Simulated microgravity‐induced mitochondrial dysfunction in rat cerebral arteries

Zhang, Ran; Ran, Hong; Cai, Li-Li; Zhu, Li; Sun, Jingyang; Peng, Liang; Liu, Xiaojuan; Zhang, Lan-Ning; Fang, Zhou; Fan, Yong-Yan; Geng, Changran

doi:10.1096/fj.13-245654

Cited by 40 publications

(26 citation statements)

References 49 publications

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“…3a, b, c). However, it is still equivocal whether PTP opening is a consequence or a cause of increasing ROS generation, since elevated ROS generation would lead to PTP opening [43,44] and VDAC1-dependent mitochondrial permeability transition (MPT) also engaged a positive feedback loop promoting ROS generation [58]. In addition to that, our study showed that significant differences of all events including [Ca 2? ]…”

Section: Discussionmentioning

confidence: 59%

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Inhibition of VDAC1 prevents Ca2+-mediated oxidative stress and apoptosis induced by 5-aminolevulinic acid mediated sonodynamic therapy in THP-1 macrophages

et al. 2014

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Ultrasound combined with endogenous protoporphyrin IX derived from 5-aminolevulinic acid (ALA-SDT) is known to induce apoptosis in multiple cancer cells and macrophages. Persistent retention of macrophages in the plaque has been implicated in the pathophysiology and progression of atherosclerosis. Here we investigated the effects of inhibition of voltage-dependent anion channel 1 (VDAC1) on ALA-SDT-induced THP-1 macrophages apoptosis. Cells were pre-treated with VDAC1 inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) disodium salt for 1 h or downregulated VDAC1 expression by small interfering RNA and exposed to ultrasound. Cell viability was assessed by MTT assay, and cell apoptosis along with necrosis was evaluated by Hoechst 33342/propidium iodide staining and flow cytometry. Levels of cytochrome c release was assessed by confocal microscope and Western blot. The levels of full length caspases, caspase activation, and VDAC isoforms were analyzed by Western blot. Intracellular reactive oxygen species generation, mitochondrial membrane permeability, and intracellular Ca(2+) [Ca(2+)]i levels were measured with fluorescent probes. We confirmed that the pharmacological inhibition of VDAC1 by DIDS notably prevented ALA-SDT-induced cell apoptosis in THP-1 macrophages. Additionally, DIDS significantly inhibited intracellular ROS generation and apoptotic biochemical changes such as inner mitochondrial membrane permeabilization, loss of mitochondrial membrane potential, cytochrome c release and activation of caspase-3 and caspase-9. Moreover, ALA-SDT elevated the [Ca(2+)]i levels and it was also notably reduced by DIDS. Furthermore, both of intracellular ROS generation and cell apoptosis were predominately inhibited by Ca(2+) chelating reagent BAPTA-AM. Intriguingly, ALA-treatment markedly augmented VDAC1 protein levels exclusively, and the downregulation of VDAC1 expression by specific siRNA also significantly abolished cell apoptosis. Altogether, these results suggest that VDAC1 plays a crucial role in ALA-SDT-induced THP-1 macrophages apoptosis, and targeting VDAC1 is a potential way regulating macrophages apoptosis, a finding that may be relevant to therapeutic strategies against atherosclerosis.

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Section: Discussionmentioning

confidence: 59%

“…Alterations in oxidative state are usually associated with the loss of mDW [43][44][45]. Therefore, a subsequent study was undertaken to investigate the relationship between the ALA-SDT-induced oxidative stress and changes of mitochondria membrane permeability.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of VDAC1 prevents Ca2+-mediated oxidative stress and apoptosis induced by 5-aminolevulinic acid mediated sonodynamic therapy in THP-1 macrophages

et al. 2014

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“…), the expression of cleaved caspase‐3 and cleaved caspase‐9, markers of apoptosis, were also found to be significantly increased in ISO‐treated cardiomyocytes. Coincidently, simulated microgravity resulted in cerebrovascular mitochondrial dysfunction, and crosstalk between NOX and mitochondria participated in the process [Zhang et al, ]. Together, these data support an essential role of nuclear calpain‐2 in the regulation of the mitochondrial machinery through modulating Bcl‐2 levels.…”

Section: Discussionmentioning

confidence: 76%

ROS‐Induced Nuclear Translocation of Calpain‐2 Facilitates Cardiomyocyte Apoptosis in Tail‐Suspended Rats

