To unite or divide: mitochondrial dynamics in the murine outer retina that preceded age related photoreceptor loss

AbstractChronic undernutrition contributes to the increase in frailty observed among elderly adults, which is a pressing issue in the sector of health care for older people worldwide. Autophagy, an intracellular recycling system, is closely associated with age-related pathologies. Therefore, decreased autophagy in aging could be involved in the disruption of energy homeostasis that occurs during undernutrition; however, the physiological mechanisms underlying this process remain unknown. Here, we showed that 70% daily food restriction (FR) induced fatal hypoglycemia in 23–26-month-old (aged) mice, which exhibited significantly lower hepatic autophagy than 9-week-old (young) mice. The liver expressions of Bcl-2, an autophagy-negative regulator, and Beclin1–Bcl-2 binding, were increased in aged mice compared with young mice. The autophagy inducer Tat-Beclin1 D11, not the mTOR inhibitor rapamycin, decreased the plasma levels of the glucogenic amino acid and restored the blood glucose levels in aged FR mice. Decreased liver gluconeogenesis, body temperature, physical activity, amino acid metabolism, and hepatic mitochondrial dynamics were observed in the aged FR mice. These changes were restored by treatment with hochuekkito that is a herbal formula containing several autophagy-activating ingredients. Our results indicate that Bcl-2 upregulation in the liver during the aging process disturbs autophagy activation, which increases the vulnerability to undernutrition. The promotion of liver autophagy may offer clinical therapeutic benefits to frail elderly patients.

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Is Retinal Metabolic Dysfunction at the Center of the Pathogenesis of Age-related Macular Degeneration?

International Journal of Molecular Sciences ◽

10.3390/ijms20030762 ◽

2019 ◽

Vol 20 (3) ◽

pp. 762 ◽

Cited By ~ 23

Author(s):

Thierry Léveillard ◽

Nancy Philp ◽

Florian Sennlaub

Keyword(s):

Macular Degeneration ◽

Aerobic Glycolysis ◽

Tricarboxylic Acid Cycle ◽

Retinal Pigment ◽

Basolateral Membrane ◽

Age Related Macular Degeneration ◽

Subretinal Space ◽

Outer Retina ◽

Choroidal Circulation ◽

Age Related

The retinal pigment epithelium (RPE) forms the outer blood–retina barrier and facilitates the transepithelial transport of glucose into the outer retina via GLUT1. Glucose is metabolized in photoreceptors via the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) but also by aerobic glycolysis to generate glycerol for the synthesis of phospholipids for the renewal of their outer segments. Aerobic glycolysis in the photoreceptors also leads to a high rate of production of lactate which is transported out of the subretinal space to the choroidal circulation by the RPE. Lactate taken up by the RPE is converted to pyruvate and metabolized via OXPHOS. Excess lactate in the RPE is transported across the basolateral membrane to the choroid. The uptake of glucose by cone photoreceptor cells is enhanced by rod-derived cone viability factor (RdCVF) secreted by rods and by insulin signaling. Together, the three cells act as symbiotes: the RPE supplies the glucose from the choroidal circulation to the photoreceptors, the rods help the cones, and both produce lactate to feed the RPE. In age-related macular degeneration this delicate ménage à trois is disturbed by the chronic infiltration of inflammatory macrophages. These immune cells also rely on aerobic glycolysis and compete for glucose and produce lactate. We here review the glucose metabolism in the homeostasis of the outer retina and in macrophages and hypothesize what happens when the metabolism of photoreceptors and the RPE is disturbed by chronic inflammation.

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Nonexudative Macular Neovascularization Supporting Outer Retina in Age-Related Macular Degeneration

Ophthalmology ◽

10.1016/j.ophtha.2020.01.040 ◽

2020 ◽

Vol 127 (7) ◽

pp. 931-947 ◽

Cited By ~ 15

Author(s):

Ling Chen ◽

Jeffrey D. Messinger ◽

Kenneth R. Sloan ◽

Thomas A. Swain ◽

Yoshimi Sugiura ◽

...

