线粒体脑肌病中FGF21及GDF15介导的能量代谢重构调控机制研究

Mitochondrial encephalomyopathy are multisystem genetic disorders with mutations in mtDNA or nDNA, which are among the most common and most complex of rare diseases. Considerable challenges remain in the area of the therapy of those patients with mitochondrial diseases and the tissue specificity and multisystem involvement seen in mitochondrial diseases. Our previous study showed that the serum concentration of FGF21 and GDF15 are remarkably elevated in patients with mitochondrial disease and also associate with clinical severity and muscle pathology. The skeletal muscle with mitochondrial dysfunction call on the adipose tissue and the liver to supply adequate fuel with systemically available FGF21, which results in the recruitment of lipid, glucose, and other fuel to skeletal muscle fibers. Moreover, muscle-derived FGF21 acts locally on muscle fiber itself via autocrine and paracrine mechanisms to compensate for the metabolic defect by enhancing glucose uptake, fatty acid oxidation, and glycolysis as well as respiratory chain complex activities. Therefore, we propose that the muscle cells with mitochondrial defect could initiate whole organism energy metabolic change by muscle-secreted cytokine including GDF15 and FGF21. We investigate whether serum FGF21 and GDF15 concentration is a valuable and reliable diagnostic biomarker of mitochondrial diseases and the role of the role of FGF21 and GDF15 on energy metabolic re-programming in mitochondrial encephalomyopathy. We will also assess the efficacy of Coenzyme Q10 and ketone body on mitochondrial diseases by serum FGF21 and GDF15 levels.

线粒体脑肌病是一组临床表现复杂的罕见疾病，缺乏有效的实验室筛选诊断方法和治疗手段。成纤维细胞生长因子（FGF21）具有调节线粒体功能以及葡萄糖和脂肪代谢的作用；生长分化因子15（GDF15）是重要的氧化应激损伤调节因子。我们前期研究提示：线粒体脑肌病的血清和肌肉组织中FGF21和GDF15明显升高，且与肌肉病理改变和病情严重程度相关。线粒体脑肌病的肌肉细胞可通过上调FGF21来促进葡萄糖及脂肪酸的利用。我们推测FGF21和GDF15可能作为线粒体能量代谢障碍的血清标志物，并通过调控机体能量代谢，对线粒体病的临床表型和转归产生影响。本研究拟采用体外分子干预和模型动物体内实验的方法对线粒体病小鼠模型进行研究，探讨FGF21和GDF15在线粒体病诊断中的价值及其对机体能量代谢调控的机制。本研究同时探索通过FGF21和GDF15血清浓度监测, 对辅酶Q10和酮体治疗线粒体病模型动物的疗效进行评价。

线粒体脑肌病是一组临床表现复杂的罕见疾病，目前仍缺乏行之有效的治疗手段。前期研究发现成纤维细胞生长因子（FGF21）和生长分化因子15（GDF15）在线粒体病患者血清中显著升高，且并与代谢密切相关，我们推测FGF21和GDF15可能通过调控机体能量代谢，对线粒体病的临床表型和转归产生影响。本研究中，我们首先检测了不同类型线粒脑肌病患者血清中GDF15的表达水平，我们发现，编码tRNA的线粒体基因突变的线粒体脑肌病患者的血清GDF15水平显著高于编码复合体1亚单位蛋白的线粒体基因突变的患者，而从表型来看，以线粒体脑病及视神经病变为主要表现的患者血清中GDF15水平显著低于线粒体肌病患者。我们继而以线粒体病脑病（Leigh综合征）小鼠模型为研究对象，该小鼠血清GDF15和FGF21水平并没有升高，我们在其发病早期开始给予口服PPAR受体激动剂苯扎贝特治疗，显著升高了其血清FGF21和GDF15水平，小鼠的生存期及神经系统症状均得到显著改善。传统观点认为PPAR激动剂主要发挥诱导线粒体增殖、增强代谢等作用，而我们未检测到苯扎贝特的代谢激活作用，我们发现苯扎贝特通过FGF21-NPY1等通路诱导了周期性低代谢状态，通过上调GDF15表达水平减少进食量，抑制生长发育。苯扎贝特一方面降低了能量需求，同时降低了细胞氧化磷酸化、减少自由基的产生，从而发挥治疗作用。因此，苯扎贝特能够明显改善线粒体脑病小鼠的生存期和表型，其背后的机制可能是通过调控GDF15和FGF21水平，降低机体和组织对能量的需求的同时显著降低了自由基对脑组织的损伤。我们推测通过调控FGF21和GDF15的表达水平可能是未来治疗线粒体脑肌病的有效手段之一。

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