Kim 2023 bioRxiv

Kim Y, Li C, Gu C, Tycksen E, Puri A, Pietka TA, Sivapackiam J, Fang Y, 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 toxic proteinopathy. https://doi.org/10.1101/2023.01.10.523171

» bioRxiv. PMID: 36711449 Open Access

Kim Yeawon, Li Chuang, Gu Chenjian, Tycksen Eric, Puri Anuradhika, Pietka Terri A, Sivapackiam Jothilingam, Fang Yili, 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) bioRxiv

Abstract: Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD- UMOD ), one of the leading hereditary kidney diseases, and Alzheimer's disease etc. There are no targeted therapies. ADTKD is also a genetic form of renal fibrosis and chronic kidney disease, which affects 500 million people worldwide. For the first time, in our newly generated mouse model recapitulating human ADTKD- UMOD carrying a leading UMOD deletion mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are severely impaired, leading to cGAS- STING activation and tubular injury. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel endoplasmic reticulum stress-regulated secreted protein. We provide the first study that inducible tubular overexpression of MANF after the onset of disease stimulates autophagy/mitophagy and clearance of the misfolded UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, resulting in protection of kidney function. Conversely, genetic ablation of endogenous MANF upregulated in the mutant mouse and human tubular cells worsens autophagy suppression and kidney fibrosis. Together, we discover MANF as a novel biotherapeutic protein and elucidate previously unknown mechanisms of MANF in regulating organelle homeostasis to treat ADTKD, which may have broad therapeutic application to treat various proteinopathies. • Keywords: MANF, ADTKD-UMOD, ER stress, Mitophagy, Autophagy, Mitochondrial biogenesis, STING, Inflammation, Fibrosis • Bioblast editor: Plangger M • O2k-Network Lab: US MO St Louis Abumrad NA

Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Other 

Organism: Mouse  Tissue;cell: Endothelial;epithelial;mesothelial cell  Preparation: Permeabilized cells 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, NS  HRR: Oxygraph-2k 

2023-02