bims-mideyd 2021-12-12 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2021‒12‒12
thirteen papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

RNA sequencing uncovers alterations in corneal endothelial metabolism, pump and barrier functions of Slc4a11 KO mice.
Cytokine and Complement Response in the Glaucomatous βB1-CTGF Mouse Model.
Protein Kinase A in Human Retina: Differential Localization of Cβ, Cα, RIIα, and RIIβ in Photoreceptors Highlights Non-redundancy of Protein Kinase A Subunits.
Effects of Ultrasound Contrast Agent-Mediated Nerve Growth Factor on Apoptosis of Retinal Ganglion Cells in Mice with Glaucoma.
A Review of Potential Novel Glaucoma Therapeutic Options Independent of Intraocular Pressure.
Inhibition of prolyl oligopeptidase: A promising pathway to prevent the progression of age-related macular degeneration.
The Application of Nitric Oxide for Ocular Hypertension Treatment.
Aged Nrf2-Null Mice Develop All Major Types of Age-Related Cataracts.
MiR-125b attenuates retinal pigment epithelium oxidative damage via targeting Nrf2/HIF-1α signal pathway.
Repressing c-Jun N-terminal kinase signaling mitigates retinal pigment epithelium degeneration in mice with failure to clear all-trans-retinal.
Oxidative distress in aging and age-related diseases: Spatiotemporal dysregulation of protein oxidation and degradation.
Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates development and early survival of retinal neurons.
Mitophagy in aging and longevity.

Exp Eye Res. 2021 Dec 03. pii: S0014-4835(21)00450-4. [Epub ahead of print]214 108884

RNA sequencing uncovers alterations in corneal endothelial metabolism, pump and barrier functions of Slc4a11 KO mice.

Diego G Ogando, Joseph A Bonanno.

  Slc4a11 KO mice show significant corneal edema, altered endothelial morphology, and mitochondrial ROS at an early age without a decrease in endothelial cell density. We examined the differential gene expression profile between wild type (WT) and KO with the goal of finding pathways related to corneal endothelial metabolic, pump and barrier function that can explain the corneal edema. Freshly dissected Corneal Endothelium-Descemet's Membrane (CEDM) and cultured Mouse Corneal Endothelial Cells (MCEC) were obtained from WT and Slc4a11 KO mice. RNA sequencing Ingenuity Pathway Analysis (IPA) predicted activation, inhibition or differential regulation of several pathways. QPCR and Western analysis validated downregulation of Glycolytic enzymes, Mitochondrial complex components and Ion transporters. Functional testing revealed decreases in endothelial lactate production, Extracellular Acidification Rate (ECAR), glutaminolysis, and Oxygen Consumption Rate (OCR) of KO CEDM in the presence of Glutamine (Gln) that was not compensated by fatty acid oxidation. Stromal lactate was significantly elevated in KO along with decreased expression of MCT1 and MCT4 lactate transporters in endothelial cells. ATP levels were 2x higher in KO CEDM, concomitant with a 3-fold decrease in Na-K-ATPase activity and reduced basolateral membrane localization. Genes for cholesterol biosynthesis, glutathione metabolism and tight and adherens junctions were elevated. Alteration of tight junction structure and cortical cytoskeleton is evident in KO corneal endothelium with a significant increase in trans-endothelial fluorescein permeability. We conclude that Slc4a11 KO induces a coordinated decrease in glycolysis, glutaminolysis, lactate transport and Na-K-ATPase activity. These changes together with an altered barrier function cause an accumulation of stromal lactate in Slc4a11 KO mice leading to chronic corneal edema.

Keywords:  Barrier function; Corneal endothelial dystrophy; Lactate transporters; Metabolism; Na-K-ATPase; Oxidative stress; RNA sequencing

DOI:  https://doi.org/10.1016/j.exer.2021.108884
Front Cell Neurosci. 2021 ;15 718087

Cytokine and Complement Response in the Glaucomatous βB1-CTGF Mouse Model.

Sabrina Reinehr, Johanna D Doerner, Ana M Mueller-Buehl, Dennis Koch, Rudolf Fuchshofer, H Burkhard Dick, Stephanie C Joachim.

