Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany.
Institute for Immunology, University Medical Center Mainz, Mainz, Germany.
Commun Biol. 2022 Jun 3;5(1):541. doi: 10.1038/s42003-022-03487-6.
Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons and GDAP1 knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolism characterized by glutamine dependence and fewer cytosolic lipid droplets. GDAP1 interacts with the actin-depolymerizing protein Cofilin-1 and beta-tubulin in a redox-dependent manner, suggesting a role for actin signaling. Consistently, GDAP1 loss causes less F-actin close to mitochondria, which restricts mitochondrial localization of the fission factor dynamin-related protein 1, instigating tubularity. GDAP1 silencing also disrupts mitochondria-ER contact sites. These changes result in lower mitochondrial Ca levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, our findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology.
Charcot-Marie-Tooth (CMT) 病 4A 是一种常染色体隐性多神经病，由神经节苷脂诱导分化相关蛋白 1 (GDAP1) 的突变引起，GDAP1 是一种假定的谷胱甘肽转移酶，它影响线粒体的形状并改变细胞内的钙稳态。在这里，我们确定了潜在的机制。我们发现，源自患者的运动神经元和 GDAP1 敲低的 SH-SY5Y 细胞表现出两种表型：更多的管状线粒体和以谷氨酰胺依赖性和更少的细胞质脂滴为特征的代谢。GDAP1 以氧化还原依赖的方式与肌动蛋白解聚蛋白 Cofilin-1 和β-微管蛋白相互作用，表明其具有肌动蛋白信号转导作用。一致地，GDAP1 的缺失导致靠近线粒体的 F-actin 减少，这限制了分裂因子 dynamin 相关蛋白 1 的线粒体定位，引发管状化。GDAP1 沉默也破坏了线粒体-内质网接触点。这些变化导致线粒体钙水平降低和丙酮酸脱氢酶复合物的抑制，解释了 GDAP1 功能丧失时的代谢变化。总之，我们的发现协调了 GDAP1 相关表型，并表明肌动蛋白信号转导的破坏与 CMT4A 的病理生理学有关。
