My previous thoughts and explanations on calcium signaling are in ‘Theories-> Calcium Signaling and G proteins’.
Mitochondrial Calcium Uptake
How does calcium uptake into the mitochondria work?
An older theory on mitochondrial calcium uptake suggested that mitochondria act as a calcium buffer for the cytosol, and that it can take up calcium that is too much in the cytosol, but this theory seems inaccurate.
An important factor in the mitochondrial calcium uptake is the mitochondrial calcium uniporter (MCU), which is located on the mitochondrial membrane. The mitochondrial calcium uniporter can transport calcium into the mitochondria, but has low calcium affinity and doesn’t take up calcium easily from the cytosol.
A newer theory says that the mitochondria are located close to sites where calcium is released into the cell (endoplasmatic reticulum).
When the endoplasmatic reticulum (calcium storage) releases calcium this will increase calcium concentrations more in direct proximity, where the mitochondria are located.
Calcium concentrations around the mitochondria would be higher than in the cytosol on average and the high calcium would ensure that the mitochondrial calcium uniporter takes up enough calcium into the mitochondria (1).
Endoplasmatic Reticulum and Mitochondrial Calcium
A study found proof for this theory. After calcium release from the endoplasmatic reticulum was triggered with inositol triphosphate, they detected very high calcium concentrations on the outer mitochondrial membrane, calcium ‘hotspots’. This supports the idea, that a strong calcium increase near the mitochondrial calcium uniporter happens, which stimulates it to take up calcium (1b).
Also, a physical link (with proteins acting as tethers) between mitochondria and the endoplasmatic reticulum has been shown to exist, which proves that they are located in close proximity (1c).
These findings show a crucial role of calcium excretion by the endoplasmatic reticulum for calcium uptake into the mitochondria. Even though there might be enough calcium in the cytosol, if excretion from the endoplasmatic reticulum doesn’t work, this calcium might not enter into the mitochondria sufficiently to stimulate the energy metabolism there.
ATP and Calcium Signaling
ATP plays a role in calcium signaling by allowing ATPases to move calcium out of the cytosol into the endoplasmatic reticulum/ calcium storage and out of the cell. This restores low calcium concentrations in the cytosol after calcium release, and is also needed to refill the calcium storage. When the next stimulus, a neurotransmitter or an incoming calcium current activates calcium release again, the endoplasmatic reticulum needs to contain calcium.
This shows how different starting points affect calcium levels differently.
If you try to stimulate calcium release directly, for example with choline (example: acetylcholine stimulates phospholipase C), this will increase calcium in the mitochondria and cytosol, but it won’t help transport calcium back out of the cytosol that much.
If you try to support calcium signaling by increasing ATP, the ATP will first remove calcium from the cytosol and the excrete into the cytosol and mitochondria. This might result in a lower cytosolic calcium than by simply increasing phospholipase C activity.
Vitamin D Receptor and Calcium
In an animal trial, chicks fed a low-calcium diet developed decreased vitamin D receptor (VDR) mRNA levels. With a low-phosphorus diet mRNA expression was higher (3). I am wondering, if calcium can influence vitamin D receptor expression.
The body works to lower high blood calcium by reducing parathormone and raising calcitonin. If calcium levels in the cell are also high though, this might increase vitamin D receptor expression. The bigger vitamin D effect might then further increase calcium and phosphorus levels.
I am unsure of how relevant this change in gene expression is at the moment, and of how much this animal trial might apply to humans.
I’ve been looking into the role of acetylcholine, although additionally I am unsure, if choline (choline tartrate) supplements are the right way to raise acetylcholine.
There are different cholinergic receptors that react to acetylcholine and in some cases also to choline. Some cholinergic receptor subgroups stimulate phospholipase C which produces inositol triphosphate. This causes the activation of the inositol triphosphate receptor and calcium release from the endoplasmatic reticulum (5,6).
Another group of cholinergic receptors are ion channels that can let calcium, sodium and potassium enter into the cell, when acetylcholine binds to the receptor.
My idea of the effect of choline is currently, that it could be relevant for basic calcium signaling, but might increase cytosolic calcium. If cytosolic calcium is already too high, this might be a problem. Choline might work into one certain direction, while some other cofactor might increase ATP more effectively, and support calcium release into the mitochondria, while also lowering cytosolic calcium. It might depend on the individual situation, whether choline is helpful or not.
I think magnesium might be more beneficial for people who have high (cytosolic?) calcium, I’m not sure though. Magnesium is needed for ATPases to transport calcium out of the cell and can antagonize calcium in muscle cells.
I think I have a tendency for low calcium at the moment and I have the feeling that magnesium can lower my calcium even more.
I’m still looking into what supplements might support calcium signaling by raising ATP. I think Q10 levels might be relevant, but I don’t see Q10 as viable supplement at the moment and would rather try improving the biosynthesis of Q10.
I think balanced calcium concentrations in the blood, the cytosol and mitochondria are important. Calcium fulfills important functions in the cytosol and mitochondria, calcium in the cytosol can influence cholesterol synthesis and glucose metabolism (I’ll be looking into that more), and calcium can stimulate the energy metabolism in the mitochondria.
Elevated cytosolic calcium can be problematic though and ATP might help move calcium from the cytosol to the endoplasmatic reticulum. Also, functioning calcium release from the endoplasmatic reticulum is crucial for calcium to enter the mitochondria.
References (with text)