Guanosine protects against Ca2+-induced mitochondrial dysfunction in rats

Courtes, Aline Alves; Carvalho, Nélson Rodrigues de; Gonçalves, Débora Farina; Hartmann, Diane Duarte; Rosa, Pâmela Carvalho da; Dobrachinski, Fernando; Franco, Jeferson Luís; Souza, Diogo O.; Soares, Félix Alexandre Antunes

doi:10.1016/j.biopha.2019.01.040

Cited by 10 publications

(7 citation statements)

References 59 publications

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“…It has been shown that dynamin-related protein 1 (Drp1), responsible for mitochondrial fission, as well as Miro, connecting mitochondria via other proteins to motor proteins, are directly or indirectly controlled by Ca 2+ [ 29 , 50 – 52 ]. Moreover, mitochondrial swelling seems to be Ca 2+ -related, too [ 53 ]. In this case, we demonstrated that inhibition of Ca 2+ influx into mitochondria with 10 μ M Ru360 completely prevents oxidative stress-induced reduction of mitochondrial length and all motility parameters (Figures 3(b) and 4(a) – 4(c) ).…”

Section: Discussionmentioning

confidence: 99%

Preventing Axonal Sodium Overload or Mitochondrial Calcium Uptake Protects Axonal Mitochondria from Oxidative Stress-Induced Alterations

Ulshöfer

Bros

Hauser

et al. 2022

Oxidative Medicine and Cellular Longevity

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In neuroinflammatory and neurodegenerative disorders such as multiple sclerosis, mitochondrial damage caused by oxidative stress is believed to contribute to neuroaxonal damage. Previously, we demonstrated that exposure to hydrogen peroxide (H2O2) alters mitochondrial morphology and motility in myelinated axons and that these changes initiate at the nodes of Ranvier, where numerous sodium channels are located. Therefore, we suggested that mitochondrial damage may lead to ATP deficit, thereby affecting the efficiency of the sodium-potassium ATPase and eventually leading to sodium overload in axons. The increased intra-axonal sodium may revert the axonal sodium-calcium exchangers and thus may lead to a pathological calcium overload in the axoplasm and mitochondria. Here, we used the explanted murine ventral spinal roots to investigate whether modulation of sodium or calcium influx may prevent mitochondrial alterations in myelinated axons during exogenous application of H2O2 inducing oxidative stress. For that, tetrodotoxin, an inhibitor of voltage-gated sodium ion channels, and ruthenium 360, an inhibitor of the mitochondrial calcium uniporter, were applied simultaneously with hydrogen peroxide to axons. Mitochondrial shape and motility were analyzed. We showed that inhibition of axonal sodium influx prevented oxidative stress-induced morphological changes (i.e., increase in circularity and area and decrease in length) and preserved mitochondrial membrane potential, which is crucial for ATP production. Blocking mitochondrial calcium uptake prevented decrease in mitochondrial motility and also preserved membrane potential. Our findings indicate that alterations of both mitochondrial morphology and motility in the contexts of oxidative stress can be counterbalanced by modulating intramitochondrial ion concentrations pharmacologically. Moreover, motile mitochondria show preserved membrane potentials, pointing to a close association between mitochondrial motility and functionality.

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Section: Discussionmentioning

confidence: 99%

Preventing Axonal Sodium Overload or Mitochondrial Calcium Uptake Protects Axonal Mitochondria from Oxidative Stress-Induced Alterations

Ulshöfer

Bros

Hauser

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…In the most recent study conducted by Courtes et al using liver mitochondria, Guo demonstrated a protective effect against Ca2+-induced mitochondrial dysfunction [127]. Interestingly, Guo improved mitochondrial function without any link to the stabilization of mitochondrial membrane potential or direct ROS scavenging.…”

