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Lead-exposed spherule mitochondria have more cristae with multiple segments than the controls. (A) The top and (B) side views display only cristae with multiple segments (30 out of 204 cristae) in a control spherule mitochondrion. The outer membrane is shown in blue. C: The top and (D) side views show only cristae with multiple segments (33 out of 98) in a lead-exposed spherule mitochondrion. Note the much greater volume of mitochondrion occupied by cristae with multiple segments in the lead spherule. Examples of typical lamellar cristae in (E) control and (F) lead mitochondria. As is common with lamellar cristae in terminal mitochondria, they are small and do not extend far across the volume. These are examples of typical cristae with multiple segments in (G) control and (H) lead mitochondria. Crista segments are tubes or small lamellae connected by joints (branch points) and are numbered (six total) in the control crista for illustration. I: A partial remodeling of Bcl-xL/Lead mitochondria produced more thicker, tubular cristae (examples shown) than found in the control mitochondria.
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Postnatal lead exposure produces rod-selective and Bax-mediated apoptosis, decreased scotopic electroretinograms (ERGs), and scotopic and mesopic vision deficits in humans and/or experimental animals. Rod, but not cone, inner segment mitochondria were considered the primary site of action. However, photoreceptor synaptic mitochondria were not exami...
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Key points
Rod photoreceptors play a key role in vision in dim light; in the mammalian retina, although rods are anatomically connected or coupled by gap junctions, a type of electrical synapse, the functional importance and regulation of rod coupling has remained elusive.
We have developed a new technique in the mouse: perforated patch‐clamp recor...
Citations
... In addition to the need for adjusting for the potential confounding role of dietary intake and other potential confounding variables while assessing associations between BPbCs and ASD, several studies have also suggested that differences in Pb concentrations could be due to varied detoxification and excretory mechanisms in children with and without ASD [10,16,17]. It has also been shown that Pb-induced toxicity is associated with chronic oxidative stress and mitochondrial dysfunction [18][19][20][21]. ...
Glutathione S-transferases (GST) are involved in the detoxification of exogenous chemicals including lead (Pb). Using data from 344 pairs of autism spectrum disorder (ASD) cases and age- and sex-matched typically developing (TD) controls (2–8 years old) from Jamaica, we investigated the interaction between three GST genes and ASD status as determinants of blood Pb concentrations (BPbCs). We found that ASD cases had lower geometric mean BPbCs than TD children (1.74 vs. 2.27 µg/dL, p < 0.01). Using a co-dominant genetic model, ASD cases with the Ile/Val genotype for the GSTP1 Ile105Val polymorphism had lower GM BPbCs than TD controls, after adjusting for a known interaction between GSTP1 and GSTT1, child’s parish, socioeconomic status, consumption of lettuce, fried plantains, and canned fish (Ile/Val: 1.78 vs. 2.13 µg/dL, p = 0.03). Similarly, among carriers of the I/I or I/D (I*) genotype for GSTT1 and GSTM1, ASD cases had lower adjusted GM BPbCs than TD controls (GSTT1 I*: 1.61 vs. 1.91 µg/dL, p = 0.01; GSTM1 I*: 1.71 vs. 2.04 µg/dL, p = 0.01). Our findings suggest that genetic polymorphisms in GST genes may influence detoxification of Pb by the enzymes they encode in Jamaican children with and without ASD.
... The glutamate receptor initiates acute intraocular hypertension, and ischemic injury induces the retinal mitochondria to release OPA1 and activate the cell death pathway, resulting in the apoptosis of inner retinal cells [15][16][17]. A decrease in oxygen consumption (QO2) at the synaptic terminal of the retina and photoreceptors indicates the continued dysfunction of mitochondrial oxidative phosphorylation, the activation of apoptotic pathways, and the apoptosis of retinal endometrium cells [18]. Retinal edema, vacuolation, and the mitochondrial disintegration of retinal cells were observed upon the intravitreal injection of methotrexate in rabbits. ...
