Lipid Metabolism Coordinates UPR^mt Induced By Decreased TCA Cycle Function In Caenorhabditis Elegans

The tricarboxylic acid ?TCA? cycle ,which plays role in mitochondria is an important metabolic pathway. The tricarboxylic acid cycle is the finally common metabolic pathway for carbohydrates,fats and amino acids. It is also a link between carbohydrates, lipids and amino acids. The tricarboxylic acid cycle is composed of a series of enzymatic reaction cycle of reaction system. In this process, acetyl coenzyme A and oxaloacetate condensation to form citrate. Citrate after four times dehydrogenation and two times decarboxylation resynthesis oxaloacetate. The NADH and FADH2 originate from tricarboxylic acid cycle enter the electron transport chain and produce ATP. At present, more and more studies show that the tricarboxylic acid cycle is closely related to metabolic diseases and the development of cancer.The mitochondrial unfloded protein response(UPR^mt) is a defensive means of mitochondrial self preservation. When the misfolded protein in the mitochondria accumulates, mitochondrial will induce UPR^mt to degradate the misfolded protein.And then transfer the signal to the nucleus to upregulae of protective genes. UPR^mt as the newly discovered intracellular stress mechanism, it is closely related to the development of diseases such as the aging, innate immune, neurodegenerative disease, type 2 diabetes and cancer.Caenorhabditis elegans as a model organism has a short growth cycle, clear genetic background etc. While UPR^mt was first discovered in mammals, the molecular mechanism involved has been more extensively studied in the model organism Caenorhabditis elegans. So we used Caenorhabditis elegans as experimental objects.Mitochondria are the energy factory of cell, which are closely related to the synthesis of fatty acids and beta oxidation. In this study, we find that mitochondrial perturbation caused by knocking down aco-2 and idha-1 not only induces UPR^mt in reproductive system specially, but also alters the lipid homeostasis through RNAi screening of genes in TCA cycle. In Celegans, aco-2 encodes aconitase that catalyze citric acid to isocitric acid, idha-1 encodes the Celegans homolog of the alpha subunit of mitochondrial isocitrate dehydrogenase that catalyze the formation of alpha-ketoglutarate from isocitrate. We hypothesized that the accumulation of lipid droplets after aco-2 or idha-1 RNAi may be related to the germline signaling pathway. Through screening, we find pha-4 mutant animals can rescue the large size of lipid droplets caused by aco-2 and idha-1 RNAi . Because aco-2 and idha-1 take part in the tricarboxylic acid cycle, we speculate that the content of citrate is increased after aco-2 or idha-1 RNAi. The results showed that the level of citrate is increased when aco-2 or idha-1 RNAi by HPLC. And we find supplement of citric acid cause the accumulation of fat and UPR^mt. ATFS-1, DVE-1 and UBL-5 are important transcription factors in UPR^mt, We also find that the atfs-1 ?tm4525?, dve-1?tm4803? and ubl-5 ?ok3389? mutant animals can inhibit the accumulation of lipid droplets after aco-2 or idha-1 RNAi.In summary, The main purpose of this paper is to explore how the TCA cycle affect the lipid metabolism and the mitochondrial unfolded protein response, and to study the mechanism between lipid metabolism and the mitochondrial unfolded protein response.