Uncoupled turnover disrupts mitochondrial quality control in diabetic retinopathy

Hombrebueno, José R.; Cairns, Lauren; Dutton, Louise; Lyons, Timothy J.; Brazil, Derek P.; Moynagh, Paul N.; Curtis, Tim M.; Xu, Heping

doi:10.1172/jci.insight.129760

Cited by 39 publications

(63 citation statements)

References 52 publications

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“…However, the timing of mitophagy management will require further investigation due to evidence in hyperglycemic mitoQC-Ins2 Akita/+ mice showing that mitophagy increases in the outer retina during early stages of diabetes and then decreases during advanced stages of the disease. 141 Age-Related Macular Degeneration. AMD ultimately results in damage to the retinal outer segments and subretinal inflammation and fibrosis [142][143][144] ; mitophagy-related studies of AMD have focused primarily on the viability of the RPE, which becomes damaged and atrophic in earlier stages of this disease.…”

Section: Retinopathymentioning

confidence: 99%

Mitophagy: An Emerging Target in Ocular Pathology

Skeie

Nishimura

Wang

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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Mitochondrial function is essential for the viability of aerobic eukaryotic cells, as mitochondria provide energy through the generation of adenosine triphosphate (ATP), regulate cellular metabolism, provide redox balancing, participate in immune signaling, and can initiate apoptosis. Mitochondria are dynamic organelles that participate in a cyclical and ongoing process of regeneration and autophagy (clearance), termed mitophagy specifically for mitochondrial (macro)autophagy. An imbalance in mitochondrial function toward mitochondrial dysfunction can be catastrophic for cells and has been characterized in several common ophthalmic diseases. In this article, we review mitochondrial homeostasis in detail, focusing on the balance of mitochondrial dynamics including the processes of fission and fusion, and provide a description of the mechanisms involved in mitophagy. Furthermore, this article reviews investigations of ocular diseases with impaired mitophagy, including Fuchs endothelial corneal dystrophy, primary open-angle glaucoma, diabetic retinopathy, and age-related macular degeneration, as well as several primary mitochondrial diseases with ocular phenotypes that display impaired mitophagy, including mitochondrial encephalopathy lactic acidosis stroke, Leber hereditary optic neuropathy, and chronic progressive external ophthalmoplegia. The results of various studies using cell culture, animal, and human tissue models are presented and reflect a growing awareness of mitophagy impairment as an important feature of ophthalmic disease pathology. As this review indicates, it is imperative that mitophagy be investigated as a targetable mechanism in developing therapies for ocular diseases characterized by oxidative stress and mitochondrial dysfunction.

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Section: Retinopathymentioning

confidence: 99%

Mitophagy: An Emerging Target in Ocular Pathology

Skeie

Nishimura

Wang

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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“…Mitophagy is a specialized form of macro-autophagy by which damaged or excessive mitochondria are selectively targeted for lysosomal degradation. Several groups have reported that Müller cells grown in high glucose exhibit enhanced mitophagy [ 119 , 120 , 121 , 124 ]. This phenomenon is thought to occur in part as a consequence of hyperglycemia-induced expression of thioredoxin-interacting protein (TXNIP), which binds to and inhibits the antioxidants thioredoxin 1 and thioredoxin 2.…”

Section: Alterations In Mitochondrial Turnovermentioning

confidence: 99%

“…When considered together with the work of Santos et al [ 114 , 127 , 128 , 129 , 186 ], these findings suggest that DR is characterized by a gradual decrease in mitochondrial content, both due to impaired biogenesis and enhanced mitophagy. Recent work by Hombrebueno et al [ 121 ] suggests that these processes have a temporal relationship. Using the spontaneous Ins2 Akita diabetic mouse model, Hombrebueno et al [ 121 ] observed enhanced PTEN-induced kinase (PINK1)-dependent mitophagy in both Müller cells and photoreceptors within the first 2 months of diabetes.…”