Mitochondria are the energy factories of cells. Mitochondrial dysfunction directly affects the function and morphology of cells. In recent years, growing evidence has shown that mitochondrial dysfunction plays an important role in neurodegenerative diseases. In the eye, some age-related diseases are considered to be neurodegenerative diseases, such as primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD). Here, we review the mechanisms of mitochondrial damage, post-injury repair, and the roles of mitochondria in various tissues of the eye. In the following sections, the potential for treating glaucoma by reducing mitochondrial damage and promoting post-injury repair is also discussed.
... As an example, Pb exposure correlates with PM 2.5 exposure [83] and adversely affects the immune and nervous systems, including behavioral problems, learning deficits, intellectual disability and ASD [84]. In animal models, Pb exposure results in mitochondrial ultrastructure damage, and/or dysfunction in neuronal tissue [85][86][87][88], and depletes mitochondrial GSH in brain [89]. Pb also results in oxidative stress by depleting GSH [86,89], decreasing superoxide dismutase activity [86,89], and increasing malondialdehyde [89], ROS production [85], and catalase expression [89]. ...
We investigate the role of the mitochondrion, an organelle highly sensitive to environmental agents, in the influence of prenatal air pollution exposure on neurodevelopment and behavior in 96 children with autism spectrum disorder (ASD) [45 with neurodevelopmental regression (NDR); 76% Male; mean (SD) age 10 y 9 m (3 y 9 m)]. Mitochondrial function was assessed using the Seahorse XFe96 in fresh peripheral blood mononuclear cells. Second and third trimester average and maximal daily exposure to fine air particulate matter of diameter ≤2.5 µm (PM2.5) was obtained from the Environmental Protection Agency’s Air Quality System. Neurodevelopment was measured using the Vineland Adaptive Behavior Scale 2nd edition and behavior was assessed using the Aberrant Behavior Checklist and Social Responsiveness Scale. Prenatal PM2.5 exposure influenced mitochondrial respiration during childhood, but this relationship was different for those with (r = 0.25–0.40) and without (r = −0.07 to −0.19) NDR. Mediation analysis found that mitochondrial respiration linked to energy production accounted for 25% (SD = 2%) and 10% (SD = 2%) of the effect of average prenatal PM2.5 exposure on neurodevelopment and behavioral symptoms, respectively. Structural equation models estimated that PM2.5 and mitochondrial respiration accounted for 34% (SD = 4%) and 36% (SD = 3%) of the effect on neurodevelopment, respectively, and that behavior was indirectly influenced by mitochondrial respiration through neurodevelopment but directly influenced by prenatal PM2.5. Our results suggest that prenatal exposure to PM2.5 disrupts neurodevelopment and behavior through complex mechanisms, including long-term changes in mitochondrial respiration and that patterns of early development need to be considered when studying the influence of environmental agents on neurodevelopmental outcomes.
... CICR is a well-known phenomenon at photoreceptor synapses (Cadetti et al., 2006;Szikra et al., 2009;Babai et al., 2010;Chen et al., 2015). In photoreceptor synapses, mitochondria are placed close to the synaptic ribbons (Johnson et al., 2007;Stone et al., 2008;Linton et al., 2010;Perkins et al., 2012;Graffe et al., 2015;Li et al., 2016) and possess a strong impact on Ca 2+ regulation in retinal ribbon synapses (Zenisek and Matthews, 2000;Wan et al., 2012;Wong et al., 2019). Also, the cation chloride co-transporter NKCC1 is enriched in photoreceptor synapses (Shen et al., 2013) that can affect presynaptic Ca 2+ (Thoreson et al., 2000(Thoreson et al., , 2002(Thoreson et al., , 2003. ...