  Glaucoma is a complex neurodegenerative disease leading to a loss of retinal ganglion cells (RGCs) and optic nerve axons. An activation of the complement system seems to contribute to cell loss in this disease. Hence, we investigated a possible initiation of the complement system and the cytokine response in the βB1-CTGF glaucoma model. In these mice, intraocular pressure is elevated, which is the main glaucoma risk factor in patients, and RGC loss occurs at 15 weeks of age. Therefore, quantitative real-time PCR and immunohistological experiments were performed in 5-, 10-, and 15-week-old βB1-CTGF animals and their corresponding wildtypes (WT) to analyze the expression of several complement system factors. We could show that mRNA levels of the terminal complement pathway components C3 and C5 (Hc) were upregulated at 10 weeks. In accordance, more C3+ and membrane attack complex+ cells were observed in transgenic retinae. Further, the C5a receptor anaphylatoxin receptor (C5ar) and the complement component C5a receptor 1 (C5ar1; CD88) mRNA levels were upregulated in 10- and 15-week-old βB1-CTGF mice. Interestingly, all three activation routes of the complement system were elevated in βB1-CTGF mice at some age. Especially C1q, as a marker of the classical pathway, was significantly increased at all investigated ages. Furthermore, mRNA expression levels of interferon-γ (Infg) were upregulated at 5 weeks, while Cxcl1 and Cxcl2 mRNA levels were upregulated at 10 and 15 weeks. The mRNA levels of the chemokines Cxcl10 were increased at all ages in βB1-CTGF mice. These results lead to the assumption that in these transgenic mice, a complement activation mainly through the classical pathway as well as a cytokine response plays a major role in cell death.

Keywords:  CXCL1; classical pathway; complement system; cytokines; glaucoma; βB1-CTGF

DOI:  https://doi.org/10.3389/fncel.2021.718087
Front Mol Neurosci. 2021 ;14 782041

Protein Kinase A in Human Retina: Differential Localization of Cβ, Cα, RIIα, and RIIβ in Photoreceptors Highlights Non-redundancy of Protein Kinase A Subunits.

Jinae N Roa, Yuliang Ma, Zbigniew Mikulski, Qianlan Xu, Ronit Ilouz, Susan S Taylor, Dorota Skowronska-Krawczyk.

  Protein kinase A (PKA) signaling is essential for numerous processes but the subcellular localization of specific PKA regulatory (R) and catalytic (C) subunits has yet to be explored comprehensively. Additionally, the localization of the Cβ subunit has never been spatially mapped in any tissue even though ∼50% of PKA signaling in neuronal tissues is thought to be mediated by Cβ. Here we used human retina with its highly specialized neurons as a window into PKA signaling in the brain and characterized localization of PKA Cα, Cβ, RIIα, and RIIβ subunits. We found that each subunit presented a distinct localization pattern. Cα and Cβ were localized in all cell layers (photoreceptors, interneurons, retinal ganglion cells), while RIIα and RIIβ were selectively enriched in photoreceptor cells where both showed distinct patterns of co-localization with Cα but not Cβ. Only Cα was observed in photoreceptor outer segments and at the base of the connecting cilium. Cβ in turn, was highly enriched in mitochondria and was especially prominent in the ellipsoid of cone cells. Further investigation of Cβ using RNA BaseScope technology showed that two Cβ splice variants (Cβ4 and Cβ4ab) likely code for the mitochondrial Cβ proteins. Overall, our data indicates that PKA Cα, Cβ, RIIα, and RIIβ subunits are differentially localized and are likely functionally non-redundant in the human retina. Furthermore, Cβ is potentially important for mitochondrial-associated neurodegenerative diseases previously linked to PKA dysfunction.

Keywords:  PKA; mitochondria; neuron; photoreceptors; retina; signaling

DOI:  https://doi.org/10.3389/fnmol.2021.782041
Comput Math Methods Med. 2021 ;2021 6084496

Effects of Ultrasound Contrast Agent-Mediated Nerve Growth Factor on Apoptosis of Retinal Ganglion Cells in Mice with Glaucoma.

Yan Ke, Lina Huang, Bingheng Chen, Jing Sima, Jiaguo Cao, Qiang Li.

