Data from Roman, Barbara et al. J. Physiol Loss of Mitochondrial Ca²⁺ Uptake Protein 3 (MICU3) Impairs Skeletal Muscle Calcium Handling and Exercise Capacity

Mitochondrial calcium ([Ca²⁺]m) plays an essential role in bioenergetics, and loss of [Ca²⁺]m homeostasis can trigger diseases and cell death in numerous cell types. Ca²⁺ uptake into mitochondria occurs via the mitochondrial Ca²⁺ uniporter (MCU), which is regulated by 3 mitochondrial Ca²⁺ uptake (MICU) proteins localized in the intermembrane space, MICU 1, 2 and 3. We generated a mouse model of systemic MICU3 ablation and examined its physiological role in skeletal muscle. We found that loss of MICU3 led to impaired exercise capacity. When the muscles were directly stimulated there was a decrease in time to fatigue. MICU3 ablation significantly increased the maximal force of the KO muscle and altered fiber type composition with an increase in the ratio of type IIb (low oxidative capacity) to type IIa (high oxidative capacity) fibers. Furthermore, MICU3-KO mitochondria have reduced uptake of Ca²⁺ and increased phosphorylation of pyruvate dehydrogenase (PDH), indicating that KO animals contain less Ca²⁺ in their mitochondria. Skeletal muscle from MICU3-KO mice exhibited lower net oxidation of NADH during electrically stimulated muscle contraction compared with WT. These data demonstrate that MICU3 plays a role in skeletal muscle physiology by setting the proper threshold for [Ca²⁺]m uptake, which is important for matching energy demand and supply in muscle.