ROS as Regulators of Mitochondrial Dynamics in Neurons

Cid-Castro, Carolina; Hernández-Espinosa, Diego Rolando; Morán, Julio

doi:10.1007/s10571-018-0584-7

Cited by 83 publications

(61 citation statements)

References 152 publications

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“…Moreover, the SIRT1 inhibitor EX‐527 induced Pomc expression after ICV injection in rats as well as enhanced α‐MSH secretion in primary hypothalamic cultures suggesting that SIRT1 may be involved in the process . The control of food intake by the NPY‐AGRP and POMC‐CART neurons is linked to mitochondrial function and the levels of ROS in the neurons . In NPY‐AGRP neurons, fasting or caloric restriction activates the AMPK pathway due to increased AMP/ATP ratio and ghrelin action, increases fatty acid oxidation, promotes mitochondrial fission and decreases ROS via UCP2 .…”

Section: Discussionmentioning

confidence: 99%

“…14 The control of food intake by the NPY-AGRP and POMC-CART neurons is linked to mitochondrial function and the levels of ROS in the neurons. 9,24,25,27,[58][59][60] In NPY-AGRP neurons, fasting or caloric restriction activates the AMPK pathway due to increased AMP/ATP ratio and ghrelin action, increases fatty acid oxidation, promotes mitochondrial fission and decreases ROS via UCP2. 16,24,25,[61][62][63][64] Conversely, in POMC-CART neurons, leptin, insulin and glucose trigger neuronal activation and increase the level of ROS.…”

Section: Discussionmentioning

confidence: 99%

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Fasting‐ and ghrelin‐induced food intake is regulated by NAMPT in the hypothalamus

et al. 2020

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Aim Neurons in the arcuate nucleus of the hypothalamus are involved in regulation of food intake and energy expenditure, and dysregulation of signalling in these neurons promotes development of obesity. The role of the rate‐limiting enzyme in the NAD+ salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), for regulation energy homeostasis by the hypothalamus has not been extensively studied. Methods We determined whether Nampt mRNA or protein levels in the hypothalamus of mice were affected by diet‐induced obesity, by fasting and re‐feeding, and by leptin and ghrelin treatment. Primary hypothalamic neurons were treated with FK866, a selective inhibitor of NAMPT, or rAAV carrying shRNA directed against Nampt, and levels of reactive oxygen species (ROS) and mitochondrial respiration were assessed. Fasting and ghrelin‐induced food intake was measured in mice in metabolic cages after intracerebroventricular (ICV)‐mediated FK866 administration. Results NAMPT levels in the hypothalamus were elevated by administration of ghrelin and leptin. In diet‐induced obese mice, both protein and mRNA levels of NAMPT decreased in the hypothalamus. NAMPT inhibition in primary hypothalamic neurons significantly reduced levels of NAD+, increased levels of ROS, and affected the expression of Agrp, Pomc and genes related to mitochondrial function. Finally, ICV‐induced NAMPT inhibition by FK866 did not cause malaise or anhedonia, but completely ablated fasting‐ and ghrelin‐induced increases in food intake. Conclusion Our findings indicate that regulation of NAMPT levels in hypothalamic neurons is important for the control of fasting‐ and ghrelin‐induced food intake.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fasting‐ and ghrelin‐induced food intake is regulated by NAMPT in the hypothalamus

et al. 2020

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“…Interestingly, Opa1 is deactivated upon ROS increase. Drp1 is activated and causes the fragmentation of mitochondria in neuronal cells ( 95 ). This is linked to iron overload, AMPK activation, MFF ( 96 ), and ubiquitination of A-kinase anchor protein 121 ( 97 ).…”

Section: Mitochondrial Dynamics Plays a Key Role In Immune Cell Metabmentioning

confidence: 99%

Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

et al. 2018

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Lack of immune system cells or impairment in differentiation of immune cells is the basis for many chronic diseases. Metabolic changes could be the root cause for this immune cell impairment. These changes could be a result of altered transcription, cytokine production from surrounding cells, and changes in metabolic pathways. Immunity and mitochondria are interlinked with each other. An important feature of mitochondria is it can regulate activation, differentiation, and survival of immune cells. In addition, it can also release signals such as mitochondrial DNA (mtDNA) and mitochondrial ROS (mtROS) to regulate transcription of immune cells. From current literature, we found that mitochondria can regulate immunity in different ways. First, alterations in metabolic pathways (TCA cycle, oxidative phosphorylation, and FAO) and mitochondria induced transcriptional changes can lead to entirely different outcomes in immune cells. For example, M1 macrophages exhibit a broken TCA cycle and have a pro-inflammatory role. By contrast, M2 macrophages undergo β-oxidation to produce anti-inflammatory responses. In addition, amino acid metabolism, especially arginine, glutamine, serine, glycine, and tryptophan, is critical for T cell differentiation and macrophage polarization. Second, mitochondria can activate the inflammatory response. For instance, mitochondrial antiviral signaling and NLRP3 can be activated by mitochondria. Third, mitochondrial mass and mobility can be influenced by fission and fusion. Fission and fusion can influence immune functions. Finally, mitochondria are placed near the endoplasmic reticulum (ER) in immune cells. Therefore, mitochondria and ER junction signaling can also influence immune cell metabolism. Mitochondrial machinery such as metabolic pathways, amino acid metabolism, antioxidant systems, mitochondrial dynamics, mtDNA, mitophagy, and mtROS are crucial for immune functions. Here, we have demonstrated how mitochondria coordinate to alter immune responses and how changes in mitochondrial machinery contribute to alterations in immune responses. A better understanding of the molecular components of mitochondria is necessary. This can help in the development of safe and effective immune therapy or prevention of chronic diseases. In this review, we have presented an updated prospective of the mitochondrial machinery that drives various immune responses.

