Figure 5. Consequences of MICU1/2 loss on mitochondrial Ca²⁺ homeostasis, shape and metabolic function.

A, relationship between cytosolic and mitochondrial [Ca²⁺] during evoked Ca²⁺ signals. MICU1/2 defective cells have an increased basal mitochondrial Ca²⁺ load, which follows linearly the increase in cytoplasmic [Ca²⁺] (reproduced with permission from Logan et al. 2014). B, increased mitochondrial Ca²⁺ load can activate mitochondrial metabolism by stimulating Ca²⁺-dependent dehydrogenases of the mitochondrial matrix. On the other hand, chronic Ca²⁺ load in the mitochondrion might also have also a metabolic cost by resulting in futile Ca²⁺ cycling (inset) and opening of the mitochondrial permeability transition pore (mPTP), both leading to depolarization. In addition, we observed increased mitochondrial fission, which might impact on the metabolic capacity of the organelle. In the human fibroblast model of the disease, no changes in ER mitochondria tethering were observed. mfn2, mitofusin 2; ERMES, ER-mitochondria encounter structures; Miro, mitochondrial Rho GTPase; MINOS: MINOS/MitOS/MICOS complexes; RC, respiratory supercomplexes; F1/FO, F1FO ATPase.