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Peroxisome Turnover and Diurnal Modulation of Antioxidant bioRxiv preprint doi: https://doi.org/10.1101/687533; this version posted July 1, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Peroxisome turnover and diurnal modulation of antioxidant activity in retinal pigment 2 epithelia utilizes microtubule-associated protein 1 light chain 3B 3 4 Lauren L. Daniele1, Jennifer Caughey1, Stefanie Volland2, Rachel C. Sharp1, Anuradha 5 Dhingra1, David S. Williams2, Nancy J. Philp3 and Kathleen Boesze-Battaglia1 6 7 1. Dept. of Biochemistry, SDM, University of Pennsylvania, Philadelphia, PA 19104, 8 2, Departments of Ophthalmology and Neurobiology, Jules Stein Eye Institute, David Geffen 9 School of Medicine, University of California, Los Angeles, Los Angeles, CA 10 3 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 11 Philadelphia, PA. 12 13 14 15 16 17 18 19 20 Running Title: Role of LC3B in RPE peroxisome regulation 21 22 23 24 * Corresponding Author 25 Kathleen Boesze-Battaglia, PhD 26 Department of Biochemistry 27 SDM 28 University of Pennsylvania 29 Philadelphia, PA 19104 30 Ph: 215-898-9167 31 e-mail: [email protected] 32 33 34 bioRxiv preprint doi: https://doi.org/10.1101/687533; this version posted July 1, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 35 Abstract (244/250 words allowed) 36 The retinal pigment epithelium (RPE) supports the outer retina through essential roles in the 37 retinoid the visual cycle, nutrient supply, ion exchange and waste removal. Each day the RPE 38 removes the oldest ~10% of photoreceptor outer segments through phagocytic uptake, which 39 peaks in a synchronous burst following light onset. Impaired degradation of phagocytosed OS 40 material by the RPE can lead to toxic accumulation of lipids, oxidative tissue damage, 41 inflammation and cell death. OSs are rich in very long chain fatty acids which are preferentially 42 catabolized in peroxisomes. Despite the importance of lipid degradation in RPE function, the 43 regulation of peroxisome number and activity relative to diurnal OS ingestion is relatively 44 unexplored. Using immunohistochemistry, immunoblotting and catalase activity assays, we 45 investigated peroxisome abundance and activity at 6 am, 7 am (at lights on), 8 am, and 3 pm, in 46 WT mice and mice lacking microtubule-associated protein 1 light chain 3B (LC3B), that have 47 impaired degradation of phagosomes. We found that catalase activity, but not protein 48 expression, is 50% higher in the morning compared with 3 pm, in RPE of WT but not LC3B-/- 49 mice. Surprisingly, we found that peroxisome abundance was stable during the day, however 50 numbers are elevated overall in LC3B-/- mice, implicating LC3B in autophagic organelle turnover 51 in RPE. Our data suggest that RPE peroxisome function is regulated in coordination with 52 phagocytosis, possibly through direct enzyme regulation, and may serve to prepare RPE 53 peroxisomes for daily surges in ingested lipid-rich OS. 54 bioRxiv preprint doi: https://doi.org/10.1101/687533; this version posted July 1, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 55 Introduction 56 57 The retinal pigment epithelium (RPE) supports photoreceptor activity and outer-segment (OS) 58 renewal through the retinoid visual cycle and ingestion of spent photoreceptor outer 59 segments (36, 41, 42, 66, 73). On a daily basis, the RPE ingests 10% of the lipid and protein- 60 rich OS, for recycling and degradation, while new OS material is added basally (69, 74). 61 Incomplete phagosome degradation in the highly oxidative environment of the RPE predisposes 62 undigested lipids to oxidative damage and the formation of lipid peroxidation adducts 63 contributing over time to an immune response and tissue damage (3, 19, 27, 35, 70). 64 65 The ingested OS are a complex mix of saturated and highly unsaturated fatty acids, which 66 make up 50% of OSs (by weight) and provide the RPE with substrate for mitochondrial and 67 peroxisomal fatty acid oxidation (FAO) (1, 23, 61, 64, 68). Within the lipid pool, OS membranes 68 are estimated to contain ~ 30% very long chain fatty acids VLCFAs (23). VLCFAs (Cƚ20) are 69 preferentially catabolized in peroxisomes via β-oxidation (64, 68). Therefore, efficient lipid 70 catabolism in the RPE requires coordination of β-oxidation pathways within both mitochondria 71 and peroxisomes (1, 23, 61). Once VLCFA are shortened, they are substrates for mitochondrial 72 β-oxidation (1, 61). Some of the resultant acetyl-CoA is funneled into the mitochondrial 73 ketogenesis pathway, producing beta hydroxybutyrate (βHB). βHB is subsequently secreted into 74 the subretinal space and taken up by photoreceptors as a metabolic substrate (1). Given their 75 intimate metabolic coordination it is not surprising that numerous micro-peroxisomes can be 76 found in RPE cells where they are contiguous with ER tubules and proximal to mitochondria (45, 77 47, 62). 