Multiple sclerosis (MS) is a demyelinating disease caused by an auto-reactive immune system. Recent studies also demonstrated synapse dysfunctions in MS patients and MS mouse models. We previously observed decreased synaptic vesicle exocytosis in photoreceptor synapses in the EAE mouse model of MS at an early, preclinical stage. In the present study, we analyzed whether synaptic defects are associated with altered presynaptic Ca 2+ signaling. Using high-resolution immu-nolabeling, we found a reduced signal intensity of Cav-channels and RIM2 at active zones in early, preclinical EAE. In line with these morphological alterations, depolarization-evoked increases of presynaptic Ca 2+ were significantly smaller. In contrast, basal presynaptic Ca 2+ was elevated. We observed a decreased expression of Na + /K +-ATPase and plasma membrane Ca 2+ ATPase 2 (PMCA2), but not PMCA1, in photoreceptor terminals of EAE mice that could contribute to elevated basal Ca 2+. Thus, complex Ca 2+ signaling alterations contribute to synaptic dysfunctions in photoreceptors in early EAE.
... CICR is a well-known phenomenon at photoreceptor synapses (Cadetti et al., 2006;Szikra et al., 2009;Babai et al., 2010;Chen et al., 2015). In photoreceptor synapses, mitochondria are placed close to the synaptic ribbons (Johnson et al., 2007;Stone et al., 2008;Linton et al., 2010;Perkins et al., 2012;Graffe et al., 2015;Li et al., 2016) and possess a strong impact on Ca 2+ regulation in retinal ribbon synapses (Zenisek and Matthews, 2000;Wan et al., 2012;Wong et al., 2019). Also, the cation chloride co-transporter NKCC1 is enriched in photoreceptor synapses (Shen et al., 2013) that can affect presynaptic Ca 2+ (Thoreson et al., 2000(Thoreson et al., , 2002(Thoreson et al., , 2003. ...
Multiple sclerosis (MS) is a demyelinating disease caused by an auto-reactive immune system. Recent studies also demonstrated synapse dysfunctions in MS patients and MS mouse models. We previously observed decreased synaptic vesicle exocytosis in photoreceptor synapses in the EAE mouse model of MS at an early, preclinical stage. In the present study, we analyzed whether synaptic defects are associated with altered presynaptic Ca2+ signaling. Using high-resolution immunolabelling, we found a reduced signal intensity of Cav-channels and RIM2 at active zones in early, preclinical EAE. In line
with these morphological alterations, depolarization-evoked increases of presynaptic Ca2+ were significantly smaller. In contrast, basal presynaptic Ca2+ was elevated. We observed a decreased expression of Na+/K+-ATPase and plasma membrane Ca2+ ATPase 2 (PMCA2), but not PMCA1, in photoreceptor terminals of EAE mice that could contribute to elevated basal Ca2+. Thus, complex Ca2+ signaling alterations contribute to synaptic dysfunctions in photoreceptors in early EAE. This article is protected by copyright. All rights reserved.
... Cristae of mitochondria were absent in many mitochondria of Sertoli cell in animals treated with BPA. This may be due to oxidative stress, Ca2+ overload, and ATP loss perhaps due to Bax-mediated effects and this shows mitochondria mediated apoptosis(Perkins et al., 2012).There were structural changes in spermatids of treated group as compared to control ones. Chromatin clumping ...
BPA is an EDC which is continuously released into the environment because of its extensive usage as plasticizer and other industrial applications. The present study establishes BPA induced alterations in mitochondrial marker enzymes and hence cause mitochondrial dysfunction. Studies were performed to evaluate the histopathological changes in tissue on exposure to different doses of BPA for different time periods. Light microscopic examination of samples was done to evaluate the possible changes caused by treatment of different doses of BPA. After getting the results in light microscopy the changes and damage caused by BPA ultra-structurally were observed. Light microscopic study showed that BPA exposure for short duration of 7 days did not resulted in significant change in histology of Rat of treated animals. Light microscopic observations showed that low doses of BPA (5 and 10 mg/kg body weight) exposure for 14 days caused reduction in the number of cells in the layers of seminiferous tubules. Highest dose of BPA treatment for 14 days caused much damage to the seminiferous tubules. There were many ultra-structural changes found in the treated groups as compared to the control group. Hence it can be stated that due to the toxic effect of BPA the mitochondrial marker enzymes have shown marked reduction in their activities. Keywords: BPA, EDCs, Light microscopic, Mitochondria and Toxicity.