Keyword(s):

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Outer Retina ◽

Age Related

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Functional and morphological assessment of age-related changes in the choroid and outer retina in pigeons

Visual Neuroscience ◽

10.1017/s0952523801182143 ◽

2001 ◽

Vol 18 (2) ◽

pp. 299-317 ◽

Cited By ~ 28

Author(s):

MALINDA E.C. FITZGERALD ◽

ELIZABETH TOLLEY ◽

SHARON FRASE ◽

YURI ZAGVAZDIN ◽

RONALD F. MILLER ◽

...

Keyword(s):

Outer Retina ◽

Age Related ◽

Morphological Assessment ◽

Age Related Changes

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Infiltration of Proinflammatory M1 Macrophages into the Outer Retina Precedes Damage in a Mouse Model of Age-Related Macular Degeneration

International Journal of Inflammation ◽

10.1155/2013/503725 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 62

Author(s):

Fernando Cruz-Guilloty ◽

Ali M. Saeed ◽

Jose J. Echegaray ◽

Stephanie Duffort ◽

Asha Ballmick ◽

...

Keyword(s):

Macular Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Lipid Peroxidation Product ◽

Outer Retina ◽

Photoreceptor Outer Segments ◽

Age Related ◽

M1 Phenotype ◽

Peroxidation Product

Age-related macular degeneration (AMD) is a major cause of blindness in the developed world. Oxidative stress and inflammation are implicated in AMD, but precise mechanisms remain poorly defined. Carboxyethylpyrrole (CEP) is an AMD-associated lipid peroxidation product. We previously demonstrated that mice immunized with CEP-modified albumin developed AMD-like degenerative changes in the outer retina. Here, we examined the kinetics of lesion development in immunized mice and the presence of macrophages within the interphotoreceptor matrix (IPM), between the retinal pigment epithelium and photoreceptor outer segments. We observed a significant and time-dependent increase in the number of macrophages in immunized mice relative to young age-matched controls prior to overt pathology. These changes were more pronounced in BALB/c mice than in C57BL/6 mice. Importantly, IPM-infiltrating macrophages were polarized toward the M1 phenotype but only in immunized mice. Moreover, when Ccr2-deficient mice were immunized, macrophages were not present in the IPM and no retinal lesions were observed, suggesting a deleterious role for these cells in our model. This work provides mechanistic evidence linking immune responses against oxidative damage with the presence of proinflammatory macrophages at sites of future AMD and experimentally demonstrates that manipulating immunity may be a target for modulating the development of AMD.

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Integrating multiple aspects of mitochondrial dynamics in neurons: Age-related differences and dynamic changes in a chronic rotenone model

Neurobiology of Disease ◽

10.1016/j.nbd.2010.09.006 ◽

2011 ◽

Vol 41 (1) ◽

pp. 189-200 ◽

Cited By ~ 52

Author(s):

Beth Arnold ◽

Steven J. Cassady ◽

Victor S. VanLaar ◽

Sarah B. Berman

Keyword(s):

Mitochondrial Dynamics ◽

Dynamic Changes ◽

Age Related

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Need for manual segmentation in optical coherence tomography angiography of neovascular age-related macular degeneration

PLoS ONE ◽

10.1371/journal.pone.0244828 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0244828

Author(s):

Supriya Dabir ◽

Vaidehi Bhatt ◽

Deepak Bhatt ◽

Mohan Rajan ◽

Preetam Samant ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Optical Coherence Tomography Angiography ◽

