Citrin mediated metabolic rewiring in response to altered basal subcellular Ca2+ 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.