References with Text

1.https://www.sciencedirect.com/science/article/pii/S0005272810005797

‘In order to reconcile in vitro experiments that unambiguously proved the low Ca2+ affinity of mCU with the data obtained by measurement of [Ca2+]m in intact cells, the so-called “microdomain hypothesis” was proposed [43,44]. According to this hypothesis, the fast mitochondrial Ca2+ uptake in intact cells depends on the close apposition between mitochondria and the sites of Ca2+ release/influx. In other words, the mCU in intact living cells can locally experience a [Ca2+] that is much higher than that measured in the bulk cytosol, i.e., high enough to ensure a strong activation of the uptake mechanism. The hypothesis was supported by a large body of indirect evidence, though the existence and amplitude of high Ca2+ microdomains on the surface of mitochondria was demonstrated directly only very recently (see below Section 3.1).’

mCU= mitochondrial calcium unipoter

1.b https://www.sciencedirect.com/science/article/pii/S0005272810005797

‘However, despite the fact that the “Ca2+ microdomain” hypothesis was taken for granted by most investigators thanks to the indirect experimental evidence mentioned above, a direct proof of Ca2+ microdomains existence on mitochondrial surface was reached only very recently by our group [100].In order to monitor in the very same cell OMM and bulk cytosolic Ca2+ variations upon cellular stimulation a nuclear and a OMM new generation FRET-based Ca2+ sensors ([60], see section 2) were generated. In cells co-transfected with OMM and nuclear targeted Ca2+ probes (challenged with an IP3 generating stimulus) we found that the mean Ca2+ rise in the two compartments appears almost indistinguishable (Fig. 1A). However, a more sophisticated statistical analysis of the images reveals the existence of small OMM, but not nuclear, regions whose [Ca2+] reaches values as high as 15–20 µM (Fig. 1B). An estimation made on the first 4 s after the stimulation shows that at least 10% of OMM surface is covered by these hot spots during the transient increase in cytosolic Ca2+ elicited by IP3 production. Classical epifluorescence and TIRF experiments were then combined in order to monitor the generation of high Ca2+ microdomains in mitochondria located near plasma membrane. By this approach we could show that Ca2+ hot spots on the surface of mitochondria occur upon opening of voltage operated calcium channels (VOCCs), but not upon capacitative Ca2+ entry (CCE). From these data and also from those of Korzeniowski and colleagues [101], it can be concluded that upon CCE activation the close apposition between Orai1 channels (located in the PM; [102]) and STIM1 (located in ER “punctae” near PM; [103]) does not allow mitochondria to be in sufficient proximity to the mouth of the PM channels to sense the local [Ca2+] hot spots. The main mechanisms participating in mitochondrial Ca2+ homeostasis and Ca2+ microdomains generation are summarized in Fig. 2.’

OMM= Outer Mitochondrial Membrane
IP3= Inositol triphosphate
PM= Plasma membrane

1.c https://www.sciencedirect.com/science/article/pii/S0005272810005797

‘the proximity of mitochondria to Ca2+ release sites is also supported by the demonstration that a physical linker between the two organelles exists [95] and also by the identification of proteins that can act as tethers, like grp75, a chaperone linking VDAC1 and IP3R [96], and mitofusin-2, that is expressed in ER and mitochondria surfaces and forms homodimers or heterodimers with mitofusin-1 [97,98].’

ER= endoplasmatic reticulum

2. https://www.ncbi.nlm.nih.gov/pubmed/1376958

‘Chickens fed a low-phosphorus diet displayed a twofold increase in VDR mRNA, but those fed a low-calcium diet exhibited a dramatic decrease in VDR mRNA’
VDR= vitamin D receptor

3. https://www.ebi.ac.uk/interpro/potm/2005_11/Page2.htm

4. https://en.wikipedia.org/wiki/Acetylcholine_receptor

http://www.genome.jp/kegg-bin/show_pathway?hsa04020
Calcium Signaling Pathway on KEGG

http://www.genome.jp/kegg-bin/show_pathway?hsa04725
KEGG Cholinergic synapse pathway