ミトコンドリア由来PEPはSLC25A35を介してグリセロ脂質合成をライセンスする

Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains the highest energy phosphate bond above ATP, and has diverse biological functions, including glycolysis, gluconeogenesis, and glyceroneogenesis. Although PEP is generally considered a cytosolic intermediate, it can also be synthesized within mitochondria by the mitochondria-localized carboxykinase (PCK2, also known as M-PEPCK). However, the mechanism by which mitochondrial PEP is delivered to the cytosolic compartment and caters to cell-specific requirements remains elusive. Here, we identify SLC25A35, a previously uncharacterized mitochondrial inner-membrane protein, as the long-sought carrier responsible for mitochondrial PEP efflux. SLC25A35 is highly expressed in lipogenic cells, such as adipocytes, which employ the mitochondrial pyruvate-to-PEP bypass, and is upregulated by lipogenic stimuli. Reconstitution studies by proteo-liposomes, together with structural analyses, demonstrated specific PEP transport by SLC25A35 in a pH gradient-dependent manner. Importantly, loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, the glycerol backbone in triglyceride, resulting in reduced glycerolipid synthesis while preserving substrate oxidation in the TCA cycle. Furthermore, blockade of SLC25A35 in the liver of obese mice markedly decreased glycerolipid accumulation, ameliorated hepatic steatosis, and improved systemic glucose homeostasis. Together, the present study identifies mitochondrial PEP transport via SLC25A35 as a metabolic checkpoint of fatty acid esterification, offering a selective target for "lipogenic mitochondria" to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and Type 2 diabetes.