... Electron microscopy analysis showed that mitochondria in rod and cone synaptic terminals appeared reduced in number and swollen, with severe disruption of their cristae. Mitochondria in the OPL are also swollen in Large myd mice, which additionally show numerous, disrupted cristae in Large vls mutants 21 , as occurs in other rodent models of retinal degeneration [50][51][52] . Impaired electron transport and oxidative stress 53 at the presynaptic terminals could consequently occur in our Pomt1 cKO mutants, as proposed for the rd10 mouse model of retinitis pigmentosa 54 . ...
Hypoglycosylation of α-dystroglycan (α-DG) resulting from deficiency of protein O-mannosyltransferase 1 (POMT1) may cause severe neuromuscular dystrophies with brain and eye anomalies, named dystroglycanopathies. The retinal involvement of these disorders motivated us to generate a conditional knockout (cKO) mouse experiencing a Pomt1 intragenic deletion (exons 3-4) during the development of photoreceptors, mediated by the Cre recombinase expressed from the cone-rod homeobox (Crx) gene promoter. In this mouse, retinal α-DG was unglycosylated and incapable of binding laminin. Retinal POMT1 deficiency caused significant impairments in both electroretinographic recordings and optokinetic reflex in Pomt1 cKO mice, and immunohistochemical analyses revealed the absence of β-DG and of the α-DG-interacting protein, pikachurin, in the outer plexiform layer (OPL). At the ultrastructural level, noticeable alterations were observed in the ribbon synapses established between photoreceptors and bipolar cells. Therefore, O-mannosylation of α-DG in the retina carried out by POMT1 is crucial for the establishment of proper synapses at the OPL and transmission of visual information from cones and rods to their postsynaptic neurons. Dystroglycanopathies, recently renamed as muscular dystrophies-dystroglycanopathies (MDDGs), constitute a heterogeneous group of recessive congenital neuromuscular diseases. These disorders are associated with a wide clinical spectrum, and with different grades of severity of muscular impairment, brain malformation and ocular abnormalities 1. The main underlying cause of these symptoms is a deficiency in the process of glycosyla-tion (mainly O-mannosylation) of dystroglycan (DG), a key component of the dystrophin-glycoprotein complex (DGC) in muscular 2 and central nervous system (CNS) tissues 3. DG acts as a nexus between the extracellular matrix (ECM) and the actin cytoskeleton, and is composed of two subunits: α-DG and β-DG. α-DG is an extra-cellular protein anchored to the cell membrane by the β-DG transmembrane subunit 4 , while on the cytoplasmic side β-DG is anchored to the cytoskeletal protein dystrophin 5. α-DG is a heavily glycosylated protein with the potential to bind, by virtue of its O-mannosyl glycans, to a large number of ECM proteins, including laminin and pikachurin 6 , the latter exclusive of the retina. Protein O-mannosyltransferase 1 (POMT1), which is the closest phylogenetic relative of yeast Pmt4 7 , acts in a heteromeric complex with POMT2 to add in the endoplasmic reticulum the initial mannose unit 8 of all O-mannosyl glycan cores that become covalently attached to α-DG, including laminin-binding residues 9 .
... Electron microscopy analysis showed that mitochondria in rod and cone synaptic terminals appeared reduced in number and swollen, with severe disruption of their cristae. Mitochondria in the OPL are also swollen in Large myd mice, which additionally show numerous, disrupted cristae in Large vls mutants 21 , as occurs in other rodent models of retinal degeneration [50][51][52] . Impaired electron transport and oxidative stress 53 at the presynaptic terminals could consequently occur in our Pomt1 cKO mutants, as proposed for the rd10 mouse model of retinitis pigmentosa 54 . ...
