A Damage-Gated Small-Molecule Chimera Selectively Enhances Mitophagy by Coupling Dysfunctional Mitochondria to Autophagy.
10 affiliations
- 1Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
- 2Chemical Department, Lomonosov Moscow State University, Moscow, Russia.
- 3Faculty of Fundamental Medicine, M.V. Lomonosov Moscow State University, Moscow, Russia.
- 4Institute of Mitoengineering, Lomonosov Moscow State University, Moscow, Russia.
- 5Pirogov Russian National Research Medical University, Moscow, Russia.
- 6Shemyakin-Ovchinnicov Institute of Bioorganic Chemistry (branch), Russian Academy of Sciences, Pushchino, Russia.
- 7Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
- 8Moscow Center for Advanced Studies, Moscow, Russia.
- 9Peoples' Friendship University of Russia named After Patrice Lumumba, Moscow, Russia.
- 10Biological Faculty, Lomonosov Moscow State University, Moscow, Russia.
Abstract
Mitophagy is a central mitochondrial quality-control pathway, and its pharmacological activation is considered to be geroprotective. However, its small-molecule activators act indirectly by perturbing metabolism or mitochondrial function, limiting selectivity and increasing toxicity. Here, we describe a chemical biology strategy for activating damage-responsive mitophagy using bifunctional small molecules that couple mitochondrial recognition to the recruitment of the autophagic machinery. We designed and synthesized a focused library of chimeric molecules and identified MG-1 as a lead compound. It had minimal effects on basal autophagy but markedly enhanced autophagic flux and mitochondrial clearance under conditions of mitochondrial stress. Biochemical analyses, together with fluorescence and electron microscopy, showed that MG-1 promotes lysosomal degradation of damaged mitochondria without acting as a direct mitochondrial uncoupler. MG-1 was well tolerated across experimental systems and improved locomotor performance in a zebrafish model of MPTP-induced mitochondrial dysfunction. These findings establish damage-gated small-molecule chimeras as a promising approach for selective control of mitochondrial quality.
Related
- Exercise hormone irisin alleviates rheumatoid arthritis by removing dysfunctional mitochondria
- Organelle-Selective Autophagy in Cancer Immunotherapy: Mitophagy and Nucleophagy-Related Nuclear Quality Control as Regulators of Tumor–Immune Interactions
- Senotherapeutic role of pemafibrate through autophagy/mitophagy regulation in chronic obstructive pulmonary disease
- Sinapaldehyde Induces Mitochondrial Dysfunction and Modulates Autophagy/Mitophagy-Associated Signaling and Apoptosis in MDA-MB-231 Triple-Negative Breast Cancer Cells
- Human amniotic mesenchymal stem cell-derived exosomes alleviate cerebral Palsy–Associated neuronal damage via TSC1/mTOR/ULK1 autophagy suppression and PINK1/Parkin mitophagy restoration
BibTeX
@article{ozhiganov2026damagegated,
title = {{A Damage-Gated Small-Molecule Chimera Selectively Enhances Mitophagy by Coupling Dysfunctional Mitochondria to Autophagy.}},
author = {Ratislav M Ozhiganov and Ekaterina А Guseva and Alexander Yu Rudenko and Konstantin G Lyamzaev and Sofya Y Sokolskaya and Julia A Golubeva and Maria V Belopolskaya and Nadezda V Andrianova and Olga V Fadeeva and Elena О Morgun and Elena A Tukhovskaya and Marina S Kazakova and Vladimir M Pavlov and Daria K Yagoda and Elena I Marusich and Rose-Lys Zaranaina and Valeriya B Vays and Irina M Vangeli and Egor Y Plotnikov and Maxim L Lovat and Lora E Bakeeva and Arkady N Murashev and Vladimir I Polshakov and Olga A Dontsova and Peter V Sergiev},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = oct,
doi = {10.1002/advs.78570},
url = {https://europepmc.org/article/MED/42958763},
note = {CC BY},
}
RIS
TY - JOUR
TI - A Damage-Gated Small-Molecule Chimera Selectively Enhances Mitophagy by Coupling Dysfunctional Mitochondria to Autophagy.
AU - Ratislav M Ozhiganov
AU - Ekaterina А Guseva
AU - Alexander Yu Rudenko
AU - Konstantin G Lyamzaev
AU - Sofya Y Sokolskaya
AU - Julia A Golubeva
AU - Maria V Belopolskaya
AU - Nadezda V Andrianova
AU - Olga V Fadeeva
AU - Elena О Morgun
AU - Elena A Tukhovskaya
AU - Marina S Kazakova
AU - Vladimir M Pavlov
AU - Daria K Yagoda
AU - Elena I Marusich
AU - Rose-Lys Zaranaina
AU - Valeriya B Vays
AU - Irina M Vangeli
AU - Egor Y Plotnikov
AU - Maxim L Lovat
AU - Lora E Bakeeva
AU - Arkady N Murashev
AU - Vladimir I Polshakov
AU - Olga A Dontsova
AU - Peter V Sergiev
PY - 2026
DA - 2026/10/29
JO - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO - 10.1002/advs.78570
UR - https://europepmc.org/article/MED/42958763
AB - Mitophagy is a central mitochondrial quality-control pathway, and its pharmacological activation is considered to be geroprotective. However, its small-molecule activators act indirectly by perturbing metabolism or mitochondrial function, limiting selectivity and increasing toxicity. Here, we describe a chemical biology strategy for activating damage-responsive mitophagy using bifunctional small molecules that couple mitochondrial recognition to the recruitment of the autophagic machinery. We designed and synthesized a focused library of chimeric molecules and identified MG-1 as a lead compound. It had minimal effects on basal autophagy but markedly enhanced autophagic flux and mitochondrial clearance under conditions of mitochondrial stress. Biochemical analyses, together with fluorescence and electron microscopy, showed that MG-1 promotes lysosomal degradation of damaged mitochondria without acting as a direct mitochondrial uncoupler. MG-1 was well tolerated across experimental systems and improved locomotor performance in a zebrafish model of MPTP-induced mitochondrial dysfunction. These findings establish damage-gated small-molecule chimeras as a promising approach for selective control of mitochondrial quality.
SN - 2198-3844
ER -