Table 2.
Summary genetic manipulations of mtCUC components and their impacts on mitochondrial Ca2+-handing profiles and cellular functions
| Gene Manipulation | Basal [Ca2+]mt | Mitochondrial Ca2+ Uptake | IMCU | In situ/In vivo Phenotype |
|---|---|---|---|---|
| MCU KO or KD | → (16, 61, 71) | ⇊ (1, 3, 5, 24, 25, 34, 42, 44, 51, 61, 64, 66, 69-72, 75, 85, 93, 102, 105, 106, 108, 115) | ⇊ (5, 13, 46, 69, 109) | In situ |
| →ΔΨmt (3, 24, 34, 52, 93) | ||||
| →Basal mitochondrial OCR (3, 61, 69, 85) | ||||
| ⇊Ca2+-dependent activation of the TCA cycle, OCR, and ATP production (3, 61, 69, 85, 93, 106) | ||||
| ⇊ (115) | ⇊Glucose-triggered ATP production (1) | |||
| →Mitochondrial morphology (3, 24, 42, 80, 92) | ||||
| ⇊Insulin secretion (93) | ||||
| ⇊Proinflammatory cytokine secretion (108) | ||||
| ⇊β-Hexosaminidase release in mast cells (34) | ||||
| ⇈Speed of synaptic vesicle endocytosis (75) | ||||
| →Basal mitochondrial ROS level (42, 69) | ||||
| ⇊Mitochondrial ROS level generation by stimuli (51, 69) | ||||
| ⇊Store-operated Ca2+ entry (25, 101, 105) | ||||
| →Proliferation or cell viability (19) | ||||
| ⇊Cell migration (105) | ||||
| ⇊Cell death rate by stimuli (19, 66) | ||||
| ⇈Cell death rate by stimuli (42) | ||||
| ⇊Replicative and oncogene-induced senescence (117) | ||||
| In vivo | ||||
| ⇊Exercise capacity and skeletal muscle performance (85) | ||||
| ⇊Skeletal muscle size (72) | ||||
| →I/R-mediated I/R-mediated heart injury (85) | ||||
| ⇊I/R-mediated I/R-mediated heart injury (61, 69) | ||||
| MCU-DN OX | ? | ⇊ (3, 24, 42, 81, 95, 118) | ? | In situ |
| →Basal mitochondrial OCR (95) | ||||
| ⇊Αpoptotic signaling activation by stimuli (81) | ||||
| In vivo | ||||
| →Resting heart rates (118) | ||||
| ⇊Fight-or-flight heart rate acceleration (118) | ||||
| ⇊Inotropic and lusitropic responses to stress (95) | ||||
| →Protection from I/R-mediated heart injury (109) | ||||
| MCU OX | ⇈ | ⇈ (24, 42, 81) | ⇈ (13) | In situ |
| ⇈Basal mitochondrial ROS level (81) | ||||
| ⇈Mitochondrial ROS generation by stimuli (81) | ||||
| ⇈Cell death rate by stimuli (24, 66, 81) | ||||
| ⇊ Speed of synaptic vesicle endocytosis (75) | ||||
| MCUb KD | ? | ⇈ (94) | ? | ? |
| MCUb OX | ? | ⇊ (81, 94) | ? | In situ |
| ⇊Basal mitochondrial superoxide levels (81) | ||||
| ⇊Mitochondrial superoxide generation by stimuli (81) | ||||
| ⇊Cell death rate by stimuli (81) | ||||
| EMRE KD | ⇊ (115) | ⇊ (102, 109, 115) | ⇊(102, 109) | ? |
| EMRE OX | ? | ? | ? | ? |
| MICU1 KO or KD | ⇈ (46, 71, 86, 109) | ⇈ (42, 77, 86) | ⇈ (46) | In situ |
| ⇊Basal ATP level (71) | ||||
| →(16, 21) | → (71) | →Basal respiration (89) | ||
| ⇊Glucose-triggered ATP production (1) | ||||
| ⇊(89) | ⇊ (1, 34, 50, 50, 51, 89, 91, 116) | |||
| ⇊Insulin secretion (1) | ||||
| ⇈at low [Ca2+]c elevation and ⇊at high [Ca2+]c elevation (2, 16, 21, 58) | →β-Hexosaminidase release in mast cells (34) | |||
| ⇈Basal mitochondrial ROS level (46, 71) | ||||
| →Basal mitochondrial ROS level (16, 42) | ||||
| ⇈Mitochondrial ROS generation during mitochondrial Ca2+ uptake(16) | ||||
| →Mitochondrial ROS generation by stimuli (42) | ||||
| ⇊Mitochondrial ROS generation by stimuli (50, 51) | ||||
| →Proliferation or cell viability (71) | ||||
| ⇈Cell death rate by stimuli (16, 71) | ||||
| ⇊Cell migration (46, 71) | ||||
| ⇈Oncogene-induced senescence (117) | ||||
| In vivo | ||||
| ⇊Liver regeneration and hepatocyte proliferation following partial hepatectomy (2) | ||||
| ⇈Proinflammatory response after partial hepatectomy (2) | ||||
| MICU1 OX | ? | → (58) | ? | ? |
| ⇊ (86) | ||||
| MICU2 KO or KD | ⇈ (77, 109) | ⇊ (91) | →(109) | ? |
| ⇈ (58, 77, 86) | ||||
| MICU2 OX | ? | → (58) | ? | ? |
| ⇊ (86) |
Because of the small number of publications available, MICU3, MCUR1, and SLC25A23 are omitted. All references are limited to reports using mammalian cells and tissues.
mtCUC, MCU-protein complex; [Ca2+]mt, mitochondrial Ca2+ concentration; MCU, mitochondrial Ca2+ uniporter; IMCU, MCU current; ΔΨmt, mitochondrial membrane potential; TCA, tricarboxylic acid cycle; ROS, reactive oxygen species; EMRE, essential MCU regulator; MICU, mitochondrial Ca2+ uptake; I/R, ischemia-reperfusion; KD, knockdown; KO, knockout; OX, overexpression; OCR, oxygen consumption rate.