Essential Regulation of Cell Bioenergetics by Constitutive InsP3 Receptor Ca2+ Transfer to Mitochondria

Cárdenas, César; Miller, Russell A.; Smith, Ian F.; Bui, Thi Ngoc Tuan; Molgó, Jordi; Müller, Marioly; Vais, Horia; Cheung, King‐Ho; Yang, Jun; Parker, Ian; Thompson, Craig B.; Birnbaum, Morris J.; Hallows, Kenneth R.; Foskett, J. Kevin

doi:10.1016/j.cell.2010.06.007

Cited by 917 publications

(1,017 citation statements)

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“…As previously reported, an impairment of mitochondrial Ca 2+ handling is associated with mitochondrial diseases. 35 Recently, Cardenas et al 6 reported that constitutively Ca 2+ release from the ER controls cellular bioenergetics and autophagy. Based on these observations, we investigated cellular Ca 2+ Figure S3d) and in permeabilized cells, where the contribution of plasma membrane or ER channels to the mitochondrial Ca 2+ response is absent (Supplementary Figure S3c).…”

Section: Resultsmentioning

confidence: 99%

“…6,39,40 Western blotting analysis of AMPK phosphorylation on Ser172 (p-AMPK) 40 revealed low p-AMPK level in resting conditions in control cells. Conversely, all patient-derived fibroblasts displayed a slight increase in p-AMPK levels, as expected in cells with deficiency of the respiratory chain complexes, but in Pat#1 this increase was dramatic.…”

Section: Resultsmentioning

confidence: 99%

“…30,31 In addition, mitochondrial Ca 2+ signaling has a role in the regulation of autophagy. 6 This complex relationship could allow, in the context of a mitochondrial disorder, the triggering of a cellular response that compensate, at least in part, the energetic defect, dampening the clinical phenotype. In this work, we investigated autophagy and mitochondrial Ca 2+ signaling in human fibroblasts from control subjects and from a set of patients carrying mutations in the mtDNA-encoded ND5 subunit of the ETC complex I.…”

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

“…5 In addition, Ca 2+ uptake in this organelle has recently been demonstrated to be a fundamental regulator of autophagy. 6,7 Autophagy is involved in physiological organelle turnover and in the removal of damaged or non-functional mitochondria by autophagy (called 'mitophagy') [8][9][10][11] and is critical for organelle quality control. Given the pivotal role of mitochondrial Ca 2+ in the adaptation of adenosine triphosphate (ATP) production to cellular energy demand, the recent identification of the channel responsible for Ca 2+ entry into the organelle, the mitochondrial Ca 2+ uniporter (MCU), is instrumental for the understanding of the regulation of mitochondrial Ca 2+ transport in both physiological and pathological conditions.…”

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Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

et al. 2015

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Mitochondrial disorders are a group of pathologies characterized by impairment of mitochondrial function mainly due to defects of the respiratory chain and consequent organellar energetics. This affects organs and tissues that require an efficient energy supply, such as brain and skeletal muscle. They are caused by mutations in both nuclear-and mitochondrial DNA (mtDNA)-encoded genes and their clinical manifestations show a great heterogeneity in terms of age of onset and severity, suggesting that patient-specific features are key determinants of the pathogenic process. In order to correlate the genetic defect to the clinical phenotype, we used a cell culture model consisting of fibroblasts derived from patients with different mutations in the mtDNA-encoded ND5 complex I subunit and with different severities of the illness. Interestingly, we found that cells from patients with the 13514A4G mutation, who manifested a relatively late onset and slower progression of the disease, display an increased autophagic flux when compared with fibroblasts from other patients or healthy donors. We characterized their mitochondrial phenotype by investigating organelle turnover, morphology, membrane potential and Ca 2+ homeostasis, demonstrating that mitochondrial quality control through mitophagy is upregulated in 13514A4G cells. This is due to a specific downregulation of mitochondrial Ca 2+ uptake that causes the stimulation of the autophagic machinery through the AMPK signaling axis. Genetic and pharmacological manipulation of mitochondrial Ca 2+ homeostasis can revert this phenotype, but concurrently decreases cell viability. This indicates that the higher mitochondrial turnover in complex I deficient cells with this specific mutation is a pro-survival compensatory mechanism that could contribute to the mild clinical phenotype of this patient. Mitochondrial disorders include a wide range of pathological conditions characterized by defects in organelle homoeostasis and energy metabolism, in particular in the electron transport chain (ETC) complexes. They are mostly caused by mutations in nuclear-or mtDNA-encoded genes of the respiratory chain complexes leading to a variety of clinical manifestations, ranging from lesions in specific tissues, such as in Leber's hereditary optic neuropathy, to complex multisystem syndromes, such as myoclonic epilepsy with ragged-red fibers, Leigh syndrome or the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). 1,2 Despite the detailed knowledge of the molecular defects in these diseases, their pathogenesis remains poorly understood. The heterogeneity of signs and symptoms depends on the diversity of the genetic background and on patient-specific compensatory mechanisms. Several studies investigated the consequences of nuclear DNA mutations on intracellular organelle physiology and Ca 2+ homeostasis. 3,4 Here we analyzed a cohort of patients with mutations in the mtDNA-encoded ND5 subunit of NADH dehydrogenase in order to correlate the clinical phenot...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

