BGP-15 Protects against Oxidative Stress- or Lipopolysaccharide-Induced Mitochondrial Destabilization and Reduces Mitochondrial Production of Reactive Oxygen Species

Sümegi, Katalin; Fekete, Katalin; Antus, Csenge; Debreceni, Balázs; Hocsák, Enikö; Gallyas, Ferenc; Sümegi, Balázs; Szabó, Andrea

doi:10.1371/journal.pone.0169372

Cited by 45 publications

(50 citation statements)

References 57 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2), likely resulting from dysfunction in the mitochondrial respiratory chain, which can induce PCD (35). BGP-15 reduces ROS levels to normal in Ikbkap −/− neurons, in support of previous work demonstrating that BGP-15 can stabilize complexes of the respiratory chain (18,28,30), especially complexes I and III (28,30). Third, our data indicate a widespread depolarization of mitochondrial networks ( Fig.…”

Section: Discussionsupporting

confidence: 90%

“…The discovery of significant impairments in mitochondrial function of mutant neurons, in particular the collapsed mitochondrial membrane potential, prompted us to measure levels of ROS (35). BGP-15 has been shown to reduce ROS in stressed mammalian cells and rodent models (17)(18)(19)30). Using the probe CellROX Deep Red, which fluoresces only when oxidized by ROS, we discovered that ROS were significantly increased in mutant neurons.…”

Section: Bgp-15 Reduces Elevated Ros In Ikbkapmentioning

confidence: 99%

“…BGP-15 is a hydroxylamine derivative that has been shown to exert cyto-and neuroprotective effects in mammalian models of injury, stress, and disease (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). These improvements in cellular function have been correlated with the activation of several intracellular pathways.…”

mentioning

confidence: 99%

See 2 more Smart Citations

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hereditary sensory and autonomic neuropathy type III, or familial dysautonomia [FD; Online Mendelian Inheritance in Man (OMIM) 223900], affects the development and long-term viability of neurons in the peripheral nervous system (PNS) and retina. FD is caused by a point mutation in the gene IKBKAP/ELP1 that results in a tissue-specific reduction of the IKAP/ELP1 protein, a subunit of the Elongator complex. Hallmarks of the disease include vasomotor and cardiovascular instability and diminished pain and temperature sensation caused by reductions in sensory and autonomic neurons. It has been suggested but not demonstrated that mitochondrial function may be abnormal in FD. We previously generated an Ikbkap/Elp1 conditional-knockout mouse model that recapitulates the selective death of sensory (dorsal root ganglia) and autonomic neurons observed in FD. We now show that in these mice neuronal mitochondria have abnormal membrane potentials, produce elevated levels of reactive oxygen species, are fragmented, and do not aggregate normally at axonal branch points. The small hydroxylamine compound BGP-15 improved mitochondrial function, protecting neurons from dying in vitro and in vivo, and promoted cardiac innervation in vivo. Given that impairment of mitochondrial function is a common pathological component of neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's, Parkinson's, and Huntington's diseases, our findings identify a therapeutic approach that may have efficacy in multiple degenerative conditions.T he autonomic nervous system is essential for homeostasis, and its disruption in familial dysautonomia (FD) can have fatal consequences resulting from cardiovascular instability, respiratory dysfunction, and/or sudden death during sleep (1-3). In addition to developmental decreases in the number of sensory and autonomic neurons, FD patients undergo a progressive loss of peripheral neurons and retinal ganglion cells. The latter loss may ultimately lead to blindness (4, 5). More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3, 6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3, 6). The protein encoded by the IKBKAP/ELP1 gene, IKAP/ELP1, is a scaffolding protein for the six-subunit Elongator complex (ELP1-ELP6), which modifies tRNAs during translation (7). Why reduction in the IKAP/ ELP1 protein results in neuronal death is unknown, and we have sought to elucidate the cellular and molecular mechanisms that cause progressive neurodegeneration in FD to help identify treatments that improve neuronal function and viability.Accumulating evidence indicates that cells from FD patients and from mouse models with deletions in the Elongator subunits Ikbkap/Elp1 or Elp3 experience intracellular stress (4,5,(8)(9)(10) resulting from the direct and/or indirect consequences of impaired translation (7, 11). The C terminus of IKAP/ELP1 has been shown to bind c-Jun N-terminal kinase (JNK) and to regulate JNK cytosolic stress signaling (12)....

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Bgp-15 Reduces Elevated Ros In Ikbkapmentioning

confidence: 99%

See 1 more Smart Citation

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…If the damage is irreversible and cannot be repaired, it eventually leads to cell apoptosis (31). Ethanol boosts oxidative stress by increasing the formation of ROS and the depletion of internal oxidative defences in cells (32). Oxidative stress is a vital apoptotic stimulant for cells, particularly in those that have a high-energy metabolism required for their rapid growth and proliferation.…”