Section: Alterations In Mitochondrial Turnovermentioning

confidence: 99%

“…Recent work by Hombrebueno et al [ 121 ] suggests that these processes have a temporal relationship. Using the spontaneous Ins2 Akita diabetic mouse model, Hombrebueno et al [ 121 ] observed enhanced PTEN-induced kinase (PINK1)-dependent mitophagy in both Müller cells and photoreceptors within the first 2 months of diabetes. While increased mitochondrial biogenesis can compensate for enhanced mitophagy, compensatory mechanisms begin to fail at 8 months of diabetes, resulting in decreased mitochondrial mass.…”

Section: Alterations In Mitochondrial Turnovermentioning

confidence: 99%

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Diabetic Retinopathy: The Role of Mitochondria in the Neural Retina and Microvascular Disease

2020

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Diabetic retinopathy (DR), a common chronic complication of diabetes mellitus and the leading cause of vision loss in the working-age population, is clinically defined as a microvascular disease that involves damage of the retinal capillaries with secondary visual impairment. While its clinical diagnosis is based on vascular pathology, DR is associated with early abnormalities in the electroretinogram, indicating alterations of the neural retina and impaired visual signaling. The pathogenesis of DR is complex and likely involves the simultaneous dysregulation of multiple metabolic and signaling pathways through the retinal neurovascular unit. There is evidence that microvascular disease in DR is caused in part by altered energetic metabolism in the neural retina and specifically from signals originating in the photoreceptors. In this review, we discuss the main pathogenic mechanisms that link alterations in neural retina bioenergetics with vascular regression in DR. We focus specifically on the recent developments related to alterations in mitochondrial metabolism including energetic substrate selection, mitochondrial function, oxidation-reduction (redox) imbalance, and oxidative stress, and critically discuss the mechanisms of these changes and their consequences on retinal function. We also acknowledge implications for emerging therapeutic approaches and future research directions to find novel mitochondria-targeted therapeutic strategies to correct bioenergetics in diabetes. We conclude that retinal bioenergetics is affected in the early stages of diabetes with consequences beyond changes in ATP content, and that maintaining mitochondrial integrity may alleviate retinal disease.

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“…Therefore, ROS can cause oxidative stress, damaging mitochondria [2], which results in a reduced efficiency of ATP production [36]. In the context of hyperglycemia, it has been shown that there is a dysregulation of mitochondrial biogenesis, leading to bioenergetics deficits [38]. Moreover, mitochondrial functional changes were detected in the retinas of diabetic rodents, before clinical manifestations of DR (pericyte loss and capillary degeneration) are present.…”

Section: The Role Of Oxidative Stress and Inflammation In Drmentioning

confidence: 99%

Extracellular Vesicles and MicroRNA: Putative Role in Diagnosis and Treatment of Diabetic Retinopathy

et al. 2020

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Diabetic retinopathy (DR) is a complex, progressive, and heterogenous retinal degenerative disease associated with diabetes duration. It is characterized by glial, neural, and microvascular dysfunction, being the blood-retinal barrier (BRB) breakdown a hallmark of the early stages. In advanced stages, there is formation of new blood vessels, which are fragile and prone to leaking. This disease, if left untreated, may result in severe vision loss and eventually legal blindness. Although there are some available treatment options for DR, most of them are targeted to the advanced stages of the disease, have some adverse effects, and many patients do not adequately respond to the treatment, which demands further research. Oxidative stress and low-grade inflammation are closely associated processes that play a critical role in the development of DR. Retinal cells communicate with each other or with another one, using cell junctions, adhesion contacts, and secreted soluble factors that can act in neighboring or long-distance cells. Another mechanism of cell communication is via secreted extracellular vesicles (EVs), through exchange of material. Here, we review the current knowledge on deregulation of cell-to-cell communication through EVs, discussing the changes in miRNA expression profiling in body fluids and their role in the development of DR. Thereafter, current and promising therapeutic agents for preventing the progression of DR will be discussed.

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Uncoupled turnover disrupts mitochondrial quality control in diabetic retinopathy

Cited by 39 publications

References 52 publications

Mitophagy: An Emerging Target in Ocular Pathology

Mitophagy: An Emerging Target in Ocular Pathology

Diabetic Retinopathy: The Role of Mitochondria in the Neural Retina and Microvascular Disease

Extracellular Vesicles and MicroRNA: Putative Role in Diagnosis and Treatment of Diabetic Retinopathy

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