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Mitochondrial dynamics control mitochondrial functions as well as their morphology. However, the role of mitochondrial dynamics in melanogenesis is largely unknown. Here, we show that mitochondrial dynamics regulate melanogenesis by modulating the ROS-ERK signaling pathway. Genetic and chemical inhibition of Drp1, a mitochondrial fission protein, increased melanin production and mitochondrial elongation in melanocytes and melanoma cells. In contrast, down-regulation of OPA1, a mitochondria fusion regulator, suppressed melanogensis but induced massive mitochondrial fragmentation in hyperpigmented cells. Consistently, treatment with CCCP, a mitochondrial fission chemical inducer, also efficiently repressed melanogenesis. Furthermore, we found that ROS production and ERK phosphorylation were increased in cells with fragmented mitochondria. And inhibition of ROS or ERK suppressed the antimelanogenic effect of mitochondrial fission in α-MSH-treated cells. In addition, the activation of ROS-ERK pathway by mitochondrial fission induced phosphorylation of serine73 on MITF accelerating its proteasomal degradation. In conclusion, mitochondrial dynamics may regulate melanogenesis by modulating ROS-ERK signaling pathway.

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The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (IDH) wild-type glioblastoma (GBM) is currently limited due to high molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of IDH wild-type GBM tumors derived from a quantitative proteomic analysis of 39 IDH wild-type GBMs as well as IDH mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (FKBP9). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (PHGDH). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.

Autophagy degrades cellular components and organelles through a cooperative process involving autophagosomes and lysosomes. Although autophagy is known to mainly regulate the turnover of cellular components, the role of autophagy in melanogenesis has not been well addressed. Here, we show that inhibition of autophagy suppresses the antimelanogenesis activity of resveratrol (RSV), a well‐known antimelanogenic agent. RSV strongly increased autophagy in melanocytes. However, the depletion of ATG5 significantly suppressed RSV‐mediated antimelanogenesis as well as RSV‐induced autophagy in melanocytes. Moreover, suppression of ATG5 retrieved the RSV‐mediated downregulation of tyrosinase and TRP1 in α‐MSH‐treated cells. Most importantly, electron microscopy analysis revealed that autophagosomes engulfed melanin or melanosomes after combined treatment of α‐MSH and RSV. Taken together, these results suggest that RSV‐mediated autophagy regulates melanogenesis.

a b s t r a c tAutophagy is a cooperative process between autophagosomes and lysosomes that degrades cellular organelles. Although autophagy regulates the turnover of cellular components, its role in melanogenesis is not clearly established. Previously, we reported that ARP101 induces autophagy in various cancer cells. Here, we show that ARP101 inhibits melanogenesis by regulation of autophagy. ARP101 inhibited a-MSH-stimulated melanin synthesis and suppressed the expression of tyrosinase and TRP1 in immortalized mouse melanocytes. ARP101 also induced autophagy in melanocytes. Knockdown of ATG5 reduced both anti-melanogenic activity and autophagy mediated by ARP101 in a-MSH treated melanocytes. Electron microscopy analysis further revealed that autophagosomes engulf melanin or melanosome in a-MSH and ARP101-treated cells. Collectively, our results suggest that ARP101 inhibits a-MSH-stimulated melanogenesis through the activation of autophagy in melanocytes.

Behçet's disease is a chronic, multisystem disorder characterized by a recurrent inflammatory reaction. Antiendothelial cell antibodies have been detected in the serum from patients with autoimmune diseases with presenting vasculitis and it is assumed that they can induce damage to the endothelial cells. In this study, we detected antiendothelial cell antibodies in the serum from patients with Behçet's disease using an enzyme-linked immunosorbent assay, electrophoresis and immunoblotting. The cytolysis of human dermal microvascular endothelial cells (HDMEC) was measured using a cytotoxicity assay. The serum from 37.4% of Behçet's disease patients showed IgM antibodies against unstimulated HDMEC while the serum from 18.4% of patients showed an increase in IgM antibody titer after IFN-gamma pretreatment. The frequency of vasculitis was higher in the IgM-positive Behçet's disease patients than in the IgM-negative patients. In Western blotting, IgM-positive Behçet's disease serum reacted with the 44 kDa HDMEC surface antigen, whereas IgM-positive systemic lupus erythematosus serum reacted with the 81 kDa HDMEC surface antigen. The reactivity to the 44 kDa protein band was also observed in cultured human umbilical vein endothelial cells but not in fibroblasts, A431 cells or SK-MEL-2 cells. Serum from Behçet's disease patients incubated with human complement or mononuclear cells produced no significant lysis of HDMEC, and cultured HDMEC were resistant to antibody-dependent cell-mediated cytotoxicity. The results suggest that antibodies against antigens on the surface of endothelial cells may play a role in inducing vasculitis in Behçet's disease, not through a direct toxic effect of an antiendothelial cell antibody but by an indirect effect involving the activation of endothelial cells to produce cytokines.

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