Calcium and ATP handling in human NADH:Ubiquinone oxidoreductase deficiency

Proper cell functioning requires precise coordination between mitochondrial ATP production and local energy demand. Ionic calcium (Ca2+) plays a central role in this coupling because it activates mitochondrial oxidative phosphorylation (OXPHOS) during hormonal and electrical cell stimulation. To determine how mitochondrial dysfunction affects cytosolic and mitochondrial Ca2+/ATP handling, we performed life-cell quantification of these parameters in fibroblast cell lines derived from healthy subjects and patients with isolated deficiency of the first OXPHOS complex (CI). In resting patient cells, CI deficiency was associated with a normal mitochondrial ([ATP]m) and cytosolic ([ATP]c) ATP concentration, a normal cytosolic Ca2+ concentration ([Ca2+]c), but a reduced Ca2+ content of the endoplasmic reticulum (ER). Furthermore, cellular NAD(P)H levels were increased, mitochondrial membrane potential was slightly depolarized, reactive oxygen species (ROS) levels were elevated and mitochondrial shape was altered. Upon stimulation with bradykinin (Bk), the peak increases in [Ca2+]c, mitochondrial Ca2+ concentration ([Ca2+]m), [ATP]c and [ATP]m were reduced in patient cells. In agreement with these results, ATP-dependent Ca2+ removal from the cytosol was slower. Here, we review the interconnection between cytosolic, endoplasmic reticular and mitochondrial Ca2+ and ATP handling, and summarize our findings in patient fibroblasts in an integrative model.