Inhibition of NAADP signalling on reperfusion protects the heart by preventing lethal calcium oscillations via two-pore channel 1 and opening of the mitochondrial permeability transition pore

Davidson, Sean M.; Foote, Kirsty; Kunuthur, Suma; Gosain, Raj; Tan, N.; Tyser, Richard; Zhao, Yong; Graeff, Richard; Ganesan, A.; Duchen, Michael R.; Patel, Sandip; Yellon, Derek M.

doi:10.1093/cvr/cvv226

Cited by 44 publications

(53 citation statements)

References 59 publications

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“…The results described in this paper provide clear structural evidence for nanojunctions between lysosomes and both the SR and mitochondria in rabbit ventricular myocytes; observations of the ultrastructural organisation which support the plausibility of earlier functional hypotheses23203543. Further, we have used Ned-19 and LysoTracker staining in live cells to localise NAADP-binding sites and showed that NAADP binding is restricted to acidic organelles in cardiac myocytes.…”

Section: Discussionsupporting

confidence: 84%

“…This information is important for constraining functional models of the calcium signalling roles of NAADP in the heart at rest and it is relevant to the contribution of NAADP signalling in the β-adrenergic response. Further, we investigated the proximity of lysosomes to mitochondria, in light of recent evidence supporting the role of NAADP signalling via TPC1 in ischaemia/reperfusion injury35.…”

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confidence: 99%

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High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with Acidic Stores (lysosomes) in the heart

Aston

Capel

Ford

et al. 2017

Sci Rep

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Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) stimulates calcium release from acidic stores such as lysosomes and is a highly potent calcium-mobilising second messenger. NAADP plays an important role in calcium signalling in the heart under basal conditions and following β-adrenergic stress. Nevertheless, the spatial interaction of acidic stores with other parts of the calcium signalling apparatus in cardiac myocytes is unknown. We present evidence that lysosomes are intimately associated with the sarcoplasmic reticulum (SR) in ventricular myocytes; a median separation of 20 nm in 2D electron microscopy and 3.3 nm in 3D electron tomography indicates a genuine signalling microdomain between these organelles. Fourier analysis of immunolabelled lysosomes suggests a sarcomeric pattern (dominant wavelength 1.80 μm). Furthermore, we show that lysosomes form close associations with mitochondria (median separation 6.2 nm in 3D studies) which may provide a basis for the recently-discovered role of NAADP in reperfusion-induced cell death. The trigger hypothesis for NAADP action proposes that calcium release from acidic stores subsequently acts to enhance calcium release from the SR. This work provides structural evidence in cardiac myocytes to indicate the formation of microdomains between acidic and SR calcium stores, supporting emerging interpretations of NAADP physiology and pharmacology in heart.

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Section: Discussionsupporting

confidence: 84%

mentioning

confidence: 99%

High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with Acidic Stores (lysosomes) in the heart

Aston

Capel

Ford

et al. 2017

Sci Rep

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“…Decreased mitochondrial calcium levels inhibited the depolarization of the mitochondrial membrane and led to cardioprotection. Davidson and colleagues focused on calcium handling and secondary messenger NAADP, testing the hypothesis of cardioprotection using an NAADP antagonist Ned-K. Post ischemia-reperfusion they observed a cardiomyocyte protective mechanism by preventing the opening of the mitochondrial permeability transition pore [38]. …”

