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

Abstract

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% ...

Age-dependent atrial arrhythmic phenotype secondary to mitochondrial dysfunction in Pgc-1β deficient murine hearts

“…Here, AF was induced by rapid atrial pacing with the noted mitochondrial defects appearing as a possible consequence of the pacing protocol and/or AF itself. Similarly, evidence of mitochondrial abnormalities have been reported in tissue samples obtained during cardiac surgery from AF patients ( Emelyanova et al, 2016 , Lin et al, 2003 , Slagsvold et al, 2014 , Tsuboi et al, 2001 ). In these studies the selected cohorts had established AF and it remains difficult to distinguish whether the observed mitochondrial lesions were caused by or resulted from AF, or indeed were a confound of ageing or other age-related conditions associated with metabolic compromise.…”

Angiotensin II affects inflammation mechanisms via AMPK-related signalling pathways in HL-1 atrial myocytes

“…All these parameters were decreased upon Ang ІІ treatment. This downregulation of mitochondria electron transport activity is correlated with mitochondria dysfunction by oxidative stress during atrial inflammation 23 . To understand the involvement of ROS in atrial inflammation, we quantified ROS levels in HL-1 cells upon Ang ІІ treatment using DCFDA dye (Fig.…”

Reduced density and altered regulation of rat atrial L-type Ca2+current in heart failure

“…Atrial I CaL is also regulated by NO through complex pathways involving cGMPdependent PKG, cGMP-inhibited phosphodiesterases, and Snitrosylation of the ␣ 1c -subunit (31,40,47,49). It has been suggested that oxidative stress may contribute to the development of the arrhythmic substrate and downregulation of I CaL during atrial remodeling and this may involve changes in the NO-dependent regulation of L-type Ca 2ϩ channels (11,21,43). The previously reported changes in atrial intracellular cGMP production together with the increased effect of phosphodiesterase inhibition on I CaL are consistent with the proposal that changes in NO/cGMP-dependent regulation of Ltype Ca 2ϩ channels may underlie both the reduced basal current and increased sensitivity to noradrenergic agonism in heart failure (4,19).…”