Mitochondrial Calcium Uniporter Structure and Function in Different Types of Muscle Tissues in Health and Disease

Тарасова, Н.В.; Vishnyakova, Polina; Logashina, Yulia A.; Elchaninov, Andrey

doi:10.3390/ijms20194823

Cited by 21 publications

(17 citation statements)

References 154 publications

(275 reference statements)

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“…In vivo molecular removal of MICU1 leads to larval lethality in Drosophila (12). Whole body knockout of MICU1 in the mouse has been shown to cause a high probability of perinatal lethality and the survived mice have physical biochemical abnormalities, ataxia and muscle weakness, recapitulating the problems observed in the human patients (18).…”

Section: Introductionmentioning

confidence: 99%

“…As a gatekeeper of MCU at low Ca 2+ levels MCU1 prevents channel opening and at high Ca 2+ levels promotes MCU opening which allows rapid response of mitochondria to calcium signals generated in the cytoplasm (2,10,11). Although Ca 2+ in ux to mitochondrial matrix is crucial for the life of a cell and its vital functions, Mitochondrial Ca 2+ uptake also drives physical mitochondrial damages leading to bioenergetics crises and programmed cell death under conditions of cellular Ca 2+ overload (12,13). In other word MCU translates cellular Ca 2+ signals into metabolic or death responses (14).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, mitochondrial Ca 2+ uptake must be strongly regulated which is achieved by sensing the cytosolic calcium ions uctuations and balancing the rates of Ca 2+ uptake and release (15). Several lines of evidence link mitochondrial Ca 2+ overload to a range of pathological conditions including cancers, diabetes, cardiovascular and neurodegenerative disorders (12,16).…”

Section: Introductionmentioning

confidence: 99%

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WITHDRAWN: Identification of a Novel MICU1 Nonsense Variant Causes Myopathy with Extrapyramidal Signs in an Iranian Consanguineous Family

Bitarafan

Khodaeian

Sardehaei

et al. 2020

Preprint

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Background: Ca2+ as a universal second messenger regulates basic biological functions including cell cycle, cell proliferation, cell differentiation and cell death. Lack of the protein mitochondrial calcium uptake1 (MICU1) which has been regarded as a gatekeeper of Ca ions, leads to the abnormal mitochondrial Ca2+ handling, excessive production of reactive oxygen species (ROS), and increased cell death. Mutations in MICU1 gene (NM_006077.3) causes a very rare neuromuscular disease, Myopathy with extrapyramidal signs (MPXPS), due to primary alterations in mitochondrial calcium signaling which demonstrates the key role of mitochondrial Ca2+ uptake. To date 6 variants have been reported in MICU1 gene in approximately 21 pedigrees.Case presentation: here we report a 44-year-old Iranian patient presented with learning disability, muscle weakness, easy fatigability, reduced tendon reflexes, ataxia, elevated hepatic transaminase, elevated serum creatine phosphokinase and gait disturbance. We Identified a novel nonsense variant c.385C>T; p.(R129*) in MICU1 gene by whole exome sequencing and segregation analysis.Conclusions: Our finding along with previous studies provides more evidence on the clinical presentation of the disease caused by pathogenic mutations in MICU1. Finding more variants and expanding the spectrum of the disease increases the diagnostic rate of molecular testing in screening of this kind of diseases and in turn improves the quality of counseling for at risk couples and helps them to minimize the risks of having affected children.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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WITHDRAWN: Identification of a Novel MICU1 Nonsense Variant Causes Myopathy with Extrapyramidal Signs in an Iranian Consanguineous Family

Bitarafan

Khodaeian

Sardehaei

et al. 2020

Preprint

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“…The balance between mitochondrial calcium entry and release is responsible for the maintenance of intracellular Ca 2+ homeostasis under normal and pathological conditions. More details about mitochondrial Ca 2+ transport systems are described in reviews [ 84 , 133 , 151 , 152 ].…”

Section: Ca 2+ Handling Mpt Pore and Diabetes mentioning

confidence: 99%

Diabetes Mellitus, Mitochondrial Dysfunction and Ca2+-Dependent Permeability Transition Pore

