Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex

Tsai, Chen-Wei; Rodriguez, Madison; Keuren, Anna M. Van; Phillips, Charles B; Shushunov, Hannah M.; Lee, Jessica E.; Garcia, Anastacia M.; Ambardekar, Amrut V.; Cleveland, Joseph C.; Reisz, Julie A.; Proenza, Catherine; Chatfield, Kathryn C.; Tsai, Ming-Feng

doi:10.1016/j.molcel.2022.09.006

Cited by 12 publications

(23 citation statements)

References 67 publications

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“…Hence, we suspect that MICU1, in parallel with other pathways, directly promotes muscle wasting and plays a greater role in sepsis-induced skeletal muscle weakness, as well as masking the muscle hypertrophy effect of MCU overexpression. Furthermore, we found that sepsis decreased the expression of MICU2, which plays a critical role in tuning the activity of MICU1 because its EF hands have a low Ca 2+ binding affinity (18,51). Similar experimental results were also presented by Debattisti et al (16), who found that knockdown or re-expression of MICU2 was consistent with MICU1 loss.…”

Section: Discussionmentioning

confidence: 99%

“…In our experiments, LPS increased MCU expression and decreased MICU1 expression, which caused [Ca 2+ ] m overload in the resting state. However, discussing the effects of both separately on [Ca 2+ ] m uptake in skeletal muscle is one-sided, given that different tissues, including skeletal muscle, express different quantities of MICU1 and MCU and that variations in [Ca 2+ ] m uptake properties among these tissues may be attributed to alterations in the MICU1:MCU protein ratio (18). Therefore, we calculated the protein ratio of MICU1 to MCU to accurately explore the influx of [Ca 2+ ] m and found that sepsis decreased the MICU1: MCU protein ratio, resulting in [Ca 2+ ] m overload and skeletal muscle atrophy (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Given the premise of sepsis, we suspect that the diverse trends in each protein may involve different triggering mechanisms and related factors. The lack of MICU1 considerably affects normal skeletal physiology (18). Consistent with our results, sepsis induces muscle fiber atrophy by decreasing MICU1 expression.…”

Section: Discussionmentioning

confidence: 99%

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Sepsis Leads to Impaired Mitochondrial Calcium Uptake and Skeletal Muscle Weakness by Reducing the Micu1:mcu Protein Ratio

Li,

Sun,

et al. 2023

Shock

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Purpose Intensive care unit-acquired weakness (ICUAW) is a severe neuromuscular complication that frequently occurs in patients with sepsis. The precise molecular pathophysiology of mitochondrial calcium uptake 1 (MICU1) and mitochondrial calcium uniporter (MCU) in ICUAW has not been fully elucidated. Here, we speculate that ICUAW is associated with MICU1:MCU protein ratio-mediated mitochondrial calcium ([Ca2+]m) uptake dysfunction. Methods Cecal ligation and perforation (CLP) was performed on C57BL/6 J mice to induce sepsis. Sham-operated animals were used as controls. Lipopolysaccharide (LPS) (5 μg/mL) was used to induce inflammation in differentiated C2C12 myoblasts. Compound muscle action potential (CMAP) was detected using a biological signal acquisition system. Grip strength was measured using a grip-strength meter. Skeletal muscle inflammatory factors were detected using ELISA kits. The cross-sectional area (CSA) of the tibialis anterior (TA) muscle was detected by hematoxylin and eosin staining. Cytosolic calcium ([Ca2+]c) levels were measured using Fluo-4 AM. Adeno-associated virus (AAV) was injected into TA muscles for 4 weeks to overexpress MICU1 prophylactically. A lentivirus was used to infect C2C12 cells to increase MICU1 expression prophylactically. Findings The results suggest that sepsis induces [Ca2+]m uptake disorder by reducing the MICU1:MCU protein ratio, resulting in skeletal muscle weakness and muscle fiber atrophy. However, MICU1 prophylactic overexpression reversed these effects by increasing the MICU1:MCU protein ratio. Conclusions ICUAW is associated with impaired [Ca2+]m uptake caused by a decreased MICU1:MCU protein ratio. MICU1 overexpression improves sepsis-induced skeletal muscle weakness and atrophy by ameliorating the [Ca2+]m uptake disorder.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Sepsis Leads to Impaired Mitochondrial Calcium Uptake and Skeletal Muscle Weakness by Reducing the Micu1:mcu Protein Ratio

Li,

Sun,

et al. 2023

Shock

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“…A tissue-specific isoform, MICU1.1, has been identified in skeletal muscle (Reane et al, 2016). A number of studies have examined the role of MICU1 and 2 in regulating MCUc in different tissues (Debattisti et al, 2019;Kamer & Mootha, 2014;Paillard et al, 2017;Reane et al, 2016;Shamseldin et al, 2017;Tsai et al, 2022); however there have been few studies investigating the 2019) demonstrated in neuronal tissue that MICU3 enhances Ca 2+ uptake into the mitochondria. MICU3 has been considered to be a neuronal-specific MICU and there has been little study of its role in non-neuronal tissue.…”

