Mitochondria-targeting moieties based on N-tethered pyridinium cations

Džajić, Ivan (author), Trunkelj, Natalija (author), Repas, Jernej (author), Kandušer, Maša (author), Smrdel, Lara (author), Pajk, Stane (author), Žiberna, Lovro (author), Mlinarič-Raščan, Irena (author), Markelc, Boštjan (author), Omerzel, Maša (author), Jesenko, Tanja (author), Tomašič, Tihomir (author), Peterlin-Mašič, Lucija (author), Cotman, Andrej Emanuel (author)

Mitochondria-targeting moieties (MTMs) are molecular fragments designed to deliver covalently tethered functional cargo to mitochondria, providing a modular strategy for chemical biology tools, imaging agents, and mitochondria-targeted therapies. Phosphonium- or nitrogen cation-based MTMs are not inert vectors and exhibit intrinsic bioactivity on mitochondrial and cellular levels to various extents. Here, we systematically evaluated a panel of N+-based cations to determine how structural features influence subcellular distribution and inherent bioactivity. Live-cell imaging of fluorescent dye conjugates revealed that 3,5-diphenylpyridinium (DPPy+) exhibits cellular uptake and mitochondrial targeting comparable to the benchmark triphenylphosphonium (TPP+), whereas conjugates with unsubstituted pyridinium preferentially accumulate in lysosomes. Profiling of inert cargo derivatives showed that DPPy+ has lower intrinsic activity on mitochondrial membrane potential and oxidative phosphorylation, as well as on cellular respiration and viability than TPP+. The combination of efficient mitochondrial delivery and low intrinsic bioactivity translated to bioactive cargo: a Kv1.3 inhibitor conjugate with DPPy+ induced apoptosis in cancer cell lines and demonstrated improved cancer selectivity relative to the TPP+ conjugate in pancreatic organoid models. These results position lipophilic pyridinium cations as effective TPP+ surrogates with enhanced biocompatibility for mitochondria-targeted therapeutic and diagnostic agents, while revealing the structure-dependent competing lysosomal accumulation of permanent nitrogen cations.

• Language: English
• Keywords: cancer, cations, fluorescentprobes, medicinal chemistry, mitochondria
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine; FFA - Faculty of Pharmacy; BF - Biotechnical Faculty
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: 13 str.
• Numbering: Vol. 65, iss. 29 , art. e7158257
• PID: 20.500.12556/RUL-184316
• UDC: 615.4:54:616-006
• ISSN on article: 1521-3773
• DOI: 10.1002/anie.7158257
• COBISS.SI-ID: 279001347
• Publication date in RUL: 03.07.2026

Record is a part of a journal

• Title: Angewandte Chemie : international edition
• Shortened title: Angew. Chem.
• Publisher: Wiley
• ISSN: 1521-3773
• COBISS.SI-ID: 21810181

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: rak, kationi, fluorescentne sonde, medicinska kemija, mitohondriji