Mitochondria-targeting moieties based on N-tethered pyridinium cations

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

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.

• Jezik: Angleški jezik
• Ključne besede: cancer, cations, fluorescentprobes, medicinal chemistry, mitochondria
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: MF - Medicinska fakulteta ; FFA - Fakulteta za farmacijo ; BF - Biotehniška fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2026
• Št. strani: 13 str.
• Številčenje: Vol. 65, iss. 29 , art. e7158257
• PID: 20.500.12556/RUL-184316
• UDK: 615.4:54:616-006
• ISSN pri članku: 1521-3773
• DOI: 10.1002/anie.7158257
• COBISS.SI-ID: 279001347
• Datum objave v RUL: 03.07.2026

Gradivo je del revije

• Naslov: Angewandte Chemie : international edition
• Skrajšan naslov: Angew. Chem.
• Založnik: Wiley
• ISSN: 1521-3773
• COBISS.SI-ID: 21810181

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: rak, kationi, fluorescentne sonde, medicinska kemija, mitohondriji