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“…Oxidative stress results from an imbalance caused by excess production of oxidants (ROS) and damage to the ROS scavenging capacity provided by antioxidants (such as SOD and GSH). Mitochondria are not only the most important source of ROS, but they are also damaged by ROS excess [18,19]. Our previous studies showed that oxidative stress plays an important role in the development of vascular hyporesponsiveness following hemorrhagic shock.…”

Section: Effects Of Calhex-231 On Mitochondrial Fission/fusion and MImentioning

confidence: 99%

“…In mammalian cells, the primary regulators of mitochondrial fission are dynamin-related protein 1 (Drp1) and fission 1 (Fis1), whereas mitochondrial fusion is regulated by mitofusin 1 (Mfn1) and mitofusin 2 (Mfn 2). Interactions between ROS and mitochondrial dynamic fusion-fission have been implicated in aging, cancer, neuropathies, and cardiovascular disorders [18,19]. We previously showed that oxidative stress and mitochondrial dysfunction are both involved in the pathogenesis of vascular hyporesponsiveness following shock.…”

Section: Introductionmentioning

confidence: 99%

The calcilytic drug Calhex-231 ameliorates vascular hyporesponsiveness in traumatic hemorrhagic shock by inhibiting oxidative stress and mitochondrial fission

Lei¹,

Peng²,

T³

et al. 2020

Preprint

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Background The calcium-sensing receptor (CaSR) plays a fundamental role in extracellular calcium homeostasis in humans. Surprisingly, CaSR is also expressed in non-homeostatic tissues and is involved in regulating diverse cellular functions. The objective of this study was to determine if Calhex-231 (Cal), a negative modulator of CaSR, may be beneficial in the treatment of traumatic hemorrhagic shock (THS) by improving cardiovascular function, and investigated its relationship to oxidative stress and the mitochondrial fusion-fission pathway. Methods Rats that had been subjected to traumatic hemorrhagic shock were used as models in this study. Hypoxia-treated vascular smooth muscle cells (VSMCs) were also used. The effects of Cal on cardiovascular function, animal survival, hemodynamic parameters, and vital organ function in THS rats were observed, and the relationship to oxidative stress and mitochondrial fusion-fission was investigated. Results Cal significantly improved hemodynamics, elevated blood pressure, increased vital organ blood perfusion and local oxygen supply, and markedly improved the survival outcomes of THS rats. Furthermore, Cal significantly improved vascular reactivity after THS, including the pressor response of THS rats to norepinephrine (NE), and also the contractile response of superior mesenteric arteries, mesenteric arterioles, and isolated VSMCs to NE. Cal also restored the THS-induced decrease in myosin light chain (MLC) phosphorylation, which is the principal mechanism responsible for VSMC contraction and vascular reactivity. Inhibition of MLC phosphorylation antagonized the Cal-induced restoration of vascular reactivity following THS. Cal decreased oxidative stress indexes and increased antioxidant enzyme levels in THS rats, and also reduced reactive oxygen species levels in hypoxic VSMCs. In addition, THS induced expression of mitochondrial fission proteins Drp1 and Fis1, and decreased expression of mitochondrial fusion protein Mfn1 in vascular tissues. Cal reduced expression of Drp1 and Fis1, but did not affect Mfn1 expression. In hypoxic VSMCs, Cal inhibited hypoxia-induced mitochondrial fragmentation and preserved mitochondrial morphology. Conclusions Calhex-231 exhibits outstanding potential for effective therapy of traumatic hemorrhagic shock, due to its ability to improve hemodynamics, increase vital organ blood perfusion, and markedly prolong animal survival. These beneficial effects result from its protection of vascular function via inhibition of oxidative stress and mitochondrial fission.

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ROS as Regulators of Mitochondrial Dynamics in Neurons

Cited by 83 publications

References 152 publications

Fasting‐ and ghrelin‐induced food intake is regulated by NAMPT in the hypothalamus

Fasting‐ and ghrelin‐induced food intake is regulated by NAMPT in the hypothalamus

Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

The calcilytic drug Calhex-231 ameliorates vascular hyporesponsiveness in traumatic hemorrhagic shock by inhibiting oxidative stress and mitochondrial fission

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