Chromaffin-cell stimulation triggers fast millimolar mitochondrial Ca2+ transients that modulate secretion

Abstract

Activation of calcium-ion (Ca²⁺) channels on the plasma membrane and on intracellular Ca²⁺ stores, such as the endoplasmic reticulum, generates local transient increases in the cytosolic Ca²⁺ concentration that induce Ca²⁺ uptake by neighbouring mitochondria. Here, by using mitochondrially targeted aequorin proteins with different Ca²⁺ affinities, we show that half of the chromaffin-cell mitochondria exhibit surprisingly rapid millimolar Ca²⁺ transients upon stimulation of cells with acetylcholine, caffeine or high concentrations of potassium ions. Our results show a tight functional coupling of voltage-dependent Ca²⁺ channels on the plasma membrane, ryanodine receptors on the endoplasmic reticulum, and mitochondria. Cell stimulation generates localized Ca²⁺ transients, with Ca²⁺ concentrations above 20–40 µM, at these functional units. Protonophores abolish mitochondrial Ca²⁺ uptake and increase stimulated secretion of catecholamines by three- to fivefold. These results indicate that mitochondria modulate secretion by controlling the availability of Ca²⁺ for exocytosis.