With an increasing incidence in recent years, glaucoma (GL) has gradually become a global public health problem for humans of all ages. Nerve growth factor (NGF) eye drops, with well-documented stable effect in the treatment of GL, can be potentiated by the administration of NGF drugs via ultrasound contrast agent (UCA). This study analyzed the efficacy of NGF+UCA on GL mice and the influencing mechanism on retinal ganglion cells and further explored the pathological changes of GL mice under different UCA irradiation duration. In this study, we established GL mouse models and treated the mouse with NGF+UCA. The effect of NGF+UCA on intraocular pressure in mice was observed; the flash visual evoked potential of mice was compared; the changes of retinal structure, inflammation index, and oxidative stress index were observed, and autophagic protein levels were tested. Finally, the influence of UCA irradiation duration on GL symptoms was observed. The results showed that the intraocular pressure of mice decreased greatly, while their flash visual evoked potential and nervous layer of retina increased, and their ganglion cells showed stronger proliferation activity and weaker apoptosis and autophagy, indicating that UCA-mediated NGF can strongly improve the pathological condition of GL mice. In addition, PI3K/AKT pathway-associated proteins were inhibited in retina under the intervention of NGF+UCA, which further suggests that the influence of UCA-mediated NGF on GL is achieved by inhibiting autophagy of retinal ganglion cells and enhancing their apoptosis via the PI3K/AKT signaling pathway. Moreover, we found that in the treatment of GL, three weeks of UCA irradiation and six weeks caused no significant difference in the pathological manifestations and ganglion cells of mice, while after six weeks of irradiation, the level of NLRP3 in mice increased. In conclusion, UCA-mediated NGF can significantly improve the pathological condition of GL mice and improve the apoptosis of retinal ganglion cells by inhibiting autophagy, which is associated with the inhibition of the PI3K/AKT signal pathway. In terms of selection of UCA irradiation duration, three weeks of irradiation is enough to yield good clinical results.

DOI: https://doi.org/10.1155/2021/6084496
Surv Ophthalmol. 2021 Dec 07. pii: S0039-6257(21)00223-X. [Epub ahead of print]

A Review of Potential Novel Glaucoma Therapeutic Options Independent of Intraocular Pressure.

Wesam Shamseldin Shalaby, Osama M Ahmed, Michael Waisbourd, L Jay Katz.

  Glaucoma, a progressive optic neuropathy characterized by retinal ganglion cell degeneration and visual field loss, is the leading cause of irreversible blindness worldwide. Intraocular pressure (IOP) is presently the only modifiable risk factor demonstrated to slow or halt disease progression; however, glaucomatous damage persists in almost 50% of patients despite significant IOP reduction. Many studies have investigated the non-IOP-related risk factors that contribute to glaucoma progression as well as interventions that can prevent or delay glaucomatous neurodegeneration and preserve vision throughout life, independently of IOP. A vast number of experimental studies have reported effective neuroprotection in glaucoma, and clinical studies are ongoing attempting to provide strong evidence of effectiveness of these interventions. In this review, we look into the current understanding of the pathophysiology of glaucoma and explore the recent advances in non-IOP related strategies for neuroprotection and neuroregeneration in glaucoma.

Keywords:  AMD, Age-related macular degeneration; BDNF, Brain derived neurotrophic factor; CNTF, Ciliary neurotrophic factor; GDNF, Glial‐derived neurotrophic factor; Glaucoma; IOP, Intraocular pressure; LoGTS, Low-Pressure Glaucoma Treatment Study; MRI, Magnetic resonance imaging; MSCs, Mesenchymal stem cells; NGF, Nerve growth factor; NTG, Normal tension glaucoma; OCTA, Optical coherence tomography angiography; PBM, hotobiomodulation; PDGF, Platelet derived growth factor; POAG, Primary open angle glaucoma; RGCs, Retinal ganglion cells; TNF-α, Tumor necrosis factor- α; bFGF, Basic fibroblast growth factor; gene therapy; intracranial pressure; intraocular pressure; neuroprotection; ocular blood flow; oxidative stress; retinal ganglion cells; stem cell therapy

DOI:  https://doi.org/10.1016/j.survophthal.2021.12.003
Biomed Pharmacother. 2021 Dec 07. pii: S0753-3322(21)01287-7. [Epub ahead of print]146 112501

Inhibition of prolyl oligopeptidase: A promising pathway to prevent the progression of age-related macular degeneration.

Laura Hellinen, Ali Koskela, Elina Vattulainen, Mikko Liukkonen, Christine Wegler, Andrea Treyer, Niklas Handin, Richard Svensson, Timo Myöhänen, Antti Poso, Kai Kaarniranta, Per Artursson, Arto Urtti.

