Mitochondrial dysfunction is an underlying pathology in numerous diseases. Delivery of diagnostic and therapeutic cargo directly into mitochondria is a powerful approach to study and treat these diseases. The triphenylphosphonium (TPP⁺) moiety is the most widely used mitochondriotropic carrier. However, studies have shown that TPP⁺ is not inert; TPP⁺ conjugates uncouple mitochondrial oxidative phosphorylation. To date, all efforts toward addressing this problem have focused on modifying lipophilicity of TPP⁺-linker-cargo conjugates to alter mitochondrial uptake, albeit with limited success. We show that structural modifications to the TPP⁺ phenyl rings that decrease electron density on the phosphorus atom can abrogate uncoupling activity as compared to the parent TPP⁺ moiety and prevent dissipation of mitochondrial membrane potential. These alterations of the TPP⁺ structure do not negatively affect the delivery of cargo to mitochondria. Results here identify the 4-CF₃-phenyl TPP⁺ moiety as an inert mitochondria-targeting carrier to safely target pharmacophores and probes to mitochondria.

中文翻译：

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一种无需解偶联氧化磷酸化即可靶向线粒体的新型三苯基鏻载体

线粒体功能障碍是许多疾病的潜在病理学。将诊断和治疗货物直接送入线粒体是研究和治疗这些疾病的有效方法。三苯基鏻 (TPP ⁺ ) 部分是最广泛使用的促线粒体载体。然而，研究表明TPP ⁺不是惰性的；TPP ⁺缀合物解偶联线粒体氧化磷酸化。迄今为止，解决这个问题的所有努力都集中在改变 TPP ⁺ -接头 - 货物缀合物的亲脂性以改变线粒体摄取，尽管成功有限。我们展示了对 TPP 的结构修改^{+与母体 TPP +}部分相比，降低磷原子上电子密度的苯环可以消除解偶联活性并防止线粒体膜电位的消散。^{TPP +}结构的这些改变不会对货物向线粒体的输送产生负面影响。此处的结果将 4-CF ₃ -苯基 TPP ⁺部分鉴定为惰性线粒体靶向载体，以安全地将药效团和探针靶向线粒体。