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

Abstract

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.

Comparing maximum rate and sustainability of pacing by mechanical vs. electrical stimulation in the Langendorff-perfused rabbit heart

“…Other sub-cellular compartments could include mechanically-induced calcium release from mitochondria (whose intra-organelle calcium concentrations may be similarly affected by stretch), 35 or acidic stores (e.g. lysosomes) 36 . Equally, mechanical effects on membrane domains, such as stretch-induced incorporation of caveolae into the sarcolemma, 37 have been reported and may play roles in electrical responses to MS 38 , 39 …”

The protein interaction networks of mucolipins and two-pore channels

“…Mutations of TRPML1 causes the rare neurodegenerative disease mucolipidosis type IV (MLIV), marked by neurological, ophthalmological, and gastric manifestations, but no discernible cardiac phenotype [2]. The existence of sarcoplasmic reticulum (SR)/LY microdomains were however recently described in cardiomyocytes, placing TRPML1 in tight association with the cardiac contractile machinery [78]. However, until now TRPML1 has not been recognised for specifically vascular or cardiac functions [79].…”

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

“…Albeit long considered to be standalone organelles, a great deal of evidence indicates that mitochondria interact physically and functionally with other cellular compartments via membrane contact sites and tethering molecules [9,10]. In particular, mitochondria establish connections with the endosomal compartment [11,12] and lysosomes [13,14]. These interactions support cytosolic shuttle systems of ions and metabolites across organelles [10,15], and participate to the regulation of cellular housekeeping processes [13,14].The mitochondrial-lysosomal axis is a major actor in mitochondrial quality control (MQC), a hierarchical network of pathways that ensure organellar homeostasis through the coordination of mitochondrial proteostasis, dynamics, biogenesis, and autophagy [16].…”

“…In particular, mitochondria establish connections with the endosomal compartment [11,12] and lysosomes [13,14]. These interactions support cytosolic shuttle systems of ions and metabolites across organelles [10,15], and participate to the regulation of cellular housekeeping processes [13,14].The mitochondrial-lysosomal axis is a major actor in mitochondrial quality control (MQC), a hierarchical network of pathways that ensure organellar homeostasis through the coordination of mitochondrial proteostasis, dynamics, biogenesis, and autophagy [16]. While continuous cycles of fusion and fission preserve mitochondrial shape and dilute damage along the network [17] mitochondrial hyper-fission segregates damaged or unnecessary organelles from the network [17].…”