Direct activation of the mitochondrial calcium uniporter by natural plant flavonoids (original) (raw)

2004, Biochemical Journal

During cell activation, mitochondria play an important role in Ca 2+ homoeostasis due to the presence of a fast and specific Ca 2+ channel in its inner membrane, the mitochondrial Ca 2+ uniporter. This channel allows mitochondria to buffer local cytosolic [Ca 2+ ] changes and controls the intramitochondrial Ca 2+ levels, thus modulating a variety of phenomena from respiratory rate to apoptosis. We have described recently that SB202190, an inhibitor of p38 MAPK (mitogen-activated protein kinase), strongly activated the uniporter. We show in the present study that a series of natural plant flavonoids, widely distributed in foods, produced also a strong stimulation of the mitochondrial Ca 2+ uniporter. This effect was of the same magnitude as that induced by SB202190 (an approx. 20-fold increase in the mitochondrial Ca 2+ uptake rate), developed without measurable delay and was rapidly reversible. In intact cells, the mitochondrial Ca 2+ peak induced by histamine was also largely increased by the flavonoids. Stimulation of the uniporter by either flavonoids or SB202190 did not require ATP, suggesting a direct effect on the uniporter or an associated protein which is not mediated by protein phosphorylation. The most active compound, kaempferol, increased the rate of mitochondrial Ca 2+ uptake by 85 + − 15 % (mean + − S.E.M., n = 4) and the histamine-induced mitochondrial Ca 2+ peak by 139 + − 19 % (mean + − S.E.M., n = 5) at a concentration of 1 µM. Given that flavonoids can reach this concentration range in plasma after ingestion of flavonoid-rich food, these compounds could be modulating the uniporter under physiological conditions.

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