Chang

Sheng

Zhang³

et al. 2015

J of Cellular Biochemistry

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Isoproterenol (ISO) induced nuclear translocation of calpain-2 which further increased susceptibility of cardiomyocyte apoptosis in tail-suspended rats. The underlying mechanisms remain elusive. In the present study, the results showed that ISO (10 nM) significantly elevated NADPH oxidases (NOXs) activity and NOXs-derived ROS productions which induced nuclear translocation of calpain-2 in cardiomyocytes of tail-suspended rats. In contrast, the inhibition of NADPH oxidase or cleavage of ROS not only reduced ROS productions, but also resisted nuclear translocation of calpain-2 and decreased ISO-induced apoptosis of cardiomyocyte in tail-suspended rats. ISO also increased the constitutive binding between calpain-2 and Ca(2+)/calmodulin-dependent protein kinase II δB (CaMK II δB) in nuclei, concomitant with the promotion of CaMK II δB degradation and subsequent down-regulation of Bcl-2 mRNA expression and the ratio of Bcl-2 to Bax protein in tail-suspended rat cardiomyocytes. These effects of ISO on cardiomyocytes were abolished by a calpain inhibitor PD150606. Inhibition of calpain significantly reduced ISO-induced loss of the mitochondrial membrane potential, cytochrome c release into the cytoplasm, as well as the activation of caspase-3 and caspase-9 in mitochondrial apoptotic pathway. In summary, the above results suggest that ISO increased NOXs-derived ROS which activated nuclear translocation of calpain-2, subsequently nuclear calpain-2 degraded CaMK II δB which reduced the ratio of Bcl-2 to Bax, and finally the mitochondria apoptosis pathway was triggered in tail-suspended rat cardiomyocytes. Therefore, calpain-2 may represent a potentially therapeutic target for prevention of oxidative stress-associated cardiomyocyte apoptosis.

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“…A recent study examining organelle function in cardiomyocytes in simulated microgravity also showed an upregulation in genes and proteins associated with microchondrial processes as well as down-regulation of cytoplasmic translational mechanisms, including ribosomes and endoplasmic reticulum65. As mitochondria have been shown to be highly susceptible to stress-related damage and dysfunction in simulated microgravity66, the upregulation of light organ transcripts associated with these processes may be a mechanism for the host squid to maintain mitochondrial and other organelle homeostasis to help regulate cellular redox control during microgravity conditions, regardless of the symbiotic state of the host.…”

Section: Discussionmentioning

confidence: 98%

Transcriptomic changes in an animal-bacterial symbiosis under modeled microgravity conditions

Casaburi

Goncharenko-Foster

Duscher

et al. 2017

Sci Rep

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Spaceflight imposes numerous adaptive challenges for terrestrial life. The reduction in gravity, or microgravity, represents a novel environment that can disrupt homeostasis of many physiological processes. Additionally, it is becoming increasingly clear that an organism’s microbiome is critical for host health and examining its resiliency in microgravity represents a new frontier for space biology research. In this study, we examine the impact of microgravity on the interactions between the squid Euprymna scolopes and its beneficial symbiont Vibrio fischeri, which form a highly specific binary mutualism. First, animals inoculated with V. fischeri aboard the space shuttle showed effective colonization of the host light organ, the site of the symbiosis, during space flight. Second, RNA-Seq analysis of squid exposed to modeled microgravity conditions exhibited extensive differential gene expression in the presence and absence of the symbiotic partner. Transcriptomic analyses revealed in the absence of the symbiont during modeled microgravity there was an enrichment of genes and pathways associated with the innate immune and oxidative stress response. The results suggest that V. fischeri may help modulate the host stress responses under modeled microgravity. This study provides a window into the adaptive responses that the host animal and its symbiont use during modeled microgravity.

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Simulated microgravity‐induced mitochondrial dysfunction in rat cerebral arteries

Cited by 40 publications

References 49 publications

Inhibition of VDAC1 prevents Ca2+-mediated oxidative stress and apoptosis induced by 5-aminolevulinic acid mediated sonodynamic therapy in THP-1 macrophages

Inhibition of VDAC1 prevents Ca2+-mediated oxidative stress and apoptosis induced by 5-aminolevulinic acid mediated sonodynamic therapy in THP-1 macrophages

ROS‐Induced Nuclear Translocation of Calpain‐2 Facilitates Cardiomyocyte Apoptosis in Tail‐Suspended Rats

Transcriptomic changes in an animal-bacterial symbiosis under modeled microgravity conditions

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