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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.

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