Nature-inspired delivery of mitochondria-targeted angiotensin receptor blocker

Jude M Phillip; Ran Lin; Andrew Cheetham; David Stern; Yukang Li; Yuzhu Wang; Han Wang; David Rini; Honggang Cui; Jeremy D Walston; Peter M Abadir

doi:10.1093/pnasnexus/pgac147

Nature-inspired delivery of mitochondria-targeted angiotensin receptor blocker

PNAS Nexus. 2022 Aug 4;1(4):pgac147. doi: 10.1093/pnasnexus/pgac147. eCollection 2022 Sep.

Authors

Jude M Phillip^{1

2

3

4}, Ran Lin^{2

3}, Andrew Cheetham², David Stern^{2

3}, Yukang Li³, Yuzhu Wang^{2

3}, Han Wang^{2

3}, David Rini⁵, Honggang Cui^{2

3}, Jeremy D Walston⁶, Peter M Abadir⁶

Affiliations

¹ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
² Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
³ Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD, USA.
⁴ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Art as Applied to Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Medicine, Division of Geriatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Abstract

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.

Keywords: Losartan; angiotensin system; mitochondria; mitochondrial targeting.

Abstract

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