PUBLICATION
Mitochondrial calcium uptake orchestrates vertebrate pigmentation via transcriptional regulation of keratin filaments
- Authors
- Tanwar, J., Ahuja, K., Sharma, A., Sehgal, P., Ranjan, G., Sultan, F., Agrawal, A., D'Angelo, D., Priya, A., Yenamandra, V.K., Singh, A., Raffaello, A., Madesh, M., Rizzuto, R., Sivasubbu, S., Motiani, R.K.
- ID
- ZDB-PUB-241114-24
- Date
- 2024
- Source
- PLoS Biology 22: e3002895e3002895 (Journal)
- Registered Authors
- Sivasubbu, Sridhar
- Keywords
- none
- MeSH Terms
-
- Mice, Knockout
- Melanosomes/metabolism
- NFATC Transcription Factors/genetics
- NFATC Transcription Factors/metabolism
- Calcium Channels/genetics
- Calcium Channels/metabolism
- Mitochondria*/metabolism
- Gene Expression Regulation
- Keratins/genetics
- Keratins/metabolism
- Calcium Signaling
- Melanocytes/metabolism
- Animals
- Mice
- Zebrafish*/metabolism
- Calcium*/metabolism
- Humans
- Pigmentation/genetics
- PubMed
- 39527653 Full text @ PLoS Biol.
Citation
Tanwar, J., Ahuja, K., Sharma, A., Sehgal, P., Ranjan, G., Sultan, F., Agrawal, A., D'Angelo, D., Priya, A., Yenamandra, V.K., Singh, A., Raffaello, A., Madesh, M., Rizzuto, R., Sivasubbu, S., Motiani, R.K. (2024) Mitochondrial calcium uptake orchestrates vertebrate pigmentation via transcriptional regulation of keratin filaments. PLoS Biology. 22:e3002895e3002895.
Abstract
Mitochondria 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping