MANF stimulates autophagy and restores mitochondrial homeostasis to treat toxic proteinopathy

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 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. ### Competing Interest Statement Y.M.Chen, S.J.Park, Y.Kim, F.Urano are inventors on a patent entitled Compositions and methods for treating and preventing endoplasmic reticulum (ER) stress-mediated kidney diseases (US 11,129,871), which was issued by US Patent and Trademark Office in Sep. 2021. Y.M.Chen and Y.Kim are inventors on a patent entitled methods of detecting biomarkers of endoplasmic reticulum (ER) stress-associated kidney diseases (US 10,156,564), which was issued by US Patent and Trademark Office on Dec. 18, 2018. J. Sivapackiam and V.S. are inventors on a non-provisional patent, entitled PET tracers for noninvasive imaging of ROS activity filed by Washington University in St. Louis, St. Louis, MO. Authors (J.S. and V.S.) declare no competing or financial interests.