Dataset Information

Mitochondrial Calcium Regulation of Redox Signaling in Cancer.

ABSTRACT: Calcium (Ca2+) uptake into the mitochondria shapes cellular Ca2+ signals and acts as a key effector for ATP generation. In addition, mitochondria-derived reactive oxygen species (mROS), produced as a consequence of ATP synthesis at the electron transport chain (ETC), modulate cellular signaling pathways that contribute to many cellular processes. Cancer cells modulate mitochondrial Ca2+ ([Ca2+]m) homeostasis by altering the expression and function of mitochondrial Ca2+ channels and transporters required for the uptake and extrusion of mitochondrial Ca2+. Regulated elevations in [Ca2+]m are required for the activity of several mitochondrial enzymes, and this in turn regulates metabolic flux, mitochondrial ETC function and mROS generation. Alterations in both [Ca2+]m and mROS are hallmarks of many tumors, and elevated mROS is a known driver of pro-tumorigenic redox signaling, resulting in the activation of pathways implicated in cellular proliferation, metabolic alterations and stress-adaptations. In this review, we highlight recent studies that demonstrate the interplay between [Ca2+]m and mROS signaling in cancer.

SUBMITTER: Delierneux C

PROVIDER: S-EPMC7072435 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Mitochondrial Calcium Regulation of Redox Signaling in Cancer.

Delierneux Céline C Kouba Sana S Shanmughapriya Santhanam S Potier-Cartereau Marie M Trebak Mohamed M Hempel Nadine N

Cells 20200212 2

Calcium (Ca2+) uptake into the mitochondria shapes cellular Ca2+ signals and acts as a key effector for ATP generation. In addition, mitochondria-derived reactive oxygen species (mROS), produced as a consequence of ATP synthesis at the electron transport chain (ETC), modulate cellular signaling pathways that contribute to many cellular processes. Cancer cells modulate mitochondrial Ca2+ ([Ca2+]m) homeostasis by altering the expression and function of m ...[more]

PMID: 32059571

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Project description:We recently showed that inhibition of neuronal activity, glutamate uptake, or reversed-Na(+)/Ca(2+)-exchange with TTX, TFB-TBOA, or YM-244769, respectively, increases mitochondrial mobility in astrocytic processes. In the present study, we examined the interrelationships between mitochondrial mobility and Ca(2+) signaling in astrocyte processes in organotypic cultures of rat hippocampus. All of the treatments that increase mitochondrial mobility decreased basal Ca(2+). As recently reported, we observed spontaneous Ca(2+) spikes with half-lives of ?1 s that spread ?6 ?m and are almost abolished by a TRPA1 channel antagonist. Virtually all of these Ca(2+) spikes overlap mitochondria (98%), and 62% of mitochondria are overlapped by these spikes. Although tetrodotoxin, TFB-TBOA, or YM-244769 increased Ca(2+) signaling, the specific effects on peak, decay time, and/or frequency were different. To more specifically manipulate mitochondrial mobility, we explored the effects of Miro motor adaptor proteins. We show that Miro1 and Miro2 are both expressed in astrocytes and that exogenous expression of Ca(2+)-insensitive Miro mutants (KK) nearly doubles the percentage of mobile mitochondria. Expression of Miro1(KK) had a modest effect on the frequency of these Ca(2+) spikes but nearly doubled the decay half-life. The mitochondrial proton ionophore, FCCP, caused a large, prolonged increase in cytosolic Ca(2+) followed by an increase in the decay time and the spread of the spontaneous Ca(2+) spikes. Photo-ablation of mitochondria in individual astrocyte processes has similar effects on Ca(2+). Together, these studies show that Ca(2+) regulates mitochondrial mobility, and mitochondria in turn regulate Ca(2+) signals in astrocyte processes.In neurons, the movement and positioning of mitochondria at sites of elevated activity are important for matching local energy and Ca(2+) buffering capacity. Previously, we demonstrated that mitochondria are immobilized in astrocytes in response to neuronal activity and glutamate uptake. Here, we demonstrate a mechanism by which mitochondria are immobilized in astrocytes subsequent to increases in intracellular [Ca(2+)] and provide evidence that mitochondria contribute to the compartmentalization of spontaneous Ca(2+) signals in astrocyte processes. Immobilization of mitochondria at sites of glutamate uptake in astrocyte processes provides a mechanism to coordinate increases in activity with increases in mitochondrial metabolism.

Project description:Mitochondria are versatile organelles that regulate several physiological functions. Many mitochondria-controlled processes are driven by mitochondrial Ca 2+ signaling. However, role of mitochondrial Ca 2+ signaling in melanosome biology remains unknown. Here, we show that pigmentation requires mitochondrial Ca 2+ uptake. In vitro gain and loss of function studies demonstrated that Mitochondrial Ca 2+ Uniporter (MCU) is crucial for melanogenesis while the MCU rheostats, MCUb and MICU1 negatively control melanogenesis. Zebrafish and mouse models showed that MCU plays a vital role in pigmentation in vivo . Mechanistically, MCU controls activation of transcription factor NFAT2 to induce expression of three keratins (keratin 5, 7 and 8), which we report as positive regulators of melanogenesis. Interestingly, keratin 5 in turn modulates mitochondrial Ca 2+ uptake thereby this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca 2+ signaling and melanogenesis. Mitoxantrone, an FDA approved drug that inhibits MCU, decreases physiological melanogenesis. Collectively, our data demonstrates a critical role for mitochondrial Ca 2+ signaling in vertebrate pigmentation and reveal the therapeutic potential of targeting MCU for clinical management of pigmentary disorders. Given the centrality of mitochondrial Ca 2+ signaling and keratin filaments in cellular physiology, this feedback loop may be functional in a variety of other pathophysiological conditions.HighlightsMCU complex mediated mitochondrial Ca 2+ uptake is a novel regulator of vertebrate pigmentation Keratin filaments bridge mitochondrial Ca 2+ signaling to melanosome biogenesis and maturation Transcription factor NFAT2 connects mitochondrial Ca 2+ dynamics to keratins expression MCU-NFAT2-Keratin 5 signaling module generates a negative feedback loop to maintain mitochondrial Ca 2+ homeostasis and to ensure optimal melanogenesis Inhibiting MCU with mitoxantrone, an FDA approved drug, leads to reduction in physiological pigmentation.

Dataset Information

Mitochondrial Calcium Regulation of Redox Signaling in Cancer.

Publications

Mitochondrial Calcium Regulation of Redox Signaling in Cancer.

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