Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents

Ryu, Dongryeol; Mouchiroud, Laurent; Andreux, Pénélope; Katsyuba, Elena; Moullan, Norman; Nicolet‐dit‐Félix, Amandine A.; Williams, Evan G.; Jha, Pooja; Sasso, Giuseppe Lo; Huzard, Damien; Aebischer, Patrick; Sandi, Carmen; Rinsch, Chris; Auwerx, Johan

doi:10.1038/nm.4132

Cited by 772 publications

(767 citation statements)

References 64 publications

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“…Among the phytoestrogens that are known, urolithins A and B (enterophytoestrogens), which are microflora metabolites from the ellagic acid that belongs to the tannins class, display both oestrogenic and antioestrogenic activities (Larrosa et al, 2006; Ryu et al, 2016). It is know that estrogen phosphorylate eNOS mainly via the serina (Ser)/threonine (Thr) kinase Akt (Förstermann and Sessa, 2012).…”

Section: Discussionmentioning

confidence: 99%

Pomegranate Extract Enhances Endothelium-Dependent Coronary Relaxation in Isolated Perfused Hearts from Spontaneously Hypertensive Ovariectomized Rats

et al. 2017

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Decline in estrogen levels promotes endothelial dysfunction and, consequently, the most prevalent cardiovascular diseases in menopausal women. The use of natural therapies such as pomegranate can change these results. Pomegranate [Punica granatum L. (Punicaceae)] is widely used as a phytotherapeutic agent worldwide, including in Brazil. We hypothesized that treatment with pomegranate hydroalcoholic extract (PHE) would improve coronary vascular reactivity and cardiovascular parameters. At the beginning of treatment, spontaneously hypertensive female rats were divided into Sham and ovariectomized (OVX) groups, which received pomegranate extract (PHE) (250 mg/kg) or filtered water (V) for 30 days by gavage. Systolic blood pressure was measured by tail plethysmography. After euthanasia, the heart was removed and coronary vascular reactivity was assessed by Langendorff retrograde perfusion technique. A dose-response curve for bradykinin was performed, followed by L-NAME inhibition. The protein expression of p-eNOS Ser1177, p-eNOS Thr495, total eNOS, p-AKT Ser473, total AKT, SOD-2, and catalase was quantified by Western blotting. The detection of coronary superoxide was performed using the protocol of dihydroethidium (DHE) staining Plasma nitrite measurement was analyzed by Griess method. Systolic blood pressure increased in both Sham-V and OVX-V groups, whereas it was reduced after treatment in Sham-PHE and OVX-PHE groups. The baseline coronary perfusion pressure was reduced in the Sham-PHE group. The relaxation was significantly higher in the treated group, and L-NAME attenuated the relaxation in all groups. The treatment has not changed p-eNOS (Ser1177), total eNOS, p-AKT (Ser473) and total AKT in any groups. However, in Sham and OVX group the treatment reduced the p-eNOS (Thr495) and SOD-2. The ovariectomy promoted an increasing in the superoxide anion levels and the treatment was able to prevent this elevation and reducing oxidative stress. Moreover, the treatment prevented the decreasing in plasmatic nitrite. We observed a reduction in total cholesterol and LDL in the Sham-PHE group. The treatment with PHE enhances the endothelium-dependent coronary relaxation and improves cardiovascular parameters, which suggests a therapeutic role of PHE.

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Section: Discussionmentioning

confidence: 99%

Pomegranate Extract Enhances Endothelium-Dependent Coronary Relaxation in Isolated Perfused Hearts from Spontaneously Hypertensive Ovariectomized Rats

et al. 2017

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“…Ryu et al recently characterized a novel mitophagy-inducer Urolithin A [4], a metabolite derived from pomegranates. Urolithin A extends the lifespan of C. elegans and improves muscle function in mice through mitochondrial maintenance via upregulation of mitophagy [111]. More work remains to be done to deduce the mechanism behind which Urolithin A increases mitophagy.…”

Section: Therapeutic Interventions That Target Mitophagymentioning

confidence: 99%

Mitophagy in neurodegeneration and aging

Fivenson

Lautrup

Sun

et al. 2017

Neurochemistry International

304

183

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Mitochondrial dysfunction contributes to normal aging and a wide spectrum of age-related diseases, including neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. It is important to maintain a healthy mitochondrial population which is tightly regulated by proteolysis and mitophagy. Mitophagy is a specialized form of autophagy that regulates the turnover of damaged and dysfunctional mitochondria, organelles that function in producing energy for the cell in the form of ATP and regulating energy homeostasis. Mechanistic studies on mitophagy across species highlight a sophisticated and integrated cellular network that regulates the degradation of mitochondria. Strategies directed at maintaining a healthy mitophagy level in aged individuals might have beneficial effects. In this review, we provide an updated mechanistic overview of mitophagy pathways and discuss the role of reduced mitophagy in neurodegeneration. We also highlight potential translational applications of mitophagy-inducing compounds, such as NAD+ and urolithins.

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“…A recent study investigates Urolithin A [72] a component of pomegranate juice, that is able to increase mitophagy in c. elegans, mice and rats. As little as 6 weeks treatment is able to improve motor performance in elderly rodents.…”

Section: Chemicalmentioning

confidence: 99%

“…It also has neuro-protective [70], cardio protective [71] and tumour-suppressive potential [85]. Metformin is a known activator of AMPK [72,73], an effect that is required for metformin's inhibitory effect on glucose production by hepatocytes [74]. It activates autophagy by both AMPKdependent [75] and -independent pathways [76].…”

Section: Metforminmentioning

confidence: 99%

Modulating Mitophagy in Mitochondrial Disease

Dombi

Mortiboys

Poulton

2019

CMC

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Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue. The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signaling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. Type 1 mitophagy due to nutrient starvation is dependent on PI3K (phosphoinositide 3-kinase) for autophagosome formation but independent of mitophagy proteins, PINK1 (PTEN-induced putative kinase 1) and Parkin. Whereas type 2 mitophagy that occurs due to damage is dependent on PINK1 and Parkin but does not require PI3K. Autophagy and mitophagy play an important role in human disease and hence could serve as therapeutic targets for the treatment of mitochondrial as well as neurodegenerative disorders. Therefore, we reviewed drugs that are known modulators of autophagy (AICAR and metformin) and may effect this by activating the AMP-activated protein kinase signaling pathways. Furthermore, we reviewed data available on supplements, such as Coenzyme Q and the quinone idebenone, that we assert rescue increased mitophagy in mitochondrial disease by benefiting mitochondrial function.

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Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents

Cited by 772 publications

References 64 publications

Pomegranate Extract Enhances Endothelium-Dependent Coronary Relaxation in Isolated Perfused Hearts from Spontaneously Hypertensive Ovariectomized Rats

Pomegranate Extract Enhances Endothelium-Dependent Coronary Relaxation in Isolated Perfused Hearts from Spontaneously Hypertensive Ovariectomized Rats

Mitophagy in neurodegeneration and aging

Modulating Mitophagy in Mitochondrial Disease

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