Citrin mediated metabolic rewiring in response to altered basal subcellular Ca(2+) homeostasis

In contrast to long-term metabolic reprogramming, metabolic rewiring represents an instant and reversible cellular adaptation to physiological or pathological stress. Ca(2+) signals of distinct spatio-temporal patterns control a plethora of signaling processes and can determine basal cellular metabolic setting, however, Ca(2+) signals that define metabolic rewiring have not been conclusively identified and characterized. Here, we reveal the existence of a basal Ca(2+) flux originating from extracellular space and delivered to mitochondria by Ca(2+) leakage from inositol triphosphate receptors in mitochondria-associated membranes. This Ca(2+) flux primes mitochondrial metabolism by maintaining glycolysis and keeping mitochondria energized for ATP production. We identified citrin, a well-defined Ca(2+)-binding component of malate-aspartate shuttle in the mitochondrial intermembrane space, as predominant target of this basal Ca(2+) regulation. Our data emphasize that any manipulation of this ubiquitous Ca(2+) system has the potency to initiate metabolic rewiring as an instant and reversible cellular adaptation to physiological or pathological stress.