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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.

Recessive dystrophic epidermolysis bullosa (RDEB) is a lifelong genodermatosis associated with blistering, wounding, and scarring caused by mutations in COL7A1, the gene encoding the anchoring fibril component, collagen VII (C7). Here, we evaluated beremagene geperpavec (B-VEC), an engineered, non-replicating COL7A1 containing herpes simplex virus type 1 (HSV-1) vector, to treat RDEB skin. B-VEC restored C7 expression in RDEB keratinocytes, fibroblasts, RDEB mice and human RDEB xenografts. Subsequently, a randomized, placebo-controlled, phase 1 and 2 clinical trial (NCT03536143) evaluated matched wounds from nine RDEB patients receiving topical B-VEC or placebo repeatedly over 12 weeks. No grade 2 or above B-VEC-related adverse events or vector shedding or tissue-bound skin immunoreactants were noted. HSV-1 and C7 antibodies sometimes presented at baseline or increased after B-VEC treatment without an apparent impact on safety or efficacy. Primary and secondary objectives of C7 expression, anchoring fibril assembly, wound surface area reduction, duration of wound closure, and time to wound closure following B-VEC treatment were met. A patient-reported pain–severity secondary outcome was not assessed given the small proportion of wounds treated. A global assessment secondary endpoint was not pursued due to redundancy with regard to other endpoints. These studies show that B-VEC is an easily administered, safely tolerated, topical molecular corrective therapy promoting wound healing in patients with RDEB.

Mapping of somatic variations has enabled understanding the progression of clonal variations from healthy skin to cutaneous malignancies. Highlighting, the adaptive nature of pigmentation, germline mutations in albinism amplify skin cancer susceptibility. However, lower incidence of non-melanoma skin cancer among subjects with acquired depigmenting skin disorder vitiligo is enigmatic and a matter of longstanding debate. To address this, we performed high-coverage exome sequencing of matched non-lesional and lesional vitiligo skin along with whole blood to account for germline variations. Our analysis suggests lower burden of somatic cancer-associated variations in exposed depigmented lesional skin compared to the non-lesional skin. A detailed investigation of vitiligo skin transcriptome reveals elevation of DNA repair and cell-proliferation pathways. Validation by comet-assay for DNA damage and cell cycle analysis of epidermal cells suggest undamaged DNA in vitiligo lesions that could be attributed to higher proliferation-coupled repair. Endorsing this, UV-signature variations are not prominent, instead SBS5 associated with endogenous mutational processes is conspicuous in both the vitiligo tissues. Our systematic pilot study indicates lower somatic mutation burden in vitiligo skin and supports the earlier demographic observation on lower risk of non-melanoma skin cancer in vitiligo subjects, providing an opportunity to learn strategies for cancer prevention from vitiligo.Brief SummaryVitiligo skin harbors decreased somatic variation burden in cancer-associated genes and a concomitant augmentation in DNA repair response, explaining the lower incidence of cutaneous malignancies.