Phillip Jude M, Lin Ran, Cheetham Andrew, Stern David, Li Yukang, Wang Yuzhu, Wang Han, Rini David, Cui Honggang, Walston Jeremy D, Abadir Peter M
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
PNAS Nexus. 2022 Aug 4;1(4):pgac147. doi: 10.1093/pnasnexus/pgac147. eCollection 2022 Sep.
Mitochondria are critical regulators of cellular function and survival. We have previously demonstrated that functional angiotensin receptors embedded within the inner mitochondrial membrane modulate mitochondrial energy production and free radical generation. The expression of mitochondrial angiotensin II type-1 receptors increases during aging, with a complementary decrease in angiotensin II type-2 receptor density. To address this age-associated mitochondrial dysfunction, we have developed a mitochondria-targeted delivery system to effectively transport angiotensin type-1 receptor blocker-Losartan (mtLOS) into the inner mitochondrial membrane. We engineered mtLOS to become active within the mitochondria after cleavage by mitochondrial peptidases. Our data demonstrate effective and targeted delivery of mtLOS into the mitochondria, compared to a free Losartan, or Losartan conjugated to a scrambled mitochondrial target signal peptide, with significant shifts in mitochondrial membrane potential upon mtLOS treatment. Furthermore, engineered mitochondrial-targeting modalities could open new avenues to transport nonmitochondrial proteins into the mitochondria, such as other macromolecules and therapeutic agents.
线粒体是细胞功能和存活的关键调节因子。我们之前已经证明，嵌入线粒体内膜的功能性血管紧张素受体可调节线粒体能量产生和自由基生成。线粒体1型血管紧张素受体的表达在衰老过程中增加，同时2型血管紧张素受体密度相应降低。为了解决这种与年龄相关的线粒体功能障碍，我们开发了一种线粒体靶向递送系统，以有效地将血管紧张素1型受体阻滞剂——氯沙坦（mtLOS）转运到线粒体内膜。我们对mtLOS进行了改造，使其在被线粒体肽酶切割后在线粒体内变得活跃。我们的数据表明，与游离氯沙坦或与混乱的线粒体靶向信号肽缀合的氯沙坦相比，mtLOS能有效且有针对性地递送至线粒体，mtLOS处理后线粒体膜电位发生显著变化。此外，工程化的线粒体靶向方式可能为将非线粒体蛋白转运到线粒体中开辟新途径，例如其他大分子和治疗剂。
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