Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease

Abstract

(1) Background: Ellagitannins are natural products occurring in pomegranate and walnuts. They are hydrolyzed in the gut to release ellagic acid, which is further metabolized by the microflora into urolithins, such as urolithin A (UA). Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegenerative diseases. In this study, we investigated the neuroprotective activity of the metabolite UA against mitochondrial dysfunction in a cellular model of early Alzheimer disease (AD). (2) Methods: In the present study we used SH-SY5Y-APP695 cells and its corresponding controls (SH-SY5Ymock) to assess UA’s effect on mitochondrial function. Using these cells we investigated mitochondrial respiration (OXPHOS), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, autophagy and levels of reactive oxygen species (ROS) in cells treated with UA. Furthermore, we assessed UA’s effect on the expression of genes related to mitochondrial bioenergetics, mitochondrial biogenesis, and autophagy via quantitative real-time PCR (qRT-PCR). (3) Results: Treatment of SH-SY5Y-APP695 cells suggests changes to autophagy corresponding with qRT-PCR results. However, LC3B-I, LC3B-II, and p62 levels were unchanged. UA (10 µM) reduced MMP, and ATP-levels. Treatment of cells with UA (1 µM) for 24 h did not affect ROS production or levels of Aβ, but significantly increased expression of genes for mitochondrial biogenesis and OXPHOS. Mitochondrial Transcription Factor A (TFAM) expression was specifically increased in SH-SY5Y-APP695. Both cell lines showed unaltered levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which is commonly associated with mitochondrial biogenesis. Results imply that biogenesis might be facilitated by estrogen-related receptor (ESRR) genes. (4) Conclusion: Urolithin A shows no effect on autophagy in SH-SY5Y-APP695 cells and its effect on mitochondrial function is limited. Instead, data suggests that UA treatment induces hormetic effects as it induces transcription of several genes related to mitochondrial biogenesis.

Are mitophagy enhancers therapeutic targets for Alzheimer’s disease?

“…These and other observations [ 128 , 129 ] strongly suggest mitophagy enhancers are promising drugs to treat patients with AD and other tauopathies. However, these drugs need to be tested carefully using mouse models, particularly recently developed humanized Abeta knock-in (hAbKI) mice that express human amyloid beta peptide and exhibit late-onset AD features [ 130 , 131 ].…”

“…Defective mitochondrial biogenesis and accumulation of dead mitochondria are the main phenomena observed in age-associated diseases such as AD. Newly developed pharmacological treatments and novel chemical modulators like urolithin A [ 77 ], tomatidine [ 78 , 79 ], and actinonin [ 80 ] might be used to promote the efficient removal of dead and/or damaged mitochondria and restore energy homeostasis. Pharmacologic agents and natural supplements that target mitophagy are potential drugs which may enhance the quality of mitochondria in aging individuals and ameliorate age-related diseases.…”

“…Studies have shown that treatments of UA slow aging, reduce age-related diseases, and improve quality of mitochondria and overall health status [ 93 ]. UA prevents inflammation and promotes mitochondrial health, biogenesis and dynamics in different cell types and in different species including worms, mice, and humans [ 94 – 96 ].…”

Identification of ellagic acid and urolithins as natural inhibitors of Aβ25–35-induced neurotoxicity and the mechanism predication using network pharmacology analysis and molecular docking

“…While Esselun et al observed that 1 μM UA had no significant effect on MMP level in control cell lines (SH-SY5Ymock) and early AD models (SH-SY5Y-APP695). Conversely, a 10-fold increased level of UA (10 μM) yielded no observable improvement other than model-specific changes and even deteriorated mitochondrial function ( 19 ). In this study, we constructed the AD model of PC12 cells in vitro , and the difference in the regulation of MMP caused by different models cannot be ignored.…”

Neurohormetic phytochemicals in the pathogenesis of neurodegenerative diseases

“…Urolithin A, a main compound found in pomegranate and walnuts, demonstrated neuroprotective effect in a cellular model of AD. Urolithin A had no effect on autophagy in SH-SY5Y-APP695 cells while exerted hormetic effects through mitochondrial biogenesis which, in turn, induced the transcription of several genes [ 76 ]. A summary of the hormesis activity of natural compounds in vitro and in vivo on AD is provided in Table 3 .…”