  Dry age-related macular degeneration (AMD) is a currently untreatable vision threatening disease. Impaired proteasomal clearance and autophagy in the retinal pigment epithelium (RPE) and subsequent photoreceptor damage are connected with dry AMD, but detailed pathophysiology is still unclear. In this paper, we discover inhibition of cytosolic protease, prolyl oligopeptidase (PREP), as a potential pathway to treat dry AMD. We showed that PREP inhibitor exposure induced autophagy in the RPE cells, shown by increased LC3-II levels and decreased p62 levels. PREP inhibitor treatment increased total levels of autophagic vacuoles in the RPE cells. Global proteomics was used to examine the phenotype of a commonly used cell model displaying AMD characteristics, oxidative stress and altered protein metabolism, in vitro. These RPE cells displayed induced protein aggregation and clear alterations in macromolecule metabolism, confirming the relevance of the cell model. Differences in intracellular target engagement of PREP inhibitors were observed with cellular thermal shift assay (CETSA). These differences were explained by intracellular drug exposure (the unbound cellular partition coefficient, Kpuu). Importantly, our data is in line with previous observations regarding the discrepancy between PREP's cleaving activity and outcomes in autophagy. This highlights the need to further explore PREP's role in autophagy so that more effective compounds can be designed to battle diseases in which autophagy induction is needed. The present work is the first report investigating the PREP pathway in the RPE and we predict that the PREP inhibitors can be further optimized for treatment of dry AMD.

Keywords:  Age-related macular degeneration; Autophagy; Prolyl oligopeptidase inhibitor; Proteomics; Retinal pigment epithelium; Target engagement

DOI:  https://doi.org/10.1016/j.biopha.2021.112501
Molecules. 2021 Dec 01. pii: 7306. [Epub ahead of print]26(23):

The Application of Nitric Oxide for Ocular Hypertension Treatment.

Binze Han, Maomao Song, Liping Li, Xinghuai Sun, Yuan Lei.

  Despite of various therapeutic methods for treating ocular hypertension and glaucoma, it still remains the leading cause of irreversible blindness. Intraocular pressure (IOP) lowering is the most effective way to slow disease progression and prevent blindness. Among the ocular hypotensive drugs currently in use, only a couple act on the conventional outflow system, which is the main pathway for aqueous humor outflow and the major lesion site resulting in ocular hypertension. Nitric oxide (NO) is a commendable new class of glaucoma drugs that acts on the conventional outflow pathway. An increasing number of nitric oxide donors have been developed for glaucoma and ocular hypertension treatment. Here, we will review how NO lowers IOP and the types of nitric oxide donors that have been developed. And a brief analysis of the advantages and challenges associated with the application will be made. The literature used in this review is based on Pubmed database search using 'nitric oxide' and 'glaucoma' as key words.

Keywords:  NO donors; conventional outflow system; glaucoma; intraocular pressure

DOI:  https://doi.org/10.3390/molecules26237306
Invest Ophthalmol Vis Sci. 2021 Dec 01. 62(15): 10

Aged Nrf2-Null Mice Develop All Major Types of Age-Related Cataracts.

Sheldon Rowan, Shuhong Jiang, Sarah G Francisco, Laura C D Pomatto, Zhiwei Ma, Xiaodong Jiao, Maria M Campos, Sandeep Aryal, Shaili D Patel, Binapani Mahaling, S Amer Riazuddin, Elia J Duh, Salil A Lachke, J Fielding Hejtmancik, Rafael de Cabo, Paul G FitzGerald, Allen Taylor.

Purpose: Age-related cataracts affect the majority of older adults and are a leading cause of blindness worldwide. Treatments that delay cataract onset or severity have the potential to delay cataract surgery, but require relevant animal models that recapitulate the major types of cataracts for their development. Unfortunately, few such models are available. Here, we report the lens phenotypes of aged mice lacking the critical antioxidant transcription factor Nfe2l2 (designated as Nrf2 -/-).Methods: Three independent cohorts of Nrf2 -/- and wild-type C57BL/6J mice were evaluated for cataracts using combinations of slit lamp imaging, photography of freshly dissected lenses, and histology. Mice were fed high glycemic diets, low glycemic diets, regular chow ad libitum, or regular chow with 30% caloric restriction.
Results: Nrf2 -/- mice developed significant opacities between 11 and 15 months and developed advanced cortical, posterior subcapsular, anterior subcapsular, and nuclear cataracts. Cataracts occurred similarly in male mice fed high or low glycemic diets, and were also observed in 21-month male and female Nrf2 -/- mice fed ad libitum or 30% caloric restriction. Histological observation of 18-month cataractous lenses revealed significant disruption to fiber cell architecture and the retention of nuclei throughout the cortical region of the lens. However, fiber cell denucleation and initiation of lens differentiation was normal at birth, with the first abnormalities observed at 3 months.
Conclusions: Nrf2 -/- mice offer a tool to understand how defective antioxidant signaling causes multiple forms of cataract and may be useful for screening drugs to prevent or delay cataractogenesis in susceptible adults.

