Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany
EMBO Rep. 2018 May;19(5). doi: 10.15252/embr.201745126. Epub 2018 Mar 27.
Mitochondria are fundamental for cellular metabolism as they are both a source and a target of nutrient intermediates originating from converging metabolic pathways, and their role in the regulation of systemic metabolism is increasingly recognized. Thus, maintenance of mitochondrial homeostasis is indispensable for a functional energy metabolism of the whole organism. Here, we report that loss of the mitochondrial matrix protease CLPP results in a lean phenotype with improved glucose homeostasis. Whole-body CLPP-deficient mice are protected from diet-induced obesity and insulin resistance, which was not present in mouse models with either liver- or muscle-specific depletion of CLPP However, CLPP ablation also leads to a decline in brown adipocytes function leaving mice unable to cope with a cold-induced stress due to non-functional adaptive thermogenesis. These results demonstrate a critical role for CLPP in different metabolic stress conditions such as high-fat diet feeding and cold exposure providing tools to understand pathologies with deregulated expression and novel insights into therapeutic approaches against metabolic dysfunctions linked to mitochondrial diseases.
线粒体对于细胞代谢至关重要，因为它们既是来自汇聚代谢途径的营养中间体的来源，也是其靶标，其在调节全身代谢中的作用正日益得到认可。因此，维持线粒体的内稳态对于整个生物体的功能性能量代谢是必不可少的。在这里，我们报告称，线粒体基质蛋白酶 CLPP 的缺失会导致瘦表型，并改善葡萄糖稳态。全身性 CLPP 缺陷型小鼠可预防饮食诱导的肥胖和胰岛素抵抗，而在肝特异性或肌肉特异性 CLPP 耗竭的小鼠模型中则不存在这种情况。然而，CLPP 缺失也会导致棕色脂肪细胞功能下降，使小鼠由于无法进行功能性适应性产热而无法应对冷应激。这些结果表明 CLPP 在不同的代谢应激条件（如高脂肪饮食喂养和暴露于寒冷环境）中发挥着关键作用，为理解表达失调的病理学提供了工具，并为针对与线粒体疾病相关的代谢功能障碍的治疗方法提供了新的见解。