Subretinal Fluid ◽

Age Related Macular Degeneration ◽

Automated Segmentation ◽

Optical Coherence ◽

Manual Segmentation ◽

Outer Retina ◽

Age Related ◽

En Face

Purpose To compare the characteristics of eyes that had manual vs. automated segmentation of choroidal neovascular membrane (CNVM) using optical coherence tomography angiography (OCTA). Methods All patients with CNVM underwent OCTA using the Zeiss Angioplex Cirrus 5000. Slabs of the avascular outer retina, outer retina to choriocapillaris (ORCC) region and choriocapillaris were generated. Manual segmentation was done when there were significant segmentation artifacts. Presence of activity of CNVM was adjudged by the presence of subretinal fluid (SRF) on structural OCT and was compared to activity detected on en face OCTA slabs based on well-defined criteria. Results Eighty-one eyes of 81 patients were recruited of which manual segmentation was required in 46 (57%). Eyes with automated segmentation had significantly more CNVM in the ORCC (75%) whereas those with manual segmentation had deeper CNVM (sub-RPE = 22%, intra-PED = 22%) (p<0.001). Twenty eyes (25%) were found to have active CNVM on both the structural OCT and OCTA while an additional 19 eyes were presumed to have active CNVM on OCTA alone. There was only modest concordance between disease activity detected using structural OCT and OCTA (Kappa = 0.47, 95% CI = 0.30 to 0.64). Conclusions Manual segmentation of OCTA is required in more than 50% eyes with CNVM and this progressively increases with increasing depth of CNVM location from the ORCC to below the RPE. There is moderate concordance between OCTA and structural OCT in determining CNVM activity.

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Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Cells ◽

10.3390/cells9030598 ◽

2020 ◽

Vol 9 (3) ◽

pp. 598 ◽

Cited By ~ 9

Author(s):

Anna Picca ◽

Riccardo Calvani ◽

Hélio José Coelho-Junior ◽

Francesco Landi ◽

Roberto Bernabei ◽

...

Keyword(s):

Quality Control ◽

Mitochondrial Dysfunction ◽

Mitochondrial Dynamics ◽

Mitochondrial Quality Control ◽

Membrane Contact Sites ◽

Contact Sites ◽

Age Related ◽

Bidirectional Communication ◽

Membrane Contact ◽

Organelle Membrane

Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca2+ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson’s disease as a prototypical geroscience condition.

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A convenient protocol for establishing a human cell culture model of the outer retina.

F1000Research ◽

10.12688/f1000research.15409.1 ◽

2018 ◽

Vol 7 ◽

pp. 1107 ◽

Cited By ~ 6

Author(s):

Savannah A. Lynn ◽

Eloise Keeling ◽

Jennifer M. Dewing ◽

David A. Johnston ◽

Anton Page ◽

...

Keyword(s):

Pigment Epithelium ◽

Retinal Pigment ◽

Experimental Manipulation ◽

Age Related Macular Degeneration ◽

Attractive Alternative ◽

Outer Retina ◽

Rpe Cells ◽

Age Related ◽

Culture Model

The retinal pigment epithelium (RPE) plays a key role in the pathogenesis of several blinding retinopathies. Alterations to RPE structure and function are reported in Age-related Macular Degeneration, Stargardt and Best disease as well as pattern dystrophies. However, the precise role of RPE cells in disease aetiology remains incompletely understood. Many studies into RPE pathobiology have utilised animal models, which only recapitulate limited disease features. Some studies are also difficult to carry out in animals as the ocular space remains largely inaccessible to powerful microscopes. In contrast, in-vitro models provide an attractive alternative to investigating pathogenic RPE changes associated with age and disease. In this article we describe the step-by-step approach required to establish an experimentally versatile in-vitro culture model of the outer retina incorporating the RPE monolayer and supportive Bruch’s membrane (BrM). We show that confluent monolayers of the spontaneously arisen human ARPE-19 cell-line cultured under optimal conditions reproduce key features of native RPE. These models can be used to study dynamic, intracellular and extracellular pathogenic changes using the latest developments in microscopy and imaging technology. We also discuss how RPE cells from human foetal and stem-cell derived sources can be incorporated alongside sophisticated BrM substitutes to replicate the aged/diseased outer retina in a dish. The work presented here will enable users to rapidly establish a realistic in-vitro model of the outer retina that is amenable to a high degree of experimental manipulation which will also serve as an attractive alternative to using animals. This in-vitro model therefore has the benefit of achieving the 3Rs objective of reducing and replacing the use of animals in research. As well as recapitulating salient structural and physiological features of native RPE, other advantages of this model include its simplicity, rapid set-up time and unlimited scope for detailed single-cell resolution and matrix studies.

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