Describe briefly the sources and possible consequences of increased cytosolic calcium in cell injury.

Sources of calcium:

1. Intracellular source: Mitochondria, Endoplasmic reticulum.

2. Extracellular source.

Consequences of increased cytosolic calcium:

• The accumulation of Ca2+ in mitochondria results in opening of the mitochondrial permeability transition pore and failure of ATP generation. 
• Increased cytosolic Ca2+ activates a number of enzymes with potentially deleterious effects on cells. These enzymes include phospholipases (which cause membrane damage), proteases (which break down both  membrane and cytoskeletal proteins), endonucleases (which are responsible for DNA and chromatin  fragmentation), and ATPases (thereby hastening ATP depletion).
• Increased intracellular Ca2+ levels also result in the induction of apoptosis, by direct activation of caspases and by increasing mitochondrial permeability.

Discuss about calcium homeostasis

1.      Body calcium contents: 1.0 – 1.5 KG in adult

2.      Distribution of calcium:

a.      99% (1200 – 1400gm) in bone, predominantly as calcium phosphate crystal known as hydroxyapatite crystal.

b.      0.5% (6 – 7 gm) in soft tissue.

c.       0.1% ( 1200 – 1400 mg) in ECF.

3.      Forms of bone calcium:

a.      Labile calcium pool (0.5 – 1.0% of bone calcium). It is readily exchangeable with ECF calcium and so act as calcium buffer to maintain serum calcium in acute calcium excess or deficit.

b.      Stable calcium pool. It is slowly exchangeable with ECF calcium and function for bone remodeling.

4.      Forms of plasma calcium and plasma calcium pool:

a.      Free (ionized) calcium – 50%

b.      Protein bound calcium – 45%

c.       Soluble calcium complex with anions – 5%

d.      It is only the free calcium which is biologically active and hormonally controlled. It is the free calcium concentration that determines body calcium status as well.

5.      Calcium balance:

a.      Intake: 1000mg/day through milk, milk products, fish, meat, vegetables.

b.      Output: 1000mg/day; urine – 200mg/day, feces – 800mg/day.

c.       20 – 30% of dietary calcium is absorbed from intestine by vit-D and parathyroid hormone.

6.      Regulation of calcium balance: It is done by three hormones: active Vit-D, parathyroid hormone and calcitonin.

7.      Calcitriol synthesis is stimulated by hypocalcaemia, hypophosphatemia and PTH. But inhibited by hypercalcemia and hyperphosphatemia. Functions of calcitriol helps to:

a.      Increase intestinal absorption of calcium and phosphate.

b.      Facilitate PTH induced bone resorption and release of calcium and phosphate.

c.       Facilitate PTH induced calcium reabsorption from distal nephron.

d.      Directly suppress PTH secretion. 

Net effect is hypercalcemia & hyperphosphatemia.

8.      PTH secretion is stimulated by hypocalcaemia and hyperphosphatemia but inhibited by hypercalcemia, hypophosphatemia and calcitriol. Functions helps to:

a.      Increase bone resorption and release of calcium and phosphate.

b.      Increase calcium reabsorption from distal nephron.

c.       Inhibit phosphate reabsorption from PCT to increase renal phosphate excretion.

d.      Stimulate calcitriol synthesis to increase intestinal absorption of calcium and phosphate.

9.      Calcitonin reduces plasma calcium and phosphate by inhibiting bone reabsorption and by increasing renal clearance of calcium and phosphate, but it is of less importance in calcium and phosphate homeostasis.