Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell Rep. 2021 Feb 2;34(5):108689. doi: 10.1016/j.celrep.2021.108689.
The epidermis regenerates continually to maintain a protective barrier at the body's surface composed of differentiating keratinocytes. Maturation of this stratified tissue requires that keratinocytes undergo wholesale organelle degradation upon reaching the outermost tissue layers to form compacted, anucleate cells. Through live imaging of organotypic cultures of human epidermis, we find that regulated breakdown of mitochondria is critical for epidermal development. Keratinocytes in the upper layers initiate mitochondrial fragmentation, depolarization, and acidification upon upregulating the mitochondrion-tethered autophagy receptor NIX. Depleting NIX compromises epidermal maturation and impairs mitochondrial elimination, whereas ectopic NIX expression accelerates keratinocyte differentiation and induces premature mitochondrial fragmentation via the guanosine triphosphatase (GTPase) DRP1. We further demonstrate that inhibiting DRP1 blocks NIX-mediated mitochondrial breakdown and disrupts epidermal development. Our findings establish mitochondrial degradation as a key step in terminal keratinocyte differentiation and define a pathway operating via the mitophagy receptor NIX in concert with DRP1 to drive epidermal morphogenesis.
表皮不断再生，以维持身体表面由分化角蛋白细胞组成的保护性屏障。这种分层组织的成熟要求角蛋白细胞在到达最外层组织层时进行整体细胞器降解，形成紧密的无核细胞。通过对人表皮器官型培养的实时成像，我们发现线粒体的调控性降解对于表皮发育至关重要。在上层的角蛋白细胞中，当上调与线粒体相连的自噬受体 NIX 时，会引发线粒体碎片化、去极化和酸化。消耗 NIX 会损害表皮成熟并阻碍线粒体的消除，而异位表达 NIX 则通过鸟嘌呤核苷酸三磷酸酶 (GTPase) DRP1 加速角蛋白细胞分化并诱导过早的线粒体碎片化。我们进一步证明，抑制 DRP1 可阻断 NIX 介导的线粒体降解并破坏表皮发育。我们的发现确立了线粒体降解作为终末角蛋白细胞分化的关键步骤，并定义了一条通过与 DRP1 协同作用的自噬受体 NIX 发挥作用的途径，以驱动表皮形态发生。
