Dysregulation of Mitochondrial Ca2+ Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1

Debattisti, Valentina; Horn, Adam; Singh, R. P.; Seifert, Erin L.; Hogarth, Marshall W.; Mázala, Davi A. G.; Huang, Kai Ting; Horváth, Rita; Jaiswal, Jyoti K.; Hajnóczky, György

doi:10.1016/j.celrep.2019.09.063

Cited by 69 publications

(74 citation statements)

References 56 publications

(88 reference statements)

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“…We show here that treatment with MCU-i4 and MCU-i11 inhibits myotube growth, in line with the role of MCU complex on skeletal muscle mass and function (Debattisti et al, 2019;Gherardi et al, 2019;Mammucari et al, 2015;Zampieri et al, 2016). In various other different settings, these compounds may serve as tools to modulate mitochondrial Ca 2+ -entry-dependent events.…”

Section: Discussionsupporting

confidence: 88%

“…Direct binding of these molecules to MICU1 was essential for their activity. Both compounds reduced mitochondrial Ca 2+ uptake in isolated myofibers from mouse flexor digitorum brevis (FDB) muscles and, in agreement with the role of MCU complex in skeletal muscle trophism (Debattisti et al, 2019;Gherardi et al, 2019;Mammucari et al, 2015), prevented myotube growth.…”

Section: Introductionsupporting

confidence: 70%

“…Both MCU-i4 and MCU-i11 inhibited mitochondrial Ca 2+ uptake in myofibers ( Figure 5C). Next, given that genetic inhibition of mitochondrial Ca 2+ uptake has been shown to decrease muscle mass (Debattisti et al, 2019;Gherardi et al, 2019;Mammucari et al, 2015), we used these two compounds in a well-established in vitro model mimicking myotube growth. For this purpose, we treated C2C12 myotubes with MCU-i4 and MCU-i11, respectively.…”

Section: Mcu-i4 and Mcu-i11 Reduce Mitochondrial Ca 2+ Uptake In Skelmentioning

confidence: 99%

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A High-Throughput Screening Identifies MICU1 Targeting Compounds

et al. 2020

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Section: Discussionsupporting

confidence: 88%

Section: Introductionsupporting

confidence: 70%

Section: Mcu-i4 and Mcu-i11 Reduce Mitochondrial Ca 2+ Uptake In Skelmentioning

confidence: 99%

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A High-Throughput Screening Identifies MICU1 Targeting Compounds

et al. 2020

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“…Mitochondria help repair and regenerate cells following PM injury, and defects in this process result in degenerative disease ( Boehler et al, 2019 ; Debattisti et al, 2019 ; Han et al, 2016 ; Horn et al, 2017 ; Sharma et al, 2012 ; Vila et al, 2017 ; Xu and Chisholm, 2014 ). PM injury in neurons and skeletal myofibers leads to mitochondrial traffic to the injury site, but even in cell types where mitochondria do not traffic to the injury site, mitochondrial signaling is required for repair ( Cheng et al, 2015 ; Han et al, 2016 ; Horn et al, 2017 ; Sharma et al, 2012 ; Vila et al, 2017 ; Xu and Chisholm, 2014 ; Zhou et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial fragmentation enables localized signaling required for cell repair

Horn

Raavicharla

Shah

et al. 2020

Journal of Cell Biology

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Plasma membrane injury can cause lethal influx of calcium, but cells survive by mounting a polarized repair response targeted to the wound site. Mitochondrial signaling within seconds after injury enables this response. However, as mitochondria are distributed throughout the cell in an interconnected network, it is unclear how they generate a spatially restricted signal to repair the plasma membrane wound. Here we show that calcium influx and Drp1-mediated, rapid mitochondrial fission at the injury site help polarize the repair response. Fission of injury-proximal mitochondria allows for greater amplitude and duration of calcium increase in these mitochondria, allowing them to generate local redox signaling required for plasma membrane repair. Drp1 knockout cells and patient cells lacking the Drp1 adaptor protein MiD49 fail to undergo injury-triggered mitochondrial fission, preventing polarized mitochondrial calcium increase and plasma membrane repair. Although mitochondrial fission is considered to be an indicator of cell damage and death, our findings identify that mitochondrial fission generates localized signaling required for cell survival.

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“…Biallelic pathogenic variants in one nuclear‐encoded protein, mitochondrial calcium uptake 1 (MICU1) have recently been described to cause myopathy with extrapyramidal signs (MPXPS). MPXPS has been reported in 41 cases (Table S1) and presents with myopathy, learning disability, and extrapyramidal movement disorder . The MICU1 protein regulates calcium influx into mitochondria through interaction with the mitochondrial calcium uniporter (MCU).…”

Section: Introductionmentioning

confidence: 99%

Developmental brain abnormalities and acute encephalopathy in a patient with myopathy with extrapyramidal signs secondary to pathogenic variants in MICU1

et al. 2020

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Mitochondria play a variety of roles in the cell, far beyond their widely recognized role in ATP generation. One such role is the regulation and sequestration of calcium, which is done with the help of the mitochondrial calcium uniporter (MCU) and its regulators, MICU1 and MICU2. Genetic variations in MICU1 and MICU2 have been reported to cause myopathy, developmental disability and neurological symptoms typical of mitochondrial disorders. The symptoms of MICU1/2 deficiency have generally been attributed to calcium regulation in the metabolic and biochemical roles of mitochondria. Here, we report a female child with heterozygous MICU1 variants and multiple congenital brain malformations on MRI. Specifically, she shows anterior perisylvian polymicrogyria, dysmorphic basal ganglia, and cerebellar dysplasia in addition to white matter abnormalities.These novel findings suggest that MICU1 is necessary for proper neurodevelopment through a variety of potential mechanisms, including calciummediated regulation of the neuronal cytoskeleton, Miro1-MCU complexmediated mitochondrial movement, or enhancing ATP production. This case provides new insight into the molecular pathogenesis of MCU dysfunction and may represent a novel diagnostic feature of calcium-based mitochondrial disease. K E Y W O R D S acute disseminated encephalomyelitis, genetic, MICU1, MICU1 deficiency, mitochondria, MPXPS *Katelynn M. Wilton and Joel A. Morales-Rosado co-first authors contributed equally to this work. † Mai-Lan Ho and Eva Morava co-corresponding authors contributed equally to this work.

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Dysregulation of Mitochondrial Ca2+ Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1

Cited by 69 publications

References 56 publications

A High-Throughput Screening Identifies MICU1 Targeting Compounds

A High-Throughput Screening Identifies MICU1 Targeting Compounds

Mitochondrial fragmentation enables localized signaling required for cell repair

Developmental brain abnormalities and acute encephalopathy in a patient with myopathy with extrapyramidal signs secondary to pathogenic variants in MICU1

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