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. Ca²⁺ signals of distinct spatio-temporal patterns control a plethora of signaling processes and can determine basal cellular metabolic setting, however, Ca²⁺ signals that define metabolic rewiring have not been conclusively identified and characterized. Here, we reveal the existence of a basal Ca²⁺ flux originating from extracellular space and delivered to mitochondria by Ca²⁺ leakage from inositol triphosphate receptors in mitochondria-associated membranes. This Ca²⁺ flux primes mitochondrial metabolism by maintaining glycolysis and keeping mitochondria energized for ATP production. We identified citrin, a well-defined Ca²⁺-binding component of malate-aspartate shuttle in the mitochondrial intermembrane space, as predominant target of this basal Ca²⁺ regulation. Our data emphasize that any manipulation of this ubiquitous Ca²⁺ system has the potency to initiate metabolic rewiring as an instant and reversible cellular adaptation to physiological or pathological stress.