Section: Discussionmentioning

confidence: 99%

Loss of mitochondrial Ca²⁺ uptake protein 3 impairs skeletal muscle calcium handling and exercise capacity

Roman,

Mastoor,

Zhang

et al. 2023

The Journal of Physiology

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Mitochondrial calcium concentration ([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 three mitochondrial Ca2+ uptake (MICU) proteins localized in the intermembrane space, MICU1, 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 fibre type composition with an increase in the ratio of type IIb (low oxidative capacity) to type IIa (high oxidative capacity) fibres. Furthermore, MICU3‐KO mitochondria have reduced uptake of Ca2+ and increased phosphorylation of pyruvate dehydrogenase, 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 wild‐type. These data demonstrate that MICU3 plays a role in skeletal muscle physiology by setting the proper threshold for mitochondrial Ca2+ uptake, which is important for matching energy demand and supply in muscle. imageKey points Mitochondrial calcium uptake is an important regulator of bioenergetics and cell death and is regulated by the mitochondrial calcium uniporter (MCU) and three calcium sensitive regulatory proteins (MICU1, 2 and 3). Loss of MICU3 leads to impaired exercise capacity and decreased time to skeletal muscle fatigue. Skeletal muscle from MICU3‐KO mice exhibits a net oxidation of NADH during electrically stimulated muscle contractions, suggesting that MICU3 plays a role in skeletal muscle physiology by matching energy demand and supply.

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“…We also used rabbit antibodies against the mitochondrial Ca 2+ uniporter (MCU) (1:1,000 dilution, No. 14997, Cell Signaling Technology, Danvers, MA) ( 39 , 40 ). The signal specificity of this antibody has been previously characterized ( 41 ).…”

Section: Methodsmentioning

confidence: 99%

Nicorandil protects podocytes via modulation of antioxidative capacity in acute puromycin aminonucleoside-induced nephrosis in rats

Yamanaka

Tamura

Kuribayashi-Okuma

et al. 2023

American Journal of Physiology-Renal Physiology

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Nephrotic syndrome, characterized by proteinuria and hypoalbuminemia, results from the dysregulation of glomerular podocytes and is a significant cause of end-stage kidney disease. Patients with idiopathic nephrotic syndrome are generally treated with immunosuppressive agents; however, these agents produce various adverse effects. Previously, we reported the renoprotective effects of a stimulator of the mitochondrial ATP-dependent potassium channel (MitKATP), nicorandil, in a remnant kidney model. Nonetheless, the cellular targets of these effects remain unknown. Here, we examined the effect of nicorandil on puromycin aminonucleoside-induced nephrosis (PAN) rats, a well-established model of podocyte injury and human nephrotic syndrome. PAN was induced using a single intraperitoneal injection. Nicorandil was administered orally at 30 mg/kg/d. We found that proteinuria and hypoalbuminemia in PAN rats were significantly ameliorated following nicorandil treatment. Immunostaining and ultrastructural analysis under electron microscopy demonstrated that podocyte injury in PAN rats showed a significant partial attenuation following nicorandil treatment. Nicorandil ameliorated the increase in the oxidative stress markers nitrotyrosine and 8-hydroxy-2-deoxyguanosine in the glomeruli. Conversely, nicorandil prevented the decrease in levels of the antioxidant enzyme manganese superoxide dismutase in PAN rats. We found that the mitochondrial Ca2+ uniporter (MCU) levels in the glomeruli were higher in PAN rats than in control rats, and this increase was significantly attenuated by nicorandil. We conclude that stimulation of MitKATP by nicorandil reduces proteinuria by attenuating podocyte injury in PAN nephrosis, which restores mitochondrial antioxidative capacity, possibly through MCU modulation. These data indicate that MitKATP may represent a novel target for podocyte injury and nephrotic syndrome.

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Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex

Cited by 12 publications

References 67 publications

Sepsis Leads to Impaired Mitochondrial Calcium Uptake and Skeletal Muscle Weakness by Reducing the Micu1:mcu Protein Ratio

Sepsis Leads to Impaired Mitochondrial Calcium Uptake and Skeletal Muscle Weakness by Reducing the Micu1:mcu Protein Ratio

Loss of mitochondrial Ca²⁺ uptake protein 3 impairs skeletal muscle calcium handling and exercise capacity

Nicorandil protects podocytes via modulation of antioxidative capacity in acute puromycin aminonucleoside-induced nephrosis in rats

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Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex

Cited by 12 publications

References 67 publications

Sepsis Leads to Impaired Mitochondrial Calcium Uptake and Skeletal Muscle Weakness by Reducing the Micu1:mcu Protein Ratio

Sepsis Leads to Impaired Mitochondrial Calcium Uptake and Skeletal Muscle Weakness by Reducing the Micu1:mcu Protein Ratio

Loss of mitochondrial Ca2+ uptake protein 3 impairs skeletal muscle calcium handling and exercise capacity

Nicorandil protects podocytes via modulation of antioxidative capacity in acute puromycin aminonucleoside-induced nephrosis in rats

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Loss of mitochondrial Ca²⁺ uptake protein 3 impairs skeletal muscle calcium handling and exercise capacity