et al. 2015

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Autophagy‐dependent alternative splicing of ribosomal protein S24 produces a more stable isoform that aids in hypoxic cell survival

Kerry,

Specker,

Mizzoni

et al. 2024

FEBS Letters

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Cells remodel splicing and translation machineries to mount specialized gene expression responses to stress. Here, we show that hypoxic human cells in 2D and 3D culture models increase the relative abundance of a longer mRNA variant of ribosomal protein S24 (RPS24L) compared to a shorter mRNA variant (RPS24S) by favoring the inclusion of a 22 bp cassette exon. Mechanistically, RPS24L and RPS24S are induced and repressed, respectively, by distinct pathways in hypoxia: RPS24L is induced in an autophagy‐dependent manner, while RPS24S is reduced by mTORC1 repression in a hypoxia‐inducible factor‐dependent manner. RPS24L produces a more stable protein isoform that aids in hypoxic cell survival and growth, which could be exploited by cancer cells in the tumor microenvironment.

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Calcium Signalling and Regulation of Cell Function

Bootman

Rietdorf

Hardy

et al. 2012

Encyclopedia of Life Sciences

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The calcium ion (Ca 2+ ) is a versatile intracellular messenger. It provides dynamic regulation of vast array of cellular processes such as gene transcription, differentiation and contraction. Ca 2+ signals range from microsecond, nanoscopic events to intercellular waves lasting for many seconds. This diversity of Ca 2+ signals arises from the wide assortment of Ca 2+ transport and Ca 2+ buffering processes employed by cells. Additional diversity in Ca 2+ signalling stems from the ability of cells to utilise different sources of Ca 2+ . The cytosol is the principal Ca 2+ signalling compartment. When Ca 2+ ions enter the cytosol they interact with numerous Ca 2+ ‐binding proteins, thereby leading to activation, or inhibition, of cellular processes. Specificity is achieved by regulating the spatial and kinetic properties of Ca 2+ signal. In this way, many concurrent Ca 2+ ‐sensitive cellular processes can be discretely regulated. A number of pathologies have been related to the breakdown of cellular Ca 2+ homoeostasis or to aberrant Ca 2+ signalling. Key Concepts: Calcium is a critical intracellular signal that controls key cell fate decisions. Calcium signals derive from multiple sources that are accessed by a diverse range of transport mechanisms. The kinetics and spatial properties of calcium signals determine their impact on cellular activity. Ca 2+ signals are tissue‐specific and are appropriate to regulate the physiological functions of individual cell types.

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Essential Regulation of Cell Bioenergetics by Constitutive InsP3 Receptor Ca2+ Transfer to Mitochondria

Cited by 917 publications

References 51 publications

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

Autophagy‐dependent alternative splicing of ribosomal protein S24 produces a more stable isoform that aids in hypoxic cell survival

Calcium Signalling and Regulation of Cell Function

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