Urolithin A suppresses high glucose-induced neuronal amyloidogenesis by modulating TGM2-dependent ER-mitochondria contacts and calcium homeostasis

Lee, Hyun Jik; Jung, Young Hyun; Choi, Gee Euhn; Kim, Jun Sung; Chae, Chang Woo; Lim, Jae Ryong; Kim, Seo Yihl; Yoon, Jee Hyeon; Cho, Ji Hyeon; Lee, Sei-Jung; Han, Ho Jae

doi:10.1038/s41418-020-0593-1

Cited by 115 publications

(80 citation statements)

References 68 publications

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“…Low micromolar UA concentrations, provided significant protection against H 2 O 2 -induced ROS and increased antioxidant enzyme activity [ 33 ] and nanomolar concentrations helped to maintain calcium homeostasis in SH-SY5Y cells [ 36 ]. Although we generally found increased cellular ROS in SY5Y-APP695, UA did not decrease basal ROS levels in either cell line.…”

Section: Discussionmentioning

confidence: 99%

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

Esselun

Theyssen

Eckert

2021

IJMS

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(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.

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Section: Discussionmentioning

confidence: 99%

“…Low doses of UA have also been reported to provide neuroprotection against H 2 O 2 induced oxidative stress in N2a [ 33 ] and SH-SY5Y [ 34 , 35 ] cells. Furthermore, multiple studies also reported increased mitochondrial function and enhanced mitochondrial biogenesis facilitated by UA [ 27 , 36 , 37 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

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

Esselun

Theyssen

Eckert

2021

IJMS

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“…Even while the role of PACS-2 as a ER-mitochondria tether scaffold lacks the necessary evidence, the depletion of this protein causes mitochondrial disconnection from the ER [126,127]. It has been proposed that two distinct domains are present in MAMs that differ in their lipid content, function and control of glucose homeostasis [128][129][130][131].…”

Section: The Role Of the Mamsmentioning

confidence: 99%

Mitostasis, Calcium and Free Radicals in Health, Aging and Neurodegeneration

et al. 2021

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Mitochondria play key roles in ATP supply, calcium homeostasis, redox balance control and apoptosis, which in neurons are fundamental for neurotransmission and to allow synaptic plasticity. Their functional integrity is maintained by mitostasis, a process that involves mitochondrial transport, anchoring, fusion and fission processes regulated by different signaling pathways but mainly by the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α also favors Ca2+ homeostasis, reduces oxidative stress, modulates inflammatory processes and mobilizes mitochondria to where they are needed. To achieve their functions, mitochondria are tightly connected to the endoplasmic reticulum (ER) through specialized structures of the ER termed mitochondria-associated membranes (MAMs), which facilitate the communication between these two organelles mainly to aim Ca2+ buffering. Alterations in mitochondrial activity enhance reactive oxygen species (ROS) production, disturbing the physiological metabolism and causing cell damage. Furthermore, cytosolic Ca2+ overload results in an increase in mitochondrial Ca2+, resulting in mitochondrial dysfunction and the induction of mitochondrial permeability transition pore (mPTP) opening, leading to mitochondrial swelling and cell death through apoptosis as demonstrated in several neuropathologies. In summary, mitochondrial homeostasis is critical to maintain neuronal function; in fact, their regulation aims to improve neuronal viability and to protect against aging and neurodegenerative diseases.

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“…Indeed, while a loose connection is needed for Ca² + delivery, tighter connections are required for lipid and protein transfer between organelles [ 227 ]. A recent study proposed urolithin A (produced in the gut microbiome) as a pharmacological tool to control ER-mitochondria contacts and Ca 2+ homeostasis in AD [ 228 ]. Urolithin A lowered mitochondrial Ca 2+ influx and significantly alleviated high glucose-induced mitochondrial ROS accumulation.…”

Section: Mams As a Potential Therapeutic Strategymentioning

confidence: 99%

“…Urolithin A lowered mitochondrial Ca 2+ influx and significantly alleviated high glucose-induced mitochondrial ROS accumulation. Most importantly urolithin A reduces the expression of APP, BACE1, as well as Aβ production and Tau phosphorylation [ 228 ].…”

Section: Mams As a Potential Therapeutic Strategymentioning

confidence: 99%

Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer’s Disease

Eysert

Kinoshita

Mary

et al. 2020

IJMS

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Alzheimer’s disease (AD) is a multifactorial neurodegenerative pathology characterized by a progressive decline of cognitive functions. Alteration of various signaling cascades affecting distinct subcellular compartment functions and their communication likely contribute to AD progression. Among others, the alteration of the physical association between the endoplasmic reticulum (ER) and mitochondria, also referred as mitochondria-associated membranes (MAMs), impacts various cellular housekeeping functions such as phospholipids-, glucose-, cholesterol-, and fatty-acid-metabolism, as well as calcium signaling, which are all altered in AD. Our review describes the physical and functional proteome crosstalk between the ER and mitochondria and highlights the contribution of distinct molecular components of MAMs to mitochondrial and ER dysfunctions in AD progression. We also discuss potential strategies targeting MAMs to improve mitochondria and ER functions in AD.

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Urolithin A suppresses high glucose-induced neuronal amyloidogenesis by modulating TGM2-dependent ER-mitochondria contacts and calcium homeostasis

Cited by 115 publications

References 68 publications

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

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

Mitostasis, Calcium and Free Radicals in Health, Aging and Neurodegeneration

Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer’s Disease

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