DOI: https://doi.org/10.1167/iovs.62.15.10
Exp Cell Res. 2021 Dec 05. pii: S0014-4827(21)00511-5. [Epub ahead of print]410(1): 112955

MiR-125b attenuates retinal pigment epithelium oxidative damage via targeting Nrf2/HIF-1α signal pathway.

Jin-Xia Liu, Dong-Yue Ma, Xin-Yu Zhi, Ming-Wu Wang, Jiang-Yue Zhao, Yu Qin.

  The retinal pigment epithelium cells (RPE) are sensitive to oxidative stimuli due to long-term exposure to various environmental stimuli. Thus, the oxidative injury of RPE cells caused by the imbalance of redox homeostasis is one of the main pathogenic factors of age-related macular degeneration (AMD). But the sophisticated mechanisms linking AMD to oxidative stress are not fully elucidated. Activation of Nrf2 signal pathway can protect RPE cells from oxidative damage. The present study investigated the regulating mechanism of miR-125b in Nrf2 cascade and evaluated its antioxidant capacity. The in vitro studies indicated that overexpression of miR-125b substantially inhibited Keap1 expression, enhanced Nrf2 expression and induced Nrf2 nuclear translocation. Importantly, functional studies demonstrated that forced expression of miR-125b could significantly elevate cell proliferation and superoxide dismutase (SOD) levels while reduce reactive oxygen species (ROS) overproduction and malondialdehyde (MDA) formation. Further studies showed that miR-125b had no effect when Nrf2 was silenced in ARPE-19 cells. Additionally, the results identified that Nrf2 silence induced ROS accumulation enhances HIF-1α protein expression, while miR-125b could offset this effect via promoting HIF-1α protein degradation. Subsequent in vivo studies demonstrated that sodium iodate induced outer retina thinner was reversed with exogenous supplementation of miR-125b, which was cancelled in Nrf2 knockout mice. In conclusion, this study illustrated that miR-125b can protect RPE from oxidative damage via targeting Nrf2/HIF-1α signal pathway and potentially may serve as a therapeutic agent of AMD.

Keywords:  Age-related macular degeneration; HIF-1α; Nrf2; Oxidative stress; miR-125b

DOI:  https://doi.org/10.1016/j.yexcr.2021.112955
Exp Eye Res. 2021 Dec 01. pii: S0014-4835(21)00443-7. [Epub ahead of print]214 108877

Repressing c-Jun N-terminal kinase signaling mitigates retinal pigment epithelium degeneration in mice with failure to clear all-trans-retinal.

Lei Tao, Danxue He, Chunyan Liao, Binxiang Cai, Chao Chen, Yan Wang, Jingmeng Chen, Zuguo Liu, Yalin Wu.

  Retinal pigment epithelium (RPE) cell apoptosis arising from all-trans-retinal (atRAL) is in close contact with the etiology of dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1), but its underlying mechanisms remain elusive. In this study, we reported that c-Jun N-terminal kinase (JNK) activation facilitated atRAL-induced apoptosis of RPE cells. Reactive oxygen species production and endoplasmic reticulum stress were identified as two of major upstream events responsible for activating JNK signaling in atRAL-loaded RPE cells. Inhibiting JNK signaling rescued RPE cells from apoptosis induced by atRAL through attenuating caspase-3 activation leading to poly-ADP-ribose polymerase (PARP) cleavage, and DNA damage response. Abca4-/-Rdh8-/- mice upon light exposure exhibit rapidly increased accumulation of atRAL in the retina, and display severe RPE degeneration, a primary attribute of dry AMD and STGD1. Reducing JNK signaling by intraperitoneally injected JNK-IN-8 was highly effective in preventing RPE atrophy and apoptosis in light-exposed Abca4-/-Rdh8-/- mice. These findings afford a further understanding for contribution of JNK activation by atRAL to retinal damage.

Keywords:  Endoplasmic reticulum stress; Macular degeneration; Reactive oxygen species; Retinal pigment epithelium; Stargardt's disease; c-Jun N-Terminal kinase (JNK)

DOI:  https://doi.org/10.1016/j.exer.2021.108877
Biochimie. 2021 Dec 07. pii: S0300-9084(21)00273-X. [Epub ahead of print]

Oxidative distress in aging and age-related diseases: Spatiotemporal dysregulation of protein oxidation and degradation.

