VDAC1 negatively regulates melanogenesis through the Ca<sup>2+</sup>-calcineurin-CRTC1-MITF pathway

Wang, Jianli; Gong, Juanjuan; Wang, Qiaochu; Tang, Tie-Shan; Li, Wei

doi:10.26508/lsa.202101350

Cited by 5 publications

(2 citation statements)

References 50 publications

(54 reference statements)

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“…Physiologically relevant doses of UV light induces rise in cytosolic Ca 2+ levels, which leads to enhanced melanin synthesis (Bellono, Kammel et al, 2013). Similarly, rise in free cytosolic Ca 2+ upon VDAC1 silencing augments melanogenesis by activating MITF mediated transcription of melanogenic genes (Wang, Gong et al, 2022). These studies demonstrate that increase in cytosolic Ca 2+ levels promotes melanogenesis.…”

Section: Discussionmentioning

confidence: 77%

Mitochondrial calcium signaling mediated transcriptional regulation of keratin filaments is a critical determinant of melanogenesis

Tanwar

Ahuja

Sharma

et al. 2023

Preprint

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Mitochondria are versatile organelles that regulate several physiological functions. Many mitochondria-controlled processes are driven by mitochondrial Ca2+ signaling. However, role of mitochondrial Ca2+ signaling in melanosome biology remains unknown. Here, we show that pigmentation requires mitochondrial Ca2+ uptake. In vitro gain and loss of function studies demonstrated that Mitochondrial Ca2+ 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 Ca2+ uptake thereby this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca2+ homeostasis and melanogenesis. Mitoxantrone, an FDA approved drug that inhibits MCU, decreases physiological melanogenesis. Collectively, our data demonstrates a critical role for mitochondrial Ca2+ signaling in vertebrate pigmentation and reveal the therapeutic potential of targeting MCU for clinical management of pigmentary disorders. Given the centrality of mitochondrial Ca2+ signaling and keratin filaments in cellular physiology, this feedback loop may be functional in a variety of other pathophysiological conditions.

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Section: Discussionmentioning

confidence: 77%

Mitochondrial calcium signaling mediated transcriptional regulation of keratin filaments is a critical determinant of melanogenesis

Tanwar

Ahuja

Sharma

et al. 2023

Preprint

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“…Mitochondria supply ATP and calcium (Ca 2+ ) to support melanosome maturation and melanin synthesis [17][18][19] . Mitochondria and melanosomes are physically in contact through the outer mitochondria membrane (OMM) protein mitofusin 2 (MFN2) that regulates mitochondria-melanosome apposition in space and time during active melanogenesis 18 .…”

Section: Introductionmentioning

confidence: 99%

MFF budding from mitochondria regulates melanosome size and maturation

Rebelo,

Maracani,

Greco

et al. 2024

Preprint

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Melanosomes are lysosome-related organelles that produce and accumulate melanin. Melanosome maturation is regulated by their association with mitochondria and requires the export and recycling of unneeded cargo via tubular carriers and fission, the mechanisms of which are unknown. Here we show that melanosome fission requires the outer mitochondrial membrane protein mitochondrial fission factor (MFF). We retrieved MFF on melanosomes at different stages of maturation and at early melanosome fission sites: upon downregulation of MFF, but not of the dynamin related protein 1 (DRP1) that executes mitochondrial fission, early melanosomes enlarged, intracellular melanin accumulated and melanosome lumen catabolism increased. The MFF interactome in melanocytes posited a role for a complex network of cytoskeletal factors in its activity. Indeed inhibition of actin nucleation was sufficient to curtail the effects of MFF silencing on melanosomes. Our data unveil an extramitochondrial role for MFF in the regulation of melanosome morphology and maturation that is independent of DRP1 but requires actin polymerization and nucleation factors.

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Natural product rhynchophylline prevents stress-induced hair graying by preserving melanocyte stem cells via the β2 adrenergic pathway suppression

Li,

Shi,

Yan

et al. 2023

Nat. Prod. Bioprospect.

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Norepinephrine (NA), a stress hormone, can accelerate hair graying by binding to β2 adrenergic receptors (β2AR) on melanocyte stem cells (McSCs). From this, NA-β2AR axis could be a potential target for preventing the stress effect. However, identifying selective blockers for β2AR has been a key challenge. Therefore, in this study, advanced computer-aided drug design (CADD) techniques were harnessed to screen natural molecules, leading to the discovery of rhynchophylline as a promising compound. Rhynchophylline exhibited strong and stable binding within the active site of β2AR, as verified by molecular docking and dynamic simulation assays. When administered to cells, rhynchophylline effectively inhibited NA-β2AR signaling. This intervention resulted in a significant reduction of hair graying in a stress-induced mouse model, from 28.5% to 8.2%. To gain a deeper understanding of the underlying mechanisms, transcriptome sequencing was employed, which revealed that NA might disrupt melanogenesis by affecting intracellular calcium balance and promoting cell apoptosis. Importantly, rhynchophylline acted as a potent inhibitor of these downstream pathways. In conclusion, the study demonstrated that rhynchophylline has the potential to mitigate the negative impact of NA on melanogenesis by targeting β2AR, thus offering a promising solution for preventing stress-induced hair graying. Graphical Abstract

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VDAC1 negatively regulates melanogenesis through the Ca²⁺-calcineurin-CRTC1-MITF pathway

Cited by 5 publications

References 50 publications

Mitochondrial calcium signaling mediated transcriptional regulation of keratin filaments is a critical determinant of melanogenesis

Mitochondrial calcium signaling mediated transcriptional regulation of keratin filaments is a critical determinant of melanogenesis

MFF budding from mitochondria regulates melanosome size and maturation

Natural product rhynchophylline prevents stress-induced hair graying by preserving melanocyte stem cells via the β2 adrenergic pathway suppression

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VDAC1 negatively regulates melanogenesis through the Ca2+-calcineurin-CRTC1-MITF pathway

Cited by 5 publications

References 50 publications

Mitochondrial calcium signaling mediated transcriptional regulation of keratin filaments is a critical determinant of melanogenesis

Mitochondrial calcium signaling mediated transcriptional regulation of keratin filaments is a critical determinant of melanogenesis

MFF budding from mitochondria regulates melanosome size and maturation

Natural product rhynchophylline prevents stress-induced hair graying by preserving melanocyte stem cells via the β2 adrenergic pathway suppression

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VDAC1 negatively regulates melanogenesis through the Ca²⁺-calcineurin-CRTC1-MITF pathway