Spautin-1 promotes PINK1-PRKN-dependent mitophagy and improves associative learning capability in an alzheimer disease animal model.

Spautin-1 is a well-known macroautophagy/autophagy inhibitor via suppressing the deubiquitinases USP10 and USP13 and promoting the degradation of the PIK3C3/VPS34-BECN1 complex, while its effect on selective autophagy remains poorly understood. Mitophagy is a selective form of autophagy for removal of damaged and superfluous mitochondria via the autophagy-lysosome pathway. Here, we report a surprising discovery that, while spautin-1 remains as an effective autophagy inhibitor, it promotes PINK1-PRKN-dependent mitophagy induced by mitochondrial damage agents. Mechanistically, spautin-1 facilitates the stabilization and activation of the full-length PINK1 at the outer mitochondrial membrane (OMM) via binding to components of the TOMM complex (TOMM70 and TOMM20), leading to the disruption of the mitochondrial import of PINK1 and prevention of PARL-mediated PINK1 cleavage. Moreover, spautin-1 induces neuronal mitophagy in Caenorhabditis elegans (C. elegans) in a PINK-1-PDR-1-dependent manner. Functionally, spautin-1 is capable of improving associative learning capability in an Alzheimer disease (AD) C. elegans model. In summary, we report a novel function of spautin-1 in promoting mitophagy via the PINK1-PRKN pathway. As deficiency of mitophagy is closely implicated in the pathogenesis of neurodegenerative disorders, the pro-mitophagy function of spautin-1 might suggest its therapeutic potential in neurodegenerative disorders such as AD.Abbreviations: AD, Alzheimer disease; ATG, autophagy related; BafA1, bafilomycin A1; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; COX4/COX IV, cytochrome c oxidase subunit 4; EBSS, Earle's balanced salt; ECAR, extracellular acidification rate; GFP, green fluorescent protein; IA, isoamyl alcohol; IMM, inner mitochondrial membrane; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MMP, mitochondrial membrane potential; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; O/A, oligomycin-antimycin; OCR, oxygen consumption rate; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; p-Ser65-Ub, phosphorylation of Ub at Ser65; TIMM23, translocase of inner mitochondrial membrane 23; TOMM, translocase of outer mitochondrial membrane; USP10, ubiquitin specific peptidase 10; USP13, ubiquitin specific peptidase 13; VAL, valinomycin; YFP, yellow fluorescent protein.

Urolithin A improves Alzheimer's disease cognition and restores mitophagy and lysosomal functions.

BACKGROUND: Compromised autophagy, including impaired mitophagy and lysosomal function, plays pivotal roles in Alzheimer's disease (AD). Urolithin A (UA) is a gut microbial metabolite of ellagic acid that stimulates mitophagy. The effects of UA's long-term treatment of AD and mechanisms of action are unknown. METHODS: We addressed these questions in three mouse models of AD with behavioral, electrophysiological, biochemical, and bioinformatic approaches. RESULTS: Long-term UA treatment significantly improved learning, memory, and olfactory function in different AD transgenic mice. UA also reduced amyloid beta (Aß) and tau pathologies and enhanced long-term potentiation. UA induced mitophagy via increasing lysosomal functions. UA improved cellular lysosomal function and normalized lysosomal cathepsins, primarily cathepsin Z, to restore lysosomal function in AD, indicating the critical role of cathepsins in UA-induced therapeutic effects on AD. CONCLUSIONS: Our study highlights the importance of lysosomal dysfunction in AD etiology and points to the high translational potential of UA. HIGHLIGHTS: Long-term urolithin A (UA) treatment improved learning, memory, and olfactory function in Alzheimer's disease (AD) mice. UA restored lysosomal functions in part by regulating cathepsin Z (Ctsz) protein. UA modulates immune responses and AD-specific pathophysiological pathways.

Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway-UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies.

Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway-UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.