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Effects of clofibrate and KH176 on life span and motor function in mitochondrial complex I-deficient mice.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 4.2 ) Pub Date : 2020-02-15 , DOI: 10.1016/j.bbadis.2020.165727 Sanne J C M Frambach 1 , Melissa A E van de Wal 1 , Petra H H van den Broek 2 , Jan A M Smeitink 3 , Frans G M Russel 1 , Ria de Haas 3 , Tom J J Schirris 1
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 4.2 ) Pub Date : 2020-02-15 , DOI: 10.1016/j.bbadis.2020.165727 Sanne J C M Frambach 1 , Melissa A E van de Wal 1 , Petra H H van den Broek 2 , Jan A M Smeitink 3 , Frans G M Russel 1 , Ria de Haas 3 , Tom J J Schirris 1
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Mitochondrial complex I (CI), the first multiprotein enzyme complex of the OXPHOS system, executes a major role in cellular ATP generation. Consequently, dysfunction of this complex has been linked to inherited metabolic disorders, including Leigh disease (LD), an often fatal disease in early life. Development of clinical effective treatments for LD remains challenging due to the complex pathophysiological nature. Treatment with the peroxisome proliferation-activated receptor (PPAR) agonist bezafibrate improved disease phenotype in several mitochondrial disease mouse models mediated via enhanced mitochondrial biogenesis and fatty acid β-oxidation. However, the therapeutic potential of this mixed PPAR (α, δ/β, γ) agonist is severely hampered by hepatotoxicity, which is possibly caused by activation of PPARγ. Here, we aimed to investigate the effects of the PPARα-specific fibrate clofibrate in mitochondrial CI-deficient (Ndufs4-/-) mice. Clofibrate increased lifespan and motor function of Ndufs4-/- mice, while only marginal hepatotoxic effects were observed. Due to the complex clinical and cellular phenotype of CI-deficiency, we also aimed to investigate the therapeutic potential of clofibrate combined with the redox modulator KH176. As described previously, single treatment with KH176 was beneficial, however, combining clofibrate with KH176 did not result in an additive effect on disease phenotype in Ndufs4-/- mice. Overall, both drugs have promising, but independent and nonadditive, properties for the pharmacological treatment of CI-deficiency-related mitochondrial diseases.
中文翻译：
氯贝特和KH176对线粒体复合体I缺陷小鼠的寿命和运动功能的影响。
线粒体复合体I（CI）是OXPHOS系统的第一个多蛋白酶复合体，在细胞ATP产生中起着重要作用。因此，这种复合物的功能障碍与遗传代谢疾病有关，包括利氏病（LD），这是生命早期经常致命的疾病。由于复杂的病理生理性质，对LD的临床有效治疗的开发仍然具有挑战性。用过氧化物酶体增殖激活受体（PPAR）激动剂苯扎贝特治疗可改善线粒体生物发生和脂肪酸β-氧化作用介导的几种线粒体疾病小鼠模型的疾病表型。但是，这种混合的PPAR（α，δ/β，γ）激动剂的治疗潜力受到肝毒性的严重阻碍，这可能是由于PPARγ活化引起的。这里，我们旨在研究PPARα特异性贝特酸氯贝特对线粒体CI缺失（Ndufs4-/-）小鼠的影响。氯贝贝特可延长Ndufs4-/-小鼠的寿命和运动功能，而仅观察到少量的肝毒性作用。由于CI缺乏症的临床和细胞表型复杂，我们还旨在研究氯贝贝酸盐与氧化还原调节剂KH176结合的治疗潜力。如前所述，用KH176进行单次治疗是有益的，但是，将氯贝贝酸盐与KH176合并使用不会对Ndufs4-/-小鼠的疾病表型产生累加作用。总体而言，这两种药物在与CI缺乏相关的线粒体疾病的药物治疗中均具有前景广阔但独立且非加性的特性。
更新日期：2020-03-19
中文翻译：
氯贝特和KH176对线粒体复合体I缺陷小鼠的寿命和运动功能的影响。
线粒体复合体I（CI）是OXPHOS系统的第一个多蛋白酶复合体，在细胞ATP产生中起着重要作用。因此，这种复合物的功能障碍与遗传代谢疾病有关，包括利氏病（LD），这是生命早期经常致命的疾病。由于复杂的病理生理性质，对LD的临床有效治疗的开发仍然具有挑战性。用过氧化物酶体增殖激活受体（PPAR）激动剂苯扎贝特治疗可改善线粒体生物发生和脂肪酸β-氧化作用介导的几种线粒体疾病小鼠模型的疾病表型。但是，这种混合的PPAR（α，δ/β，γ）激动剂的治疗潜力受到肝毒性的严重阻碍，这可能是由于PPARγ活化引起的。这里，我们旨在研究PPARα特异性贝特酸氯贝特对线粒体CI缺失（Ndufs4-/-）小鼠的影响。氯贝贝特可延长Ndufs4-/-小鼠的寿命和运动功能，而仅观察到少量的肝毒性作用。由于CI缺乏症的临床和细胞表型复杂，我们还旨在研究氯贝贝酸盐与氧化还原调节剂KH176结合的治疗潜力。如前所述，用KH176进行单次治疗是有益的，但是，将氯贝贝酸盐与KH176合并使用不会对Ndufs4-/-小鼠的疾病表型产生累加作用。总体而言，这两种药物在与CI缺乏相关的线粒体疾病的药物治疗中均具有前景广阔但独立且非加性的特性。
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