bims-mideyd Biomed News
on Mitochondrial dysfunction in eye diseases
Issue of 2022‒02‒06
two papers selected by
Raji Shyam
Indiana University Bloomington


  1. Front Cell Dev Biol. 2021 ;9 759421
      Background: Diabetic retinopathy (DR) is one of the most important microvascular diseases of diabetes. Our previous research demonstrated that bile acid G-protein-coupled membrane receptor (TGR5), a novel cell membrane receptor of bile acid, ameliorates the vascular endothelial cell dysfunction in DR. However, the precise mechanism leading to this alteration remains unknown. Thus, the mechanism of TGR5 in the progress of DR should be urgently explored. Methods: In this study, we established high glucose (HG)-induced human retinal vascular endothelial cells (RMECs) and streptozotocin-induced DR rat in vitro and in vivo. The expression of TGR5 was interfered through the specific agonist or siRNA to study the effect of TGR5 on the function of endothelial cell in vitro. Western blot, immunofluorescence and fluorescent probes were used to explore how TGR5 regulated mitochondrial homeostasis and related molecular mechanism. The adeno-associated virus serotype 8-shTGR5 (AAV8-shTGR5) was performed to evaluate retinal dysfunction in vivo and further confirm the role of TGR5 in DR by HE staining, TUNEL staining, PAS staining and Evans Blue dye. Results: We found that TGR5 activation alleviated HG-induced endothelial cell apoptosis by improving mitochondrial homeostasis. Additionally, TGR5 signaling reduced mitochondrial fission by suppressing the Ca2+-PKCδ/Drp1 signaling and enhanced mitophagy through the upregulation of the PINK1/Parkin signaling pathway. Furthermore, our result indicated that Drp1 inhibited mitophagy by facilitating the hexokinase (HK) 2 separation from the mitochondria and HK2-PINK1/Parkin signaling. In vivo, intraretinal microvascular abnormalities, including retinal vascular leakage, acellular capillaries and apoptosis, were poor in AAV8-shTGR5-treated group under DR, but this effect was reversed by pretreatment with the mitochondrial fission inhibitor Mdivi-1 or autophagy agonist Rapamycin. Conclusion: Overall, our findings indicated that TGR5 inhibited mitochondrial fission and enhanced mitophagy in RMECs by regulating the PKCδ/Drp1-HK2 signaling pathway. These results revealed the molecular mechanisms underlying the protective effects of TGR5 and suggested that activation of TGR5 might be a potential therapeutic strategy for DR.
    Keywords:  TGR5; diabetic retinopathy; mitochondrial fission; mitochondrial homeostasis; mitophagy
    DOI:  https://doi.org/10.3389/fcell.2021.759421
  2. J Vis. 2022 Feb 01. 22(3): 45
      Mitochondria are cellular organelles chiefly intended for energy production. Mammalian photoceptors aggregate numerous mitochondria in the ellipsoid region immediately adjacent to their light-sensitive outer segments to support the high metabolic demands of phototransduction. However, these complex, lipid-rich organelles are also poised to affect the passage of light into the outer segment, an essential step in the transduction of physical energy into cellular signals. Here we show, via live-imaging and computational modeling, that despite this risk of light scattering or absorption, such tightly packed mitochondria concentrate light for entry into the outer segment. Intriguingly, this "microlens"-like feature of cone mitochondria delivers light with an angular dependence akin to the Stiles-Crawford effect (SCE), providing a simple explanation for this essential visual phenomenon that improves resolution. Given the pivotal role that photoreceptor mitochondria play in multiple retinal degenerative diseases, this new insight into their optical properties provides critical information for the accurate interpretation of non-invasive ophthalmic imaging results and lends support for using SCE as an early diagnostic tool.
    DOI:  https://doi.org/10.1167/jov.22.3.45