Section: Mitochondrial Transcription Factor a (Tfam)mentioning

confidence: 99%

Mitochondrial pathways to cardiac recovery: TFAM

2016

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Mitochondrial dysfunction underlines a multitude of pathologies; however, studies are scarce that rescue the mitochondria for cellular resuscitation. Exploration into the protective role of mitochondrial Transcription factor A (TFAM) and its mitochondrial functions respective to cardiomyocyte death are in need of further investigation. TFAM is a gene regulator that acts to mitigate calcium mishandling and ROS production by wrapping around mitochondrial DNA (mtDNA) complexes. TFAM’s regulatory functions over serca2a, NFAT and Lon protease contribute to cardiomyocyte stability. Calcium and ROS dependent proteases, calpains and matrix metallo-proteinases (MMP’s) are abundantly found upregulated in the failing heart. TFAM’s regulatory role over ROS production and calcium mishandling leads to further investigation into the cardioprotective role of exogenous TFAM. In an effort to restabilize physiological and contractile activity of cardiomyocytes in HF models, we propose that TFAM-packed exosomes (TFAM-PE) will act therapeutically by mitigating mitochondrial dysfunction. Notably, this is the first mention of exosomal delivery of transcription factors in the literature. Here we elucidate the role of TFAM in mitochondrial rescue and focus on its therapeutic potential.

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“…A further development concerning the role of NAADP and TPCs during ischaemia and reperfusion is the observation that an antagonist of NAADP that is structurally related to Ned-19 (termed Ned-K) suppressed Ca 2+ oscillations in rat cardiomyocytes exposed to simulated ischaemia and reoxygenation (Davidson et al, 2015). Ned-K also reduced cell death under these conditions.…”

Section: Other Sites For Naadp Actionmentioning

confidence: 99%

“…In addition, in whole hearts subjected to ischaemia and reperfusion, Ned-19 reduced infarct size. Another important observation was that hearts from transgenic mice lacking TPC1 proteins also showed reduced reperfusion injury compared with WT controls (Davidson et al, 2015).…”

Section: Other Sites For Naadp Actionmentioning

confidence: 99%

The Roles of NAADP, Two Pore Channels and Lysosomes in Ca<SUP>2+</SUP> Signaling in Cardiac Muscle

Terrar¹

2015

messenger

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Evidence concerning the effects of NAADP in heart muscle is reviewed and provides a convincing case for actions of endogenous NAADP to enhance Ca 2+ transients accompanying action potentials in both ventricular and atrial cardiac myocytes. The mechanism supplements the accepted scheme for excitation-contraction coupling by which Ca 2+ entry through L-type Ca 2+ channels triggers further release of Ca 2+ from the sarcoplasmic reticulum (SR) to generate Ca 2+ transients accompanying action potentials. Actions of NAADP in cardiac myocytes depend on lysosomes. Effects of NAADP lead to Ca 2+ release from lysosomes via TPC2 proteins. L-type Ca 2+ channels remain unaffected by NAADP under these conditions. When Ca 2+ transients accompanying action potentials are enhanced following actions of NAADP, at least some effects are associated with an increased amount of Ca 2+ loaded into the SR. Whether these effects on SR Ca 2+ content are sufficient to account for the actions of NAADP on Ca 2+ transients associated with action potentials remains to be established, and additional effects on ryanodine receptors (RyRs) that arise from cytosolic NAADP or associated local changes in cytosolic Ca 2+ close to RyRs must also be considered. NAADP is synthesized by ADP-ribosyl cyclase, probably associated with SR membranes. When -adrenoceptors are activated, there is an increase in endogenous NAADP levels contributing to the increase in amplitude of Ca 2+ transients accompanying action potentials. Excessive stimulation of this pathway causes arrhythmias, and chronic stimulation leads to both hypertrophy and arrhythmias. The observations support a role for NAADP and TPC2 proteins in both acute and chronic effects of -adrenoceptor stimulation in the heart.

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Inhibition of NAADP signalling on reperfusion protects the heart by preventing lethal calcium oscillations via two-pore channel 1 and opening of the mitochondrial permeability transition pore

Cited by 44 publications

References 59 publications

High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with Acidic Stores (lysosomes) in the heart

High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with Acidic Stores (lysosomes) in the heart

Mitochondrial pathways to cardiac recovery: TFAM

The Roles of NAADP, Two Pore Channels and Lysosomes in Ca<SUP>2+</SUP> Signaling in Cardiac Muscle

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