Lutein upregulates the PGC‐1α, NRF1, and TFAM expression by AMPK activation and downregulates ROS to maintain mtDNA integrity and mitochondrial biogenesis in hyperglycemic ARPE‐19 cells and rat retina

Abstract

Hyperglycemia (HG) affects cellular organelle including mitochondrion in retina that diminishes mitochondrial biogenesis by downregulation of nuclear transcription factors peroxisome proliferator‐activated receptor‐γ coactivator‐1 (PGC‐1α) and mitochondrial transcription factor A (TFAM). Mitochondrial dysfunction has been linked to diabetic retinopathy (DR). Carotenoids reported to modulate mitochondrial biogenesis in HG. Aim of the study was to explore the role of lutein, oxidized lutein (purified upon UV oxidation of lutein) and drug metformin, on mitochondrial biogenesis in HG‐induced ARPE‐19 cells and rat retina. Results showed higher uptake of lutein and oxidized lutein in ARPE‐19 cells and rat retina of HG group than the control groups. Further, lutein and oxidized lutein augmented the AMPK phosphorylation and activation of mitochondrion signaling molecule TFAM (protein expression) and mRNA expression of PGC‐1α, TFAM, and nuclear respiratory factor 1 (responsible for mitochondria biogenesis) along with lowered reactive oxygen species in HG compared with control and metformin groups. Higher mRNA expression of nicotinamide adenine dinucleotide dehydrogenase subunits mt‐ND1, mt‐ND4, mt‐ND6, and cytochrome C that aid maintenance of mtDNA integrity was also evidenced. To conclude, lutein and oxidized lutein found to upsurge mitochondrial biogenesis in ARPE‐19 cells and rat retina under HG, which may be due to upregulation of AMPK phosphorylation. Finally, lutein and oxidized lutein may provide a therapeutic basis to ameliorate HG‐induced DR.

Edaravone prevents high glucose-induced injury in retinal Müller cells through thioredoxin1 and the PGC-1α/NRF1/TFAM pathway

“…Zhang et al (2018) reported that high glucose caused a time-dependent decrease in the expression of PGC-1a, NRF1 and TFAM in mouse podocytes, and an increase in ROS levels in cells and mitochondria. The study by Nanjaiah and Vallikannan (2019) revealed that hyperglycaemia affected mitochondria in the retina, and diminished mitochondrial biogenesis by downregulation of PGC-1a and TFAM. To further explore the mechanism of action of TRX1, TRX1 overexpression and siRNA methods were used to examine the changes in cell viability, apoptosis, ROS generation and mitochondrial potential.…”

Comparison of Antioxidant Properties of Dehydrolutein with Lutein and Zeaxanthin, and their Effects on Cultured Retinal Pigment Epithelial Cells

“…There are numerous reports showing that lutein and/or zeaxanthin can modulate expression of several antioxidant enzymes, and can activate the nuclear factor erythroid 2-related factor 2 (Nrf2) signalling responsible for the expression of antioxidant response element (ARE) genes, and, subsequently, the synthesis of antioxidant and detoxification proteins [ 68 , 69 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. It has been reported that DMSO can activate Nrf2 [ 90 ].…”

RNA-Seq Profiling to Investigate the Mechanism of Qishen Granules on Regulating Mitochondrial Energy Metabolism of Heart Failure in Rats

“…Under the action of PGC-1α, the capacity of mitochondrial DNA increased approximately, the mitochondria proliferate, and the density increased, and mitochondrial biosynthesis was activated. PGC-1α can activate the downstream targets NRF1 and NRF2, and then NRF1/2 binds to the nuclear mitochondrial transcription factor TFAM to regulate the replication and transcription of mtDNA [39][40][41], thereby promoting mitochondrial biosynthesis. In myocardial cells, the PGC-1α/NRF1/TFAM pathway is essential for regulating the mitochondrial function and antioxidant response [8].…”