Enabling Mitochondrial Uptake of Lipophilic Dications Using Methylated Triphenylphosphonium Moieties

• Type: Article in International Scientific Journal
• Date: 2019

Authors

Ong, HC (Author) Other; Hu, Z (Author) Other; Coimbra, JTS (Author) Other; Ramos, MJ (Author) FCUP; Kon, OL (Author) Other; Xing, BG (Author) Other; Yeow, EKL (Author) Other; Pedro A Fernandes (Author) FCUP; Garcia, F (Author) Other

Journal

Title: Inorganic Chemistry

Vol. 58

Pages: 8293-8299

ISSN: 0020-1669

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 14 Citations

Scopus - 15 Citations

Other information

Authenticus ID: P-00Q-RPX

DOI: 10.1021/acs.inorgchem.8b03380

Abstract (EN): Triphenylphosphonium (TPP+) species comprising multiple charges, i.e., bis-TPP+, are predicted to be superior mitochondrial-targeting vectors and are expected to have mitochondrial accumulations 1000-fold greater than TPP+, the current "gold standard". However, bis-TPP+ vectors linked by short hydrocarbon chains (n < 5) are unable to be taken up by the mitochondria, thus hindering their development as mitochondrial delivery vectors. Through the incorporation of methylated TPP+ moieties (T*PP+), we successfully enabled the accumulation of bis-TPP+ with a short linker chain in isolated mitochondria, as measured by high performance liquid chromatography. These experimental results are further supported by molecular dynamics and ab initio calculations, revealing the strong correlations between mitochondria uptake and molecular volume, surface area, and chemical hardness. Most notably, the molecular volume has been shown to be a strong predictor of accumulation for both mono- and bis-TPP+ salts. Our study underscores the potential of T*PP+ moieties as alternative mitochondrial vectors to overcome low permeation into the mitochondria.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 7