78 79 Peroxisomes are ubiquitous organelles highly enriched in liver, intestine, adipose tissue and 80 brain. In addition to their functions in α and β oxidation-mediated catabolism of fatty acids (48) 81 peroxisomes play essential roles in ether lipid synthesis, docosahexaenoic acid (DHA) 82 synthesis, and bile acid synthesis. Peroxisomes are also sites for both the generation and 83 reduction of reactive oxygen and nitrogen species (ROS and RNS) which serve as mediators for 84 cellular signaling (56, 72). The most abundant of these is hydrogen peroxide, produced as a 85 byproduct of the initial desaturation of Acyl-CoA esters by Acyl CoA Oxidases (ACOXs) in the 86 committed step of peroxisome fatty acid oxidation (64, 68). Hydrogen peroxide generated in the 87 ACOX reaction is rapidly degraded by the antioxidant enzyme, catalase. Peroxisome antioxidant 88 activity declines with cellular age (44). Dysregulation of peroxisome antioxidant capacity with bioRxiv preprint doi: https://doi.org/10.1101/687533; this version posted July 1, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 89 age may have broad cellular impact as inhibition of catalase activity in fibroblasts resulted in 90 increased mitochondrial ROS levels and disrupted activity (44, 67, 71). Catalase activity is also 91 lower in peroxisomes of human primary RPE from aged donors, and those with age-related 92 macular degeneration (AMD) (46), and paradoxically, this is accompanied by an overabundance 93 of peroxisomes (6, 7, 21), suggesting a role for impaired peroxisome turnover in declining 94 peroxisome function. 95 Although countless studies have focused on understanding peroxisome proliferator-activated 96 receptor (PPAR) regulation, and correlation with disease (50, 60, 63, 76), to our knowledge little 97 information is available regarding the activity and numbers of peroxisomes in the RPE 98 over a 12hr light/dark cycle. In this study, we investigate peroxisome function and dynamics in 99 the context of phagocytic degradative processes in RPE cells. We find that catalase activity is 100 increased by ~50% during the time of peak phagocytosis, and this diurnal regulation of 101 antioxidant activity is absent in mice lacking LC3B. We also find that while LC3B-dependent 102 processes contribute to peroxisome turnover, peroxisome number does not depend on time of 103 day. Our data suggest peroxisome function in the RPE is regulated dynamically in coordination 104 with phagocytosis, likely through direct regulation of enzyme activity. Catalase activity can be 105 regulated through diverse post-translational modifications (9, 10, 16, 26, 39, 59) which are often 106 sensitive to the redox state of the cell. Elevated catalase activity during the early morning 107 suggests the possibility of a homeostatic mechanism to ready RPE peroxisomes for the daily 108 synchronous surge in ingested lipid-rich outer segments. bioRxiv preprint doi: https://doi.org/10.1101/687533; this version posted July 1, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 109 Results 110 111 Mouse RPE contain abundant peroxisomes. 112 Fatty acids comprised of 20 carbons and longer are catabolized in peroxisomes (64, 68), where 113 the rate limiting step is desaturation of a fatty acyl-CoA by the enzyme ACOX1, producing the 114 byproduct hydrogen peroxide (H2O2) (Fig.1A). Catalase, the most abundant peroxisomal 115 antioxidant, reduces H2O2 produced in peroxisomes during this reaction, preventing its toxic 116 accumulation. Using a publicly available microarray data set (GSE10246; Fig 1B) we analyzed 117 gene expression profiles of peroxisome lipid-associated proteins in mouse tissues. RPE express 118 fatty acid transporters and peroxisome β-oxidation enzymes. Three members of the ABC lipid- 119 transporter superfamily reside in peroxisomes, these include, Abcd1 (ALDP), Abcd2 (ALDR) 120 and Abcd3 (PMP70). Of these, Abcd1 is expressed in RPE (mouse) in relative abundance with 121 levels of Abcd3 in RPE similar to that in liver (Fig. 1B). Transcripts for Acox1, and catalase as 122 well as 3-ketoacyl-CoA thiolase (Acaa1/thiolase) are highly expressed in liver but are also 123 enriched in the RPE relative to retina, cornea and neural tissues (Fig 1A, B). Two thiolase genes 124 are expressed in mouse, Acaa1a, and Acaa1b, with the expression of thiolase b restricted to 125 liver, with lower expression in kidney, intestine and adipose tissue (13). The complete β- 126 oxidation of polyunsaturated fatty acids (FA) within peroxisomes requires additional enzymes, 127 due to the presence of cis- and trans- double bonds (68), including peroxisome 2,4, Di-enoyl 128 CoA reductase (Decr2).
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