conditions. Therefore, the development of effective and safe therapeutic strategies for GC-induced muscle atrophy has significant clinical implications. Some natural compounds have been shown to effectively prevent muscle atrophy under several wasting conditions. Dihydromyricetin (DM), the most abundant flavonoid in Ampelopsis grossedentata, has a broad range of health benefits, but its effects on muscle atrophy are unclear. The purpose of this study was to evaluate the effects and underlying mechanisms of DM on muscle atrophy induced by the synthetic GC dexamethasone (Dex). Methods: The effects of DM on Dex-induced muscle atrophy were assessed in Sprague-Dawley rats and L6 myotubes. Muscle mass and myofiber cross-sectional areas were analyzed in gastrocnemius muscles. Muscle function was evaluated by a grip strength test. Myosin heavy chain (MHC) content and myotube diameter were measured in myotubes. Mitochondrial morphology was observed by transmission electron microscopy and confocal laser scanning microscopy. Mitochondrial DNA (mtDNA) was quantified by real-time PCR. Mitochondrial respiratory chain complex activities were examined using the MitoProfile Rapid Microplate Assay Kit, and mitochondrial membrane potential was assessed by JC-1 staining. Protein levels of mitochondrial biogenesis and dynamics markers were detected by western blotting. Myotubes were transfected with siRNAs targeting peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), mitochondrial transcription factor A (TFAM) and mitofusin-2 (mfn2) to determine the underlying mechanisms. Results: In vivo, DM preserved muscles from weight and average fiber cross-sectional area losses and improved grip strength. In vitro, DM prevented the decrease in MHC content and myotube diameter. Moreover, DM stimulated mitochondrial biogenesis and promoted mitochondrial fusion, rescued the reduced mtDNA content, improved mitochondrial morphology, prevented the collapse in mitochondrial membrane potential and enhanced mitochondrial respiratory chain complex activities; these changes restored mitochondrial function and improved protein metabolism, contributing to the prevention of Dex-induced muscle atrophy. Furthermore, the protective effects of DM on mitochondrial function and muscle atrophy were alleviated by PGC-1α siRNA, TFAM siRNA and mfn2 siRNA transfection in vitro. Conclusion: DM attenuated Dex-induced muscle atrophy by reversing mitochondrial dysfunction, which was partially mediated by the PGC-1α/TFAM and PGC-1α/mfn2 signaling pathways. Our findings may open new avenues for identifying natural compounds that improve mitochondrial function as promising candidates for the management of muscle atrophy.

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Mitochondria and arrhythmias

Cited by 113 publications

References 208 publications

Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation

Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation

Biochemical and Electrophysiological Modification of Amyloid Transthyretin on Cardiomyocytes

Dihydromyricetin Attenuates Dexamethasone-Induced Muscle Atrophy by Improving Mitochondrial Function via the PGC-1α Pathway

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