Disordered maturation of mitochondrial matrix proteins in adipose tissue leads to local and systemic metabolic and inflammatory derangements in adipocyte-specific Mipep knockout mice

Most mitochondrial matrix proteins encoded in the nuclear genome are synthesized in the cytoplasm. These proteins subsequently undergo maturation through the cleavage of a signal sequence at the N-terminus by one or two mitochondrial signal peptidases, which is essential for their function within mitochondria. The present study demonstrates that adipocyte-specific knockout of one mitochondrial signal peptidase, mitochondrial intermediate peptidase (MIPEP), resulted in disordered mitochondrial proteostasis of MIPEP substrate proteins and their defective maturation. MIPEP deficiency in white and brown adipocytes suppressed the expression of adipocyte differentiation, lipid metabolism, and mitochondrial biogenesis genes. These alterations led to lipoatrophy in white adipose tissue and the whitening of brown adipose tissue. Additionally, it induced an atypical mitochondrial unfolded protein response and local inflammation in white and brown adipose tissue. Furthermore, it induced fatty liver and splenomegaly and caused systemic impairments in glucose metabolism and inflammation. These findings indicate that maturation defects of certain mitochondrial matrix proteins and subsequent proteostasis disorders in white and brown adipocytes cause chronic and systemic inflammatory and metabolic derangements. To investigate the function of MIPEP, we established adipose-specific Mipep Knockout (aMKO) mice by crossing Mipepflox/flox mice with Adiponectin-Cre mice. We then performed gene expression profiling analysis using data obtained from RNA-seq of genital white adipose tissue (gWAT) and brown adipose tissue (BAT) derived from control and aMKO mice (n =4 each). Comparative gene expression profiling analysis of RNA-seq data for control and aMKO mice in each gWAT and BAT.绝大多数由核基因组编码的线粒体基质蛋白均在细胞质中合成。此类蛋白后续需经1或2种线粒体信号肽酶（mitochondrial signal peptidases）切割其N端信号序列以完成成熟过程，该过程对其在线粒体内发挥功能至关重要。本研究证实，针对线粒体信号肽酶之一的线粒体中间肽酶（mitochondrial intermediate peptidase, MIPEP）开展脂肪细胞特异性敲除，会导致MIPEP底物蛋白的线粒体蛋白质稳态失衡及其成熟过程缺陷。白色脂肪细胞与棕色脂肪细胞中的MIPEP缺失，会抑制脂肪细胞分化、脂质代谢及线粒体生物发生相关基因的表达。上述改变会引发白色脂肪组织的脂肪萎缩以及棕色脂肪组织的白色化。此外，该敲除模型还会在白色与棕色脂肪组织中诱导非典型线粒体未折叠蛋白反应及局部炎症。进一步而言，该模型会诱发脂肪肝与脾肿大，并造成葡萄糖代谢与炎症相关的全身性功能损伤。上述研究结果表明，部分线粒体基质蛋白的成熟缺陷以及由此引发的白色与棕色脂肪细胞内蛋白质稳态失衡，会导致慢性全身性炎症与代谢紊乱。为探究MIPEP的功能，本研究通过将Mipepflox/flox小鼠与Adiponectin-Cre小鼠杂交，构建了脂肪组织特异性Mipep敲除（aMKO）小鼠模型。随后，本研究利用对照组与aMKO小鼠（每组n=4）的生殖周白色脂肪组织（genital white adipose tissue, gWAT）与棕色脂肪组织（brown adipose tissue, BAT）的RNA测序（RNA-seq）数据，开展了基因表达谱分析，并针对各组gWAT与BAT的RNA-seq数据，完成了对照组与aMKO小鼠的对比基因表达谱分析。