Reporting a rare form of myopathy, myopathy with extrapyramidal signs, in an Iranian family using next generation sequencing: a case report

Mojbafan, Marzieh; Nojehdeh, Somayeh Takrim; Rahiminejad, Faezeh; Nilipour, Yalda; Tonekaboni, Seyed Hasan; Zeinali, Sirous

doi:10.1186/s12881-020-01016-y

Cited by 12 publications

(11 citation statements)

References 24 publications

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“…In this study, we showed that neuron-specific homozygous MICU1 deletion in mouse leads to altered neuronal Ca 2+ homeostasis and progressive motor and cognitive dysfunction likely in both males and females. These phenotypes recapitulate those previously reported in patient fibroblasts/lymphoblasts and the symptoms displayed by many MICU1-deficient male and female patients ( 12 – 15 , 62 , 63 ). Heterozygous micu1 neurons and nKO mice have no significant impairments, which is consistent with literature on most individuals with heterozygous MICU1 mutation ( 14 , 15 , 62 ).…”

Section: Discussionsupporting

confidence: 88%

Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients

et al. 2022

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Dysregulation of mitochondrial Ca 2+ homeostasis has been linked to neurodegenerative diseases. Mitochondrial Ca 2+ uptake is mediated via the calcium uniporter complex that is primarily regulated by MICU1, a Ca 2+ -sensing gatekeeper. Recently, human patients with MICU1 loss-of-function mutations were diagnosed with neuromuscular and cognitive impairments. While studies in patient-derived cells revealed altered mitochondrial calcium signaling, the neuronal pathogenesis was difficult to study. To fill this void, we created a neuron-specific MICU1-KO mouse model. These animals show progressive, abnormal motor and cognitive phenotypes likely caused by the degeneration of motor neurons in the spinal cord and the cortex. We found increased susceptibility to mitochondrial Ca 2+ overload-induced excitotoxic insults and cell death in MICU1-KO neurons and MICU1-deficient patient-derived cells, which can be blunted by inhibiting the mitochondrial permeability transition pore. Thus, our study identifies altered neuronal mitochondrial Ca 2+ homeostasis as causative in the clinical symptoms of MICU1-deficient patients and highlights potential therapeutic targets.

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Section: Discussionsupporting

confidence: 88%

Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients

et al. 2022

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“…Furthermore, our results showed that MICU1 was essential for bioenergetic homeostasis and cell death signaling events (specifically, mPTP opening as opposed to apoptogen release from cristae bottlenecks). These effects could explain the lethal phenotype observed in MICU1 knockout mice and fly models ( 15 , 31 , 32 ), because our results suggest that loss of MICU1 could induce cell death signaling through both the necrotic and apoptotic pathways and would also explain why MICU1 mutations and/or genetic loss are linked to severe phenotypes ( 29 , 30 , 32 , 60 – 63 ).…”

Section: Discussionmentioning

confidence: 77%

MICU1 regulates mitochondrial cristae structure and function independently of the mitochondrial Ca ²⁺ uniporter channel

et al. 2023

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MICU1 is a calcium (Ca 2+ )–binding protein that regulates the mitochondrial Ca 2+ uniporter channel complex (mtCU) and mitochondrial Ca 2+ uptake. MICU1 knockout mice display disorganized mitochondrial architecture, a phenotype that is distinct from that of mice with deficiencies in other mtCU subunits and, thus, is likely not explained by changes in mitochondrial matrix Ca 2+ content. Using proteomic and cellular imaging techniques, we found that MICU1 localized to the mitochondrial contact site and cristae organizing system (MICOS) and directly interacted with the MICOS components MIC60 and CHCHD2 independently of the mtCU. We demonstrated that MICU1 was essential for MICOS complex formation and that MICU1 ablation resulted in altered cristae organization, mitochondrial ultrastructure, mitochondrial membrane dynamics, and cell death signaling. Together, our results suggest that MICU1 is an intermembrane space Ca 2+ sensor that modulates mitochondrial membrane dynamics independently of matrix Ca 2+ uptake. This system enables distinct Ca 2+ signaling in the mitochondrial matrix and at the intermembrane space to modulate cellular energetics and cell death in a concerted manner.

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“…Loss-of-function mutations in MICU1 have been linked to a muscle and brain disorder characterized by muscle weakness, cognitive deficits, and abnormal involuntary movements including chorea, tremor, dystonic posturing, and orofacial dyskinesias (Logan et al, 2014;Bhosale et al, 2017;Mojbafan et al, 2020;Wilton et al, 2020;Kohlschmidt et al, 2021). Studies performed using fibroblast and lymphoblasts derived from these patients indicate that MICU1 deficiency causes a chronic activation of the MCU cx , even in the presence of low cytosolic Ca 2+ concentrations, resulting in mitochondrial damage (Logan et al, 2014;Bhosale et al, 2017;Wilton et al, 2020;Kohlschmidt et al, 2021).…”

Section: Loss-of-function Micu1 Mutations Produce Abnormal Involuntar...mentioning

confidence: 99%

Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery

Novorolsky

Kasheke

Hakim

et al. 2023

Front. Cell. Neurosci.

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The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca2+) uptake supports NVU function by buffering Ca2+ and stimulating energy production. However, excessive mitochondrial Ca2+ uptake causes toxic mitochondrial Ca2+ overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca2+ uptake and efflux in the brain are mediated by the mitochondrial Ca2+ uniporter complex (MCUcx) and sodium/Ca2+/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCUcx inhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca2+ overloading. These findings suggest that combining MCUcx inhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCUcx inhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCUcx, or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticle-based approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues.

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Reporting a rare form of myopathy, myopathy with extrapyramidal signs, in an Iranian family using next generation sequencing: a case report

Abstract: Background: Myopathy with extrapyramidal signs (MPXPS) is an autosomal recessive mitochondrial disorder which is caused by mutation in mitochondrial calcium uptake 1 (MICU1) gene located on chromosome 10q22.

Cited by 12 publications

References 24 publications

Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients

Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients

MICU1 regulates mitochondrial cristae structure and function independently of the mitochondrial Ca ²⁺ uniporter channel

Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery

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Reporting a rare form of myopathy, myopathy with extrapyramidal signs, in an Iranian family using next generation sequencing: a case report

Abstract: Background: Myopathy with extrapyramidal signs (MPXPS) is an autosomal recessive mitochondrial disorder which is caused by mutation in mitochondrial calcium uptake 1 (MICU1) gene located on chromosome 10q22.

Cited by 12 publications

References 24 publications

Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients

Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients

MICU1 regulates mitochondrial cristae structure and function independently of the mitochondrial Ca 2+ uniporter channel

Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery

Contact Info

Product

Resources

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MICU1 regulates mitochondrial cristae structure and function independently of the mitochondrial Ca ²⁺ uniporter channel