{"doi":"10.1101/2023.05.26.542250","title":"Mitochondrial calcium signaling mediated transcriptional regulation of keratin filaments is a critical determinant of melanogenesis","abstract":"Abstract 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. Highlights MCU 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","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":396489,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9595,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1172312,"name":"Kriti Ahuja","orcid":null,"position":1,"is_corresponding":false},{"id":313730,"name":"Akshay Sharma","orcid":"0000-0003-3281-2081","position":2,"is_corresponding":false},{"id":245329,"name":"Paras Sehgal","orcid":"0000-0002-0593-8933","position":3,"is_corresponding":false},{"id":245330,"name":"Gyan Ranjan","orcid":"0000-0003-3161-4796","position":4,"is_corresponding":false},{"id":1171949,"name":"Farina Sultan","orcid":"0000-0003-3417-2428","position":5,"is_corresponding":false},{"id":1171950,"name":"Anshu Priya","orcid":"0000-0002-3711-8286","position":6,"is_corresponding":false},{"id":660638,"name":"Manigandan Venkatesan","orcid":"0000-0003-0044-4472","position":7,"is_corresponding":false},{"id":1171951,"name":"V.K. Yenamandra","orcid":"0000-0003-0502-9665","position":8,"is_corresponding":false},{"id":1171952,"name":"Archana Singh","orcid":"0000-0003-1388-9489","position":9,"is_corresponding":false},{"id":244493,"name":"Muniswamy Madesh","orcid":"0000-0001-6745-9092","position":10,"is_corresponding":false},{"id":245333,"name":"Sridhar Sivasubbu","orcid":"0000-0003-2411-4240","position":11,"is_corresponding":false},{"id":1171953,"name":"Rajender K. Motiani","orcid":"0000-0002-8971-9008","position":12,"is_corresponding":false},{"id":1171948,"name":"Jyoti Tanwar","orcid":"0000-0001-9610-6405","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:31.472087Z","pmid":"37292659","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}