Hypoglycosylation of α-dystroglycan (α-DG) resulting from deficiency of protein O-mannosyltransferase 1 (POMT1) may cause severe neuromuscular dystrophies with brain and eye anomalies, named dystroglycanopathies. The retinal involvement of these disorders motivated us to generate a conditional knockout (cKO) mouse experiencing a Pomt1 intragenic deletion (exons 3-4) during the development of photoreceptors, mediated by the Cre recombinase expressed from the cone-rod homeobox (Crx) gene promoter. In this mouse, retinal α-DG was unglycosylated and incapable of binding laminin. Retinal POMT1 deficiency caused significant impairments in both electroretinographic recordings and optokinetic reflex in Pomt1 cKO mice, and immunohistochemical analyses revealed the absence of β-DG and of the α-DG-interacting protein, pikachurin, in the outer plexiform layer (OPL). At the ultrastructural level, noticeable alterations were observed in the ribbon synapses established between photoreceptors and bipolar cells. Therefore, O-mannosylation of α-DG in the retina carried out by POMT1 is crucial for the establishment of proper synapses at the OPL and transmission of visual information from cones and rods to their postsynaptic neurons.
... Photoreceptors are highly metabolically active cells and account for much of the energy consumption in the retina. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] The major photoreceptor energy substrate in vivo is glucose. [4][5][6][7][8][9][10][11][12][13][14][15][16] Glucose metabolism also performs many non-energetic roles in photoreceptors. ...
... [1][2][3][4][5][6][7][8][9][10][11][12][13][14] The major photoreceptor energy substrate in vivo is glucose. [4][5][6][7][8][9][10][11][12][13][14][15][16] Glucose metabolism also performs many non-energetic roles in photoreceptors. 4,[17][18][19][20] Additionally, photoreceptors have the capacity to utilize alternative energy substrates such as lactate, amino acids and highenergy phosphate groups. ...
... Mitochondria are distributed throughout the inner segment and synaptic terminal. 6,9,11,35 The different architectures of rod and cone outer segments represent a major distinctive feature of the two photoreceptor cell types. Cones are conical shaped cells and their outer segments are generally shorter than rods. ...
Photoreceptors are the first order neurons of the visual pathway, converting light into electrical signals. Rods and cones are the two main types of photoreceptors in the mammalian retina. Rods are specialized for sensitivity at the expense of resolution and are responsible for vision in dimly lit conditions. Cones are responsible for high acuity central vision and colour vision. Many human retinal diseases are characterized by a progressive loss of photoreceptors. Photoreceptors consist of four primary regions: outer segments, inner segments, cell bodies, and synaptic terminals. Photoreceptors consume large amounts of energy and, therefore, energy metabolism may be a critical juncture that links photoreceptor function and survival. Cones require more energy than rods, and cone degeneration is the main cause of clinically significant vision loss in retinal diseases. Photoreceptor segments are capable of utilising various energy substrates, including glucose, to meet their large energy demands. The pathways by which photoreceptor segments meet their energy demands remain incompletely understood. Improvements in the understanding of glucose metabolism in photoreceptor segments may provide insight into the reasons why photoreceptors degenerate due to energy failure. This may, in turn, assist in developing bio-energetic therapies aimed at protecting photoreceptors.
... Consistent with these results, we observed a dose-dependent increase in the number of RPCs, prolongation of RPC proliferation, and selective increase in the number of rods and BCs in adult mice [21] and Long- Evans hooded rats [19] . This is in marked contrast to postnatal or adult lead exposure, at similar blood lead levels, which produces rod-selective apoptosis [22,23], photoreceptor synaptic degeneration [24], and hippocampal granule cell apoptosis [25,26], synaptic dysfunction, and degeneration [27]. We hypothesized that the increased number of RPCs accelerates the development of rods and BCs and increases the abundance of the functional synaptic markers of these cell types as they differentiate and mature. ...
... We observed the same phenotypic effects of GLE in C57BL/6J mice [29] and Long-Evans hooded rats [19]. Despite the rd8 mutation [30,31], we did not observe dysplasia, irregularities in retinal layer thickness, or the displacement of photoreceptors at any experimental time point in this or in our previous studies [21,24,29,32]. Briefly, naïve females were given either tap (control) or 55 parts per million (ppm) lead acetate containing drinking water (GLE group) for two weeks before mating, during pregnancy, and until PN10, after which the lead was replaced with tap water. ...
