Mitochondria and Ca(2+)in cell physiology and pathophysiology.
There is now a consensus that mitochondria take up and accumulate Ca(2+)during physiological [Ca(2+)](c)signalling. This contribution will consider some of the functional consequences of mitochondrial Ca(2+)uptake for cell physiology and pathophysiology. The ability to remove Ca(2+)from local cytosol enables mitochondria to regulate the [Ca(2+)] in microdomains close to IP3-sensitive Ca(2+)-release channels. The [Ca(2+)] sensitivity of these channels means that, by regulating local [Ca(2+)](c), mitochondrial Ca(2+)uptake modulates the rate and extent of propagation of [Ca(2+)](c)waves in a variety of cell types. The coincidence of mitochondrial Ca(2+)uptake with oxidative stress may open the mitochondrial permeability transition pore (mPTP). This is a catastrophic event for the cell that will initiate pathways to cell death either by necrotic or apoptotic pathways. A model is presented in which illumination of an intramitochondrial fluorophore is used to generate oxygen radical species within mitochondria. This causes mitochondrial Ca(2+)loading from SR and triggers mPTP opening. In cardiomyocytes, mPTP opening leads to ATP consumption by the mitochondrial ATPase and so results in ATP depletion, rigor and necrotic cell death. In central mammalian neurons exposed to glutamate, a cellular Ca(2+)overload coincident with NO production also causes loss of mitochondrial potential and cell death, but mPTP involvement has proven more difficult to demonstrate unequivocally.
Duchen
M R
MR
Mitochondrial Biology Group and Life Sciences Imaging Consortium, Department of Physiology, University College London, Gower Street, London, WC1E 6BT, UK. m.duchen@ucl.ac.uk
D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D005971:Glutamates / Q000633:toxicity; D008928:Mitochondria / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D018384:Oxidative Stress
D015220:Calcium Channels; D005971:Glutamates; D009498:Neurotoxins; D002118:Calcium