Highly active antiretroviral therapy has been associated with the emergence of lipodystrophy syndromes that have clinical features commonly seen in patients with mitochondrial dysfunction. The effect of therapeutic protease inhibitors (PIs) on mitochondrial function is unknown. Mitochondrial matrix space proteins possess an amino-terminal leader peptide that is removed by the mitochondrial processing protease (MPP). Lack of cleavage could result in non- or dysfunctional mitochondrial proteins. The effects of different PIs on protease processing using pure MPP or yeast mitochondria, recognized models for mammalian counterparts, were examined in vitro. Multiple PIs were found to inhibit MPP, evidenced by accumulation of immature pALDH and decreased levels of processed ALDH. Both indinavir and amprenavir at 5.0 mg/ml resulted in significant inhibition of MPP. Although inhibition of MPP was also observed with ritonavir and saquinavir, the inhibition was difficult to quantify due to background inhibition of MPP by DMSO that was required to solubilize the drugs for the in vitro studies. Indinavir was also shown to inhibit MPP within yeast mitochondria. Lack of processing may impair mitochondrial function and contribute to the observed mitochondrial dysfunctions in patients receiving HAART and implicated in antiretroviral-associated lipodystrophy.

中文翻译：

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酵母中 HIV-1 蛋白酶抑制剂抑制线粒体蛋白酶加工的体外证据：可能导致脂肪代谢障碍综合征

高活性抗逆转录病毒治疗与脂肪营养不良综合征的出现有关，这些综合征具有在线粒体功能障碍患者中常见的临床特征。治疗性蛋白酶抑制剂 (PI) 对线粒体功能的影响尚不清楚。线粒体基质空间蛋白具有被线粒体加工蛋白酶 (MPP) 去除的氨基末端前导肽。缺乏切割可能导致线粒体蛋白无功能或功能失调。在体外检查了不同 PI 对使用纯 MPP 或酵母线粒体（哺乳动物对应物的公认模型）的蛋白酶加工的影响。发现多种 PI 抑制 MPP，未成熟 pALDH 的积累和加工的 ALDH 水平降低证明了这一点。茚地那韦和安普那韦均为 5。0 mg/ml 导致 MPP 的显着抑制。虽然也观察到利托那韦和沙奎那韦对 MPP 的抑制作用，但由于 DMSO 对 MPP 的背景抑制作用是在体外研究中溶解药物所必需的，因此这种抑制作用难以量化。茚地那韦也被证明可以抑制酵母线粒体内的 MPP。缺乏处理可能会损害线粒体功能，并导致在接受 HAART 的患者中观察到的线粒体功能障碍，并与抗逆转录病毒相关的脂肪代谢障碍有关。