... Thus, the Otx2 and Chx10 expression patterns in , the OSs were intensely rhodopsin-IR, and there was extensive labeling in the ISs, ONL, and OPL. In the distal OPL, the smaller rod spherules [24] were colabeled (yellow pixels), whereas the larger cone pedicles in the proximal OPL [24] were only recoverin-IR (green pixels). In the GLE retinas at (M, Q, and U) PN5 and (N, R, and V) PN7, the ISs, ONL, and OPL were rhodopsin-IR and recoverin- IR, and an increased amount of colabeling was seen in all the layers. ...
Purpose
Studies of neuronal development in the retina often examine the stages of proliferation, differentiation, and synaptic development, albeit independently. Our goal was to determine if a known neurotoxicant insult to a population of retinal progenitor cells (RPCs) would affect their eventual differentiation and synaptic development. To that end, we used our previously published human equivalent murine model of low-level gestational lead exposure (GLE). Children and animals with GLE exhibit increased scotopic electroretinogram a- and b-waves. Adult mice with GLE exhibit an increased number of late-born RPCs, a prolonged period of RPC proliferation, and an increased number of late-born rod photoreceptors and rod and cone bipolar cells (BCs), with no change in the number of late-born Müller glial cells or early-born neurons. The specific aims of this study were to determine whether increased and prolonged RPC proliferation alters the spatiotemporal differentiation and synaptic development of rods and BCs in early postnatal GLE retinas compared to control retinas.
Methods
C57BL/6N mouse pups were exposed to lead acetate via drinking water throughout gestation and until postnatal day 10, which is equivalent to the human gestation period for retinal neurogenesis. RT-qPCR, immunohistochemical analysis, and western blots of well-characterized, cell-specific genes and proteins were performed at embryonic and early postnatal ages to assess rod and cone photoreceptor differentiation, rod and BC differentiation and synaptic development, and Müller glial cell differentiation.
Results
Real-time quantitative PCR (RT-qPCR) with the rod-specific transcription factors Nrl, Nr2e3, and Crx and the rod-specific functional gene Rho, along with central retinal confocal studies with anti-recoverin and anti-rhodopsin antibodies, revealed a two-day delay in the differentiation of rod photoreceptors in GLE retinas. Rhodopsin immunoblots supported this conclusion. No changes in glutamine synthetase gene or protein expression, a marker for late-born Müller glial cells, were observed in the developing retinas. In the retinas from the GLE mice, anti-PKCα, -Chx10 (Vsx2) and -secretagogin antibodies revealed a two- to three-day delay in the differentiation of rod and cone BCs, whereas the expression of the proneural and BC genes Otx2 and Chx10, respectively, increased. In addition, confocal studies of proteins associated with functional synapses (e.g., vesicular glutamate transporter 1 [VGluT1], plasma membrane calcium ATPase [PMCA], transient receptor potential channel M1 [TRPM1], and synaptic vesicle glycoprotein 2B [SV2B]) revealed a two-day delay in the formation of the outer and inner plexiform layers of the GLE retinas. Moreover, several markers revealed that the initiation of the differentiation and intensity of the labeling of early-born cells in the retinal ganglion cell and inner plexiform layers were not different in the control retinas.
Conclusions
Our combined gene, confocal, and immunoblot findings revealed that the onset of rod and BC differentiation and their subsequent synaptic development is delayed by two to three days in GLE retinas. These results suggest that perturbations during the early proliferative stages of late-born RPCs fated to be rods and BCs ultimately alter the coordinated time-dependent progression of rod and BC differentiation and synaptic development. These GLE effects were selective for late-born neurons. Although the molecular mechanisms are unknown, alterations in soluble neurotrophic factors and/or their receptors are likely to play a role. Since neurodevelopmental delays and altered synaptic connectivity are associated with neuropsychiatric and behavioral disorders as well as cognitive deficits, future work is needed to determine if similar effects occur in the brains of GLE mice and whether children with GLE experience similar delays in retinal and brain neuronal differentiation and synaptic development.
