Kim 2023 Nat Commun
| Kim Y, Li C, Gu C, Fang Y, Tycksen E, Puri A, Pietka TA, Sivapackiam J, Kidd K, Park SJ, Johnson BG, Kmoch S, Duffield JS, Bleyer AJ, Jackrel ME, Urano F, Sharma V, Lindahl M, Chen YM (2023) MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice. Nat Commun 14:6493. https://doi.org/10.1038/s41467-023-42154-0 |
Kim Yeawon, Li Chuang, Gu Chenjian, Fang Yili, Tycksen Eric, Puri Anuradhika, Pietka Terri A, Sivapackiam Jothilingam, Kidd Kendrah, Park Sun-Ji, Johnson Bryce G, Kmoch Stanislav, Duffield Jeremy S, Bleyer Anthony J, Jackrel Meredith E, Urano Fumihiko, Sharma Vijay, Lindahl Maria, Chen Ying Maggie (2023) Nat Commun
Abstract: Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.
• Bioblast editor: Plangger M • O2k-Network Lab: US MO St Louis Abumrad NA
Labels: MiParea: Respiration, Genetic knockout;overexpression
Organism: Mouse
Tissue;cell: Kidney
Preparation: Permeabilized cells
Coupling state: LEAK, OXPHOS, ET
Pathway: N, NS
HRR: Oxygraph-2k
2024-04
