Direct activation of the mitochondrial calcium uniporter by natural plant flavonoids.
During cell activation, mitochondria play an important role in Ca2+ homoeostasis due to the presence of a fast and specific Ca2+ channel in its inner membrane, the mitochondrial Ca2+ uniporter. This channel allows mitochondria to buffer local cytosolic [Ca2+] changes and controls the intramitochondrial Ca2+ 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 Ca2+ uniporter. This effect was of the same magnitude as that induced by SB202190 (an approx. 20-fold increase in the mitochondrial Ca2+ uptake rate), developed without measurable delay and was rapidly reversible. In intact cells, the mitochondrial Ca2+ 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 Ca2+ uptake by 85+/-15% (mean+/-S.E.M., n=4) and the histamine-induced mitochondrial Ca2+ peak by 139+/-19% (mean+/-S.E.M., n=5) at a concentration of 1 microM. 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.
Instituto de Biología y Genética Molecular, Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid and Consejo Superior de Investigaciones Científicas, Ramón y Cajal, 7, E-47005 Valladolid, Spain.
Mayte
M
Montero
Carmen D
CD
Lobatón
Esther
E
Hernández-Sanmiguel
Jaime
J
Santodomingo
Laura
L
Vay
Alfredo
A
Moreno
Javier
J
Alvarez
D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000502:physiology*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000502:physiology; D015394:Molecular Structure
D002135:Calcium-Binding Proteins; D005419:Flavonoids; D024101:Mitochondrial Proteins; D002118:Calcium