Exploring the In Vivo Role of the Mitochondrial Calcium Uniporter in Brown Fat Bioenergetics

Flicker, Daniel; Sancak, Yasemin; Mick, Eran; Goldberger, Olga; Mootha, Vamsi K.

doi:10.1016/j.celrep.2019.04.013

Cited by 38 publications

(38 citation statements)

References 112 publications

(150 reference statements)

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“…In vitro and in vivo experiments in this study show that stimulation of Ca 2+ extrusion is indispensable for physiological uncoupled energy expenditure in BA. At first, the results presented here might contrast with a recent report showing in vivo that BAT-MCU KO mice are as cold tolerant as their WT littermates and presenting no basal or adrenergic-stimulated phenotype 20 . However, while BAT function seems to be independent of mitochondrial Ca 2+ uptake by MCU, once it is present in the mitochondrial matrix, Ca 2+ levels must be tightly regulated by NCLX activity to prevent Ca 2+ overload, activation of mPTP and ultimately cell death.…”

Section: Discussioncontrasting

confidence: 99%

“…While a rise in mitochondrial calcium has been documented during activation of thermogenesis in BAT, its functional role and regulation has not yet been elucidated. Recently Flicker et al 20 found that mitochondrial Ca 2+ uptake through the mitochondrial calcium uniporter is inconsequential for BAT thermogenic function. However, the role of Ca 2+ extrusion pathway has not been investigated.…”

Section: Resultsmentioning

confidence: 99%

“…The contribution of mitochondrial Ca 2+ elevation to coldstimulated thermogenesis is poorly understood. Surprisingly, a recent study that explored mice lacking MCU in BAT found that Ca 2+ uptake through MCU is dispensable for BAT-mediated thermogenesis; neither a basal nor a cold-stimulated phenotype were found in these mice 20 . This observation, coupled with early mitochondrial Ca 2+ studies showing that Na + -dependent mitochondrial Ca 2+ extrusion is essential for brown adipocyte (BA) uncoupled respiration 21 , bring up the possibility that Ca 2+ extrusion rather than entry may be essential in BAT activation.…”

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confidence: 93%

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NCLX prevents cell death during adrenergic activation of the brown adipose tissue

et al. 2020

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A sharp increase in mitochondrial Ca 2+ marks the activation of brown adipose tissue (BAT) thermogenesis, yet the mechanisms preventing Ca 2+ deleterious effects are poorly understood. Here, we show that adrenergic stimulation of BAT activates a PKA-dependent mitochondrial Ca 2+ extrusion via the mitochondrial Na + /Ca 2+ exchanger, NCLX. Adrenergic stimulation of NCLX-null brown adipocytes (BA) induces a profound mitochondrial Ca 2+ overload and impaired uncoupled respiration. Core body temperature, PET imaging of glucose uptake and VO 2 measurements confirm a thermogenic defect in NCLX-null mice. We show that Ca 2+ overload induced by adrenergic stimulation of NCLX-null BAT, triggers the mitochondrial permeability transition pore (mPTP) opening, leading to a remarkable mitochondrial swelling and cell death. Treatment with mPTP inhibitors rescue mitochondrial function and thermogenesis in NCLX-null BAT, while calcium overload persists. Our findings identify a key pathway through which BA evade apoptosis during adrenergic stimulation of uncoupling. NCLX deletion transforms the adrenergic pathway responsible for thermogenesis activation into a death pathway.

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Section: Discussioncontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 93%

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NCLX prevents cell death during adrenergic activation of the brown adipose tissue

et al. 2020

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“…Mitochondrial Ca 2+ uptake which has been long established as a key mediator of cell survival, metabolism and death needs to be tightly regulated (1,2). The predominant mechanism among ion transporters capable of Ca 2+ uptake into mitochondria is through a highly Ca 2+ -selective ion channel located in the inner membrane called the Mitochondrial Calcium Uniporter (MCU), driven by electrochemical gradient across the inner mitochondrial membrane (IMM) (3)(4)(5)(6). Mitochondrial Calcium Uptake 1 (MICU1), a regulatory subunit that shields mitochondria from Ca 2+ overload, is required for uniporter-mediated Ca 2+ uptake (7).…”

Section: Introductionmentioning

confidence: 99%

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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“…Given this, it is surprising that zebrafish cone photoreceptors express extremely low levels of MCU 12 . MCU has been widely thought to be the sole route of Ca 2+ entry into mitochondria in eukaryotes, as loss of MCU completely inhibits mitochondrial Ca 2+ uptake in skeletal muscle, liver, heart, brown adipose tissue, and a wide variety of cell lines 15 – 19 . Despite this, it is possible that certain specialized cell types might not rely solely on MCU for mitochondrial Ca 2+ uptake, since it also has been observed that brain mitochondria lacking MCU expression do not have a complete loss of mitochondrial Ca 2+ uptake 20 .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Calcium Uniporter (MCU) deficiency reveals an alternate path for Ca2+ uptake in photoreceptor mitochondria

Bisbach

Hutto

Poria

et al. 2020

Sci Rep

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Rods and cones use intracellular Ca2+ to regulate many functions, including phototransduction and neurotransmission. The Mitochondrial Calcium Uniporter (MCU) complex is thought to be the primary pathway for Ca2+ entry into mitochondria in eukaryotes. We investigate the hypothesis that mitochondrial Ca2+ uptake via MCU influences phototransduction and energy metabolism in photoreceptors using a mcu-/- zebrafish and a rod photoreceptor-specific Mcu-/- mouse. Using genetically encoded Ca2+ sensors to directly examine Ca2+ uptake in zebrafish cone mitochondria, we found that loss of MCU reduces but does not eliminate mitochondrial Ca2+ uptake. Loss of MCU does not lead to photoreceptor degeneration, mildly affects mitochondrial metabolism, and does not alter physiological responses to light, even in the absence of the Na+/Ca2+, K+ exchanger. Our results reveal that MCU is dispensable for vertebrate photoreceptor function, consistent with its low expression and the presence of an alternative pathway for Ca2+ uptake into photoreceptor mitochondria.

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Exploring the In Vivo Role of the Mitochondrial Calcium Uniporter in Brown Fat Bioenergetics

Cited by 38 publications

References 112 publications

NCLX prevents cell death during adrenergic activation of the brown adipose tissue

NCLX prevents cell death during adrenergic activation of the brown adipose tissue

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

Mitochondrial Calcium Uniporter (MCU) deficiency reveals an alternate path for Ca2+ uptake in photoreceptor mitochondria

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