TY - JOUR
T1 - Mitochondrial calcium uptake orchestrates vertebrate pigmentation via transcriptional regulation of keratin filaments
AU - Tanwar, Jyoti
AU - Ahuja, Kriti
AU - Sharma, Akshay
AU - Sehgal, Paras
AU - Ranjan, Gyan
AU - Sultan, Farina
AU - Agrawal, Anushka
AU - D’Angelo, Donato
AU - Priya, Anshu
AU - Yenamandra, Vamsi K.
AU - Singh, Archana
AU - Raffaello, Anna
AU - Madesh, Muniswamy
AU - Rizzuto, Rosario
AU - Sivasubbu, Sridhar
AU - Motiani, Rajender K.
N1 - Publisher Copyright:
© 2024 Tanwar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2024/11
Y1 - 2024/11
N2 - AU Mitochondria: Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly regulate several physiological functions through : mitochondrial Ca2+ dynamics. 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 demonstrate that mitochondrial Ca2+ uniporter (MCU) is crucial for melanogenesis while MCU rheostat, MCUb negatively control melanogenesis. Zebrafish, MCU+/- and MCUb-/- mice models show that MCU complex drives pigmentation in vivo. Mechanistically, MCU silencing activates transcription factor NFAT2 to induce expression of keratin (5, 7, and 8) filaments. Interestingly, keratin5 in turn augments mitochondrial Ca2+ uptake and potentiates melanogenesis by regulating melanosome biogenesis and maturation. Hence this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca2+ signaling and pigmentation. Notably, mitoxantrone, an FDA approved drug that inhibits MCU, reduces pigmentation thereby highlighting therapeutic potential of targeting mitochondrial Ca2+ uptake for clinical management of pigmentary disorders. Taken together, we reveal an MCU-NFAT2-Keratin5 driven signaling axis that acts as a critical determinant of mitochondrial Ca2+ uptake and pigmentation. Given the vital role of mitochondrial Ca2+ signaling and keratin filaments in cellular physiology, this feedback loop could be operational in a variety of other patho-physiological processes.
AB - AU Mitochondria: Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly regulate several physiological functions through : mitochondrial Ca2+ dynamics. 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 demonstrate that mitochondrial Ca2+ uniporter (MCU) is crucial for melanogenesis while MCU rheostat, MCUb negatively control melanogenesis. Zebrafish, MCU+/- and MCUb-/- mice models show that MCU complex drives pigmentation in vivo. Mechanistically, MCU silencing activates transcription factor NFAT2 to induce expression of keratin (5, 7, and 8) filaments. Interestingly, keratin5 in turn augments mitochondrial Ca2+ uptake and potentiates melanogenesis by regulating melanosome biogenesis and maturation. Hence this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca2+ signaling and pigmentation. Notably, mitoxantrone, an FDA approved drug that inhibits MCU, reduces pigmentation thereby highlighting therapeutic potential of targeting mitochondrial Ca2+ uptake for clinical management of pigmentary disorders. Taken together, we reveal an MCU-NFAT2-Keratin5 driven signaling axis that acts as a critical determinant of mitochondrial Ca2+ uptake and pigmentation. Given the vital role of mitochondrial Ca2+ signaling and keratin filaments in cellular physiology, this feedback loop could be operational in a variety of other patho-physiological processes.
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U2 - 10.1371/journal.pbio.3002895
DO - 10.1371/journal.pbio.3002895
M3 - Article
C2 - 39527653
AN - SCOPUS:85208965357
SN - 1544-9173
VL - 22
JO - PLoS biology
JF - PLoS biology
IS - 11
M1 - e3002895
ER -