Belosludtsev

Belosludtseva

Dubinin

2020

IJMS

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Diabetes mellitus is one of the most common metabolic diseases in the developed world, and is associated either with the impaired secretion of insulin or with the resistance of cells to the actions of this hormone (type I and type II diabetes, respectively). In both cases, a common pathological change is an increase in blood glucose—hyperglycemia, which eventually can lead to serious damage to the organs and tissues of the organism. Mitochondria are one of the main targets of diabetes at the intracellular level. This review is dedicated to the analysis of recent data regarding the role of mitochondrial dysfunction in the development of diabetes mellitus. Specific areas of focus include the involvement of mitochondrial calcium transport systems and a pathophysiological phenomenon called the permeability transition pore in the pathogenesis of diabetes mellitus. The important contribution of these systems and their potential relevance as therapeutic targets in the pathology are discussed.

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“…MCU is a highly selective Ca 2+ channel which comprises a membrane-spanning 40-kDa protein that forms a low-conductance Ca 2+ -selective pore. MCU exists as a large protein complex (~480 kDa) comprising MICU1 and MICU2 which give it its Ca 2+ sensitivity (Tarasova et al, 2019 ). This SR/ER–mitochondria interaction and contact points have never been studied in DMD hearts.…”

Section: Introductionmentioning

confidence: 99%

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

Angebault

Panel

Lacote

et al. 2021

Front. Cell Dev. Biol.

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Besides skeletal muscle dysfunction, Duchenne muscular dystrophy (DMD) exhibits a progressive cardiomyopathy characterized by an impaired calcium (Ca2+) homeostasis and a mitochondrial dysfunction. Here we aimed to determine whether sarco-endoplasmic reticulum (SR/ER)–mitochondria interactions and mitochondrial function were impaired in dystrophic heart at the early stage of the pathology. For this purpose, ventricular cardiomyocytes and mitochondria were isolated from 3-month-old dystrophin-deficient mice (mdx mice). The number of contacts points between the SR/ER Ca2+ release channels (IP3R1) and the porine of the outer membrane of the mitochondria, VDAC1, measured using in situ proximity ligation assay, was greater in mdx cardiomyocytes. Expression levels of IP3R1 as well as the mitochondrial Ca2+ uniporter (MCU) and its regulated subunit, MICU1, were also increased in mdx heart. MICU2 expression was however unchanged. Furthermore, the mitochondrial Ca2+ uptake kinetics and the mitochondrial Ca2+ content were significantly increased. Meanwhile, the Ca2+-dependent pyruvate dehydrogenase phosphorylation was reduced, and its activity significantly increased. In Ca2+-free conditions, pyruvate-driven complex I respiration was decreased whereas in the presence of Ca2+, complex I-mediated respiration was boosted. Further, impaired complex I-mediated respiration was independent of its intrinsic activity or expression, which remains unchanged but is accompanied by an increase in mitochondrial reactive oxygen species production. Finally, mdx mice were treated with the complex I modulator metformin for 1 month. Metformin normalized the SR/ER-mitochondria interaction, decreased MICU1 expression and mitochondrial Ca2+ content, and enhanced complex I-driven respiration. In summary, before any sign of dilated cardiomyopathy, the DMD heart displays an aberrant SR/ER-mitochondria coupling with an increase mitochondrial Ca2+ homeostasis and a complex I dysfunction. Such remodeling could be reversed by metformin providing a novel therapeutic perspective in DMD.

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Mitochondrial Calcium Uniporter Structure and Function in Different Types of Muscle Tissues in Health and Disease

Cited by 21 publications

References 154 publications

WITHDRAWN: Identification of a Novel MICU1 Nonsense Variant Causes Myopathy with Extrapyramidal Signs in an Iranian Consanguineous Family

WITHDRAWN: Identification of a Novel MICU1 Nonsense Variant Causes Myopathy with Extrapyramidal Signs in an Iranian Consanguineous Family

Diabetes Mellitus, Mitochondrial Dysfunction and Ca2+-Dependent Permeability Transition Pore

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

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