We review the key developments in our understanding of subcorneal pustular dermatosis (SCPD, also known as Sneddon-Wilkinson disease) over the past 50 years. SCPD is a rare, chronic, sterile pustular eruption that was first described by Sneddon and Wilkinson in 1956. The primary lesions are pea-sized pustules classically described as half-pustular, half-clear flaccid fluid blisters. Histologically the salient feature is a subcorneal accumulation of neutrophils, suggesting the presence of chemoattractants such as tumour necrosis factor (TNF)alpha in the uppermost epidermis. However, to date its exact pathophysiology is unknown. Cases in association with pyoderma gangrenosum, benign monoclonal IgA gammopathy and multiple myeloma are well documented. There are anecdotal reports of SCPD associated with other internal malignancies such as chronic lymphocytic leukaemia, thymoma, apudoma and epidermoid carcinoma of the lung. The treatment of choice is dapsone. Therapeutic alternatives include retinoids, phototreatment with psoralen ultraviolet (UV) A, broadband or narrow band UVB and corticosteroids. Anecdotal uses of tacalcitol, ketoconazole, azithromycin, tetracycline, minocycline, vitamin E, ciclosporin, colchicine, mizoribine, mebhydrolin, infliximab and adalimumab with mycophenolate mofetil have all been reported.
Mitochondrial dynamics is important for life. At center stage for mitochondrial dynamics, the balance between mitochondrial fission and fusion is a set of dynamin‐related GTP ases that drive mitochondrial fission and fusion. Fission is executed by the GTP ases Drp1 and Dyn2, whereas the GTP ases Mfn1, Mfn2, and OPA 1 promote fusion. Recruitment of Drp1 to mitochondria is a critical step in fission. In yeast, Fis1p recruits the Drp1 homolog Dnm1p to mitochondria through Mdv1p and Caf4p, but whether human Fis1 ( hF is1) promotes fission through a similar mechanism as in yeast is not established. Here, we show that hF is1‐mediated mitochondrial fragmentation occurs in the absence of Drp1 and Dyn2, suggesting that they are dispensable for hF is1 function. hF is1 instead binds to Mfn1, Mfn2, and OPA 1 and inhibits their GTP ase activity, thus blocking the fusion machinery. Consistent with this, disruption of the fusion machinery in Drp1 −/− cells phenocopies the fragmentation phenotype induced by hF is1 overexpression. In sum, our data suggest a novel role for hF is1 as an inhibitor of the fusion machinery, revealing an important functional evolutionary divergence between yeast and mammalian Fis1 proteins.
Mitochondria are highly dynamic organelles and important for a variety of cellular functions. They constantly undergo fission and fusion events, referred to as mitochondrial dynamics, which affects the shape, size, and number of mitochondria in the cell, as well as mitochondrial subcellular transport, mitochondrial quality control (mitophagy), and programmed cell death (apoptosis). Dysfunctional mitochondrial dynamics is associated with various human diseases. Mitochondrial dynamics is mediated by a set of mitochondria-shaping proteins in both yeast and mammals. In this review, we describe recent insights into the potential molecular mechanisms underlying mitochondrial fusion and fission, particularly highlighting the coordinating roles of different mitochondria-shaping proteins in the processes, as well as the roles of the endoplasmic reticulum (ER), the actin cytoskeleton and membrane phospholipids in the regulation of mitochondrial dynamics. We particularly focus on emerging roles for the mammalian mitochondrial proteins Fis1, Mff, and MIEFs (MIEF1 and MIEF2) in regulating the recruitment of the cytosolic Drp1 to the surface of mitochondria and how these proteins, especially Fis1, mediate crosstalk between the mitochondrial fission and fusion machineries. In summary, this review provides novel insights into the molecular mechanisms of mammalian mitochondrial dynamics and the involvement of these mechanisms in apoptosis and autophagy.
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