Section: Discussionmentioning

confidence: 99%

NOX4/ROS mediate ethanol‑induced apoptosis via MAPK signal pathway in L‑02 cells

Yang

Zhong

et al. 2018

Int J Mol Med

View full text Add to dashboard Cite

The aim of the present study was to assess the molecular mechanism of ethanol‑induced oxidative stress‑mediated apoptosis in L‑02 liver cells in order to elucidate novel pathways associated with alcoholic liver disease. L‑02 cells were treated with 400 mM ethanol with or without inhibitors. The cell viability was measured by an MTT assay. Cell apoptosis was assessed by flow cytometry and a single‑stranded DNA (ssDNA) assay. Intracellular reactive oxygen species (ROS) production of L‑02 cells was determined using the 2',7'‑dichlorofluorescein‑diacetate dye. The protein expression of c‑Jun N‑terminal kinase (JNK), phosphorylated (p)‑JNK, P38, p‑P38, NADPH oxidase (NOX)1, NOX4, p22phox, B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein were measured by western blot analysis. The mRNA expression of NOX1, NOX4 and p22phox was measured by reverse transcription polymerase chain reaction analysis. The results indicated that after treatment with various concentrations of ethanol for the indicated durations, L‑02 cells were displayed a significant decrease in cell viability in a dose‑and time‑dependent manner. Ethanol‑induced apoptosis and cell death of L‑02 cells was accompanied by the generation of ROS, elevated expression of NOX, as well as phosphorylation of JNK and P‑38. In addition, increased expression of Bcl‑2 was induced by 400 mM ethanol. Furthermore, treatment with NOX inhibitor attenuated the ethanol‑induced a decrease in cell viability, and an increase in apoptosis and Bcl‑2 expression. In conclusion, ethanol induced apoptosis in the L‑02 hepatocyte cell line via generation of ROS and elevated expression of NOX4. This indicated that activation of JNK and p38 in the mitogen‑activated protein kinase pathway promotes apoptosis in L‑02 cells.

show abstract

“…Among them, Larsson and colleagues have shown that BGP‐15 prevents mitochondrial dysfunction that is associated with the increased mitochondrial ROS production in the diaphragm and limb muscles during the ICU conditions. In line with this, BGP‐15 has been reported to attenuate lipopolysaccharide (LPS)‐induced collapse of mitochondrial membrane potential and ROS production in LPS‐sensitive U‐251 glioma cells, suggesting that BGP‐15 could be a novel mitochondrial drug candidate for the prevention of ROS‐related disease progression.…”

mentioning

confidence: 63%

BGP‐15: A potential therapeutic agent for critical illness myopathy

Yamada

2020

Acta Physiologica

View full text Add to dashboard Cite

In the current issue of Acta Physiologica, Larsson and colleagues examined the effect of chaperone co-inducer BGP-15 on impaired contractile function of the slow-twitch soleus muscles in a rat intensive care unit (ICU) model. 1 They found that BGP-15 improves myofibrillar function in the soleus muscle after 5 days exposure to the ICU condition, which is accompanied by improved mitochondrial morphology/biogenesis and reduced oxidative post-translational modifications (PTMs) of myosin molecules. These findings highlight the critical role of mitochondrial oxidative stress-induced myosin PTMs in myofibrillar dysfunction at the early stage of ICU admission and indicate BGP-15 as a potent candidate for therapeutic application in ICU-acquired weakness.With the significant improvements in modern intensive care medicine, mortality of ICU patients has dropped; on the other hand, it increases incidence of muscle weakness and paralysis, typically referred to as critical illness myopathy (CIM). Triggering factors for CIM include sepsis, mechanical ventilation, muscle unloading, steroid treatment or denervation. 2 CIM is marked by muscle atrophy, a preferential myosin loss, and reduction of electrical excitability. CIM is not reproduced only by disuse, denervation, steroid treatment or sepsis, however the combination of denervation and a highdose steroid induces a selective loss of myosin and membrane hypoexcitability. This steroid-denervation (S-D) model was first developed over 30 years ago and has long been used to mimic the muscle pathology found in CIM patients.During the past decade, Larsson and colleagues have significantly contributed to improve our understanding of the mechanism underlying CIM using unique experimental porcine and rodent ICU models that allow mechanical ventilation with pharmacological post-synaptic neuromuscular blockade for several weeks. 2 Altered mechano-signalling seems involved in triggering a major part of selective myosin loss in experimental CIM models, and passive mechanical loading of the muscle partially ameliorates the CIM phenotype. Similar results were obtained using S-D rat model; mechanical load induced by neuromuscular electrical stimulation (NMES) prevents myofibrillar dysfunction and preferential skeletal muscle myosin loss. 3 ICU-based NMES has recently been introduced for the treatment of CIM. However, owing to the heterogeneity of critically ill patients and also reduced electrical excitability of target skeletal muscles, the effectiveness of NMES for CIM prevention remains to be determined. Accordingly, the development of an effective pharmacological intervention is required for treating patients with CIM.An ICU model established by Larsson and colleagues also provides novel insights regarding the time course changes in contractile function as well as the molecular alterations in skeletal muscles, and highlights the PTMs of myosin as a causative factor in the myofibrillar dysfunction observed at the early stage of CIM. Heat shock protein (HSP) 72 is one of the most abundant HSP...

show abstract

BGP-15 Protects against Oxidative Stress- or Lipopolysaccharide-Induced Mitochondrial Destabilization and Reduces Mitochondrial Production of Reactive Oxygen Species

Cited by 45 publications

References 57 publications

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

NOX4/ROS mediate ethanol‑induced apoptosis via MAPK signal pathway in L‑02 cells

BGP‐15: A potential therapeutic agent for critical illness myopathy

Contact Info

Product

Resources

About