Sergey Zavadskiy, Susanna Sologova, Nurbubu Moldogazieva.

  The concept of oxidative distress had arisen from the assessment of cellular response to high concentrations of reactive species that result from an imbalance between oxidants and antioxidants and cause biomolecular damage. The intracellular distribution and flux of reactive species dramatically change in time and space contributing to the remodeling of the redox landscape and sensitivity of protein residues to oxidants. Here, we hypothesize that compromised spatiotemporal control of generation, conversions, and removal of reactive species underlies protein damage and dysfunction of protein degradation machineries. This leads to the accumulation of oxidatively damaged proteins resulted in an age-dependent decline in the organismal adaptability to oxidative stress. We highlight recent data obtained with the use of various cell cultures, animal models, and patients on irreversible and non-repairable oxidation of key redox-sensitive residues. Multiple reaction products include peptidyl hydroperoxides, alcohols, carbonyls, and carbamoyl moieties as well as Tyr-Tyr, Trp-Tyr, Trp-Trp, Tyr-Cys, His-Lys, His-Arg, and Tyr-Lys cross-links. These lead to protein fragmentation, misfolding, covalent cross-linking, oligomerization, aggregation, and ultimately, causing impaired protein function and turnover. 20S proteasome and autophagy-lysosome pathways are two major types of machinery for the degradation and elimination of oxidatively damaged proteins. Spatiotemporal dysregulation of these pathways under oxidative distress conditions is implicated in aging and age-related disorders such as neurodegenerative and cardiovascular diseases and diabetes. Future investigations in this field allow the discovery of new drugs to target components of dysregulated cell signaling and protein degradation machinery to combat aging and age-related chronic diseases.

Keywords:  Aging and age-related diseases; Autophagy-lysosome; Oxidative stress; Proteasome; Protein oxidation and damage; Spatiotemporal regulation

DOI:  https://doi.org/10.1016/j.biochi.2021.12.002
Elife. 2021 Dec 08. pii: e71185. [Epub ahead of print]10

Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates development and early survival of retinal neurons.

David Sokolov, Emily R Sechrest, Yekai Wang, Connor Nevin, Jianhai Du, Saravanan Kolandaivelu.

  Despite mounting evidence that the mammalian retina is exceptionally reliant on proper NAD+ homeostasis for health and function, the specific roles of subcellular NAD+ pools in retinal development, maintenance, and disease remain obscure. Here, we show that deletion of the nuclear-localized NAD+ synthase nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1) in the developing murine retina causes early and severe degeneration of photoreceptors and select inner retinal neurons via multiple distinct cell death pathways. This severe phenotype is associated with disruptions to retinal central carbon metabolism, purine nucleotide synthesis, and amino acid pathways. Furthermore, transcriptomic and immunostaining approaches reveal dysregulation of a collection of photoreceptor and synapse-specific genes in NMNAT1 knockout retinas prior to detectable morphological or metabolic alterations. Collectively, our study reveals previously unrecognized complexity in NMNAT1-associated retinal degeneration and suggests a yet-undescribed role for NMNAT1 in gene regulation during photoreceptor terminal differentiation.

Keywords:  developmental biology; mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.71185
IUBMB Life. 2021 Dec 10.

Mitophagy in aging and longevity.

Jing Guo, Wei-Chung Chiang.

  The clearance of damaged or unwanted mitochondria by autophagy (also known as mitophagy) is a mitochondrial quality control mechanism postulated to play an essential role in cellular homeostasis, metabolism, and development and confers protection against a wide range of diseases. Proper removal of damaged or unwanted mitochondria is essential for organismal health. Defects in mitophagy are associated with Parkinson's, Alzheimer's disease, cancer, and other degenerative disorders. Mitochondria regulate organismal fitness and longevity via multiple pathways, including cellular senescence, stem cell function, inflammation, mitochondrial unfolded protein response (mtUPR), and bioenergetics. Thus, mitophagy is postulated to be pivotal for maintaining organismal healthspan and lifespan and the protection against aged-related degeneration. In this review, we will summarize recent understanding of the mechanism of mitophagy and aspects of mitochondrial functions. We will focus on mitochondria-related cellular processes that are linked to aging and examine current genetic evidence that supports the hypothesis that mitophagy is a pro-longevity mechanism.

Keywords:  aging; longevity; mitophagy

DOI:  https://doi.org/10.1002/iub.2585