https://ror.org/024z2rq82 Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
https://ror.org/024z2rq82 Institute of Plant Biochemistry, Cluster of Excellence on Plant Sciences (CEPLAS), Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Life Sci Alliance. 2024 Oct 11;7(12). doi: 10.26508/lsa.202403038. Print 2024 Dec.
Mitochondria play central roles in metabolism and metabolic disorders such as type 2 diabetes. MIC26, a mitochondrial contact site and cristae organising system complex subunit, was linked to diabetes and modulation of lipid metabolism. Yet, the functional role of MIC26 in regulating metabolism under hyperglycemia is not understood. We used a multi-omics approach combined with functional assays using WT and KO cells cultured in normoglycemia or hyperglycemia, mimicking altered nutrient availability. We show that MIC26 has an inhibitory role in glycolysis and cholesterol/lipid metabolism under normoglycemic conditions. Under hyperglycemia, this inhibitory role is reversed demonstrating that MIC26 is critical for metabolic adaptations. This is partially mediated by alterations of mitochondrial metabolite transporters. Furthermore, deletion led to a major metabolic rewiring of glutamine use and oxidative phosphorylation. We propose that MIC26 acts as a metabolic "rheostat," that modulates mitochondrial metabolite exchange via regulating mitochondrial cristae, allowing cells to cope with nutrient overload.
线粒体在代谢和代谢紊乱（如 2 型糖尿病）中发挥核心作用。MIC26 是线粒体接触位点和嵴组织系统复合物亚基，与糖尿病和脂质代谢的调节有关。然而，MIC26 在高血糖条件下调节代谢的功能作用尚不清楚。我们使用多组学方法结合使用 WT 和 KO 细胞在正常血糖或高血糖下培养的功能测定，模拟改变的营养可用性。我们表明，MIC26 在正常血糖条件下对糖酵解和胆固醇/脂质代谢具有抑制作用。在高血糖下，这种抑制作用被逆转，表明 MIC26 对于代谢适应至关重要。这部分是通过改变线粒体代谢物转运蛋白介导的。此外，缺失导致谷氨酰胺利用和氧化磷酸化的主要代谢重排。我们提出 MIC26 作为一种代谢“变阻器”，通过调节线粒体嵴来调节线粒体代谢物交换，使细胞能够应对营养超负荷。