Section: Guanosine Prevents Mitochondrial Dysfunctionmentioning

confidence: 96%

“…On the molecular level, the impairment of mitochondria results in increased reactive oxygen species (ROS) production, redox homeostasis disruption, and activation of apoptotic cell death [124][125][126]. The main events that contribute to mitochondrial dysfunction are excess Ca2+, mitochondrial swelling, loss of mitochondrial membrane potential, impaired oxidative phosphorylation, and accumulation of ROS [127]. Mitochondrial membrane depolarization is a well-known marker of mitochondrial dysfunction [126].…”

Section: Guanosine Prevents Mitochondrial Dysfunctionmentioning

confidence: 99%

“…Several studies have postulated that Guo can prevent mitochondrial damage by direct ROS scavenging and/or via activation of molecular pathways that induce antioxidant effects [103,107]. More recent studies vastly diminished the role of Guo as a direct antioxidant, showing no or little involvement in nitric oxide (NO) scavenging activity [127,129]. Therefore, the mechanism of action which is responsible for the Guo effect on mitochondria is probably related to its ability to activate molecular pathways which then elicit antioxidant effects.…”

Section: Guanosine Prevents Mitochondrial Dysfunctionmentioning

confidence: 99%

“…In this study, Guo prevented in vitro Ca2+-induced mitochondrial impairment by reduction of mitochondrial swelling and ROS levels. Moreover, Guo boosted mitochondrial metabolism and helped to establish energy homeostasis [127].…”

Section: Guanosine Prevents Mitochondrial Dysfunctionmentioning

confidence: 99%

See 2 more Smart Citations

Neuroprotective Effects of Guanosine in Ischemic Stroke—Small Steps towards Effective Therapy

Chojnowski

Opiełka

Nazar

et al. 2021

IJMS

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Guanosine (Guo) is a nucleotide metabolite that acts as a potent neuromodulator with neurotrophic and regenerative properties in neurological disorders. Under brain ischemia or trauma, Guo is released to the extracellular milieu and its concentration substantially raises. In vitro studies on brain tissue slices or cell lines subjected to ischemic conditions demonstrated that Guo counteracts destructive events that occur during ischemic conditions, e.g., glutaminergic excitotoxicity, reactive oxygen and nitrogen species production. Moreover, Guo mitigates neuroinflammation and regulates post-translational processing. Guo asserts its neuroprotective effects via interplay with adenosine receptors, potassium channels, and excitatory amino acid transporters. Subsequently, guanosine activates several prosurvival molecular pathways including PI3K/Akt (PI3K) and MEK/ERK. Due to systemic degradation, the half-life of exogenous Guo is relatively low, thus creating difficulty regarding adequate exogenous Guo distribution. Nevertheless, in vivo studies performed on ischemic stroke rodent models provide promising results presenting a sustained decrease in infarct volume, improved neurological outcome, decrease in proinflammatory events, and stimulation of neuroregeneration through the release of neurotrophic factors. In this comprehensive review, we discuss molecular signaling related to Guo protection against brain ischemia. We present recent advances, limitations, and prospects in exogenous guanosine therapy in the context of ischemic stroke.

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Vitamin A deficiency from maternal gestation may contribute to autistic-like behaviors and gastrointestinal dysfunction in rats through the disrupted purine and tryptophan metabolism

Cheng

Sun

et al. 2023

Behavioural Brain Research

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Guanosine protects against Ca2+-induced mitochondrial dysfunction in rats

Cited by 10 publications

References 59 publications

Preventing Axonal Sodium Overload or Mitochondrial Calcium Uptake Protects Axonal Mitochondria from Oxidative Stress-Induced Alterations

Preventing Axonal Sodium Overload or Mitochondrial Calcium Uptake Protects Axonal Mitochondria from Oxidative Stress-Induced Alterations

Neuroprotective Effects of Guanosine in Ischemic Stroke—Small Steps towards Effective Therapy

Vitamin A deficiency from maternal gestation may contribute to autistic-like behaviors and gastrointestinal dysfunction in rats through the disrupted purine and tryptophan metabolism

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