Mitochondria and Ca2+ in cell physiology and pathophysiology
M. R. Duchen
There is now a consensus that mitochondria take up and accumulate Ca2+ during physiological [Ca2+]c signalling. This contribution will consider some of the functional consequences of mitochondrial Ca2+ uptake for cell physiology and pathophysiology. The ability to remove Ca2+ from local cytosol enables mitochondria to regulate the [Ca2+] in microdomains close to IP3-sensitive Ca2-release channels. The [Ca2+] sensitivity of these channels means that, by regulating local [Ca2+]c, mitochondrial Ca2+ uptake modulates the rate and extent of propagation of [Ca2+]c waves in a variety of cell types. The coincidence of mitochondrial Ca2+ 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 Ca2 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 Ca2+ overload coincident with NO production also causes loss of mitochondrial potential and cell death, but mPTP involvement has proven more difficult to demonstrate unequivocally.