Proteomic Profiling Revealed Mitochondrial Dysfunction in Photoreceptor Cells under Hyperglycemia

Abstract

Diabetic retinopathy (DR) was identified as a leading cause of blindness and vision impairment in 2020. In addition to vasculopathy, DR has been found to involve retinal neurons, including amacrine cells and retinal ganglion cells. Despite possessing features that are susceptible to diabetic conditions, photoreceptor cells have received relatively little attention with respect to the development of DR. Until recently, studies have suggested that photoreceptors secret proinflammatory molecules and produce reactive oxygen species that contribute to the development of DR. However, the effect of hyperglycemia on photoreceptors and its underlying mechanism remains elusive. In this study, the direct effect of high glucose on photoreceptor cells was investigated using a 661w photoreceptor-like cell line. A data-independent sequential window acquisition of all theoretical mass spectra (SWATH)-based proteomic approach was employed to study changes induced by high glucose in the proteomic profile of the cells. The results indicated that high glucose induced a significant increase in apoptosis and ROS levels in the 661w cells, with mitochondrial dysfunction among the major affected canonical pathways. The involvement of mitochondrial dysfunction was further supported by increased mitochondrial fission and reduced mitochondrial bioenergetics. Collectively, these findings provide a biological basis for a possible role of photoreceptors in the pathogenesis of DR.

Coenzyme Q10 eyedrops conjugated with vitamin E TPGS alleviate neurodegeneration and mitochondrial dysfunction in the diabetic mouse retina

“…Defective mitochondrial biogenesis and changes in energy metabolic profile have been implicated in various cell types and tissues affected by type 2 diabetes ( Jheng et al, 2012 ; Forbes and Thorburn, 2018 ; Pinti et al, 2019 ). In addition, mitochondrial dysfunction has been observed in various retinal cells, including retinal endothelial cells, Müller cells, and photoreceptor cells under simulated hyperglycemia ( Trudeau et al, 2010 ; Tien et al, 2017 ; Lam et al, 2022 ). Recently, our lab has demonstrated a compromised mitochondrial biogenesis in the retina of db/db mice, in which functional and structural changes in the neuroretina were observed, compared to their non-diabetic heterozygous littermate ( Lam et al, 2023 ).…”

“…Furthermore, high metabolic activity and constant exposure to damaging light radiation may render the retina more vulnerable to oxidative stress under diabetic conditions. Therefore, there is growing interest in using antioxidants to treat DR. Our previous studies have demonstrated the involvement of mitochondrial dysfunction in DR using both in vitro and in vivo models ( Lam et al, 2022 , 2023 ). Similar findings have also been observed in other retinal cell types, such as retinal endothelial cells and Müller cells under simulated hyperglycemia ( Trudeau et al, 2010 ; Tien et al, 2017 ).…”

Ketone Esters partially and selectively rescue mitochondrial bioenergetics after acute cervical spinal cord injury in rats: A time-course

“…For example, KD has been proven to have a therapeutic effect on glucose levels after TBI (Ritter, Robertson et al 1996). Indeed, high-glucose levels have been associated with induction of mitochondrial dysfunction in cardiac models, retina, and neurons (Russell, Golovoy et al 2002;Dassanayaka, Readnower et al 2015;Fiorello, Treweeke et al 2020;Lam, Cheung et al 2022). Contrary to KD, in our experience, KE treatment alone does not change glucose levels to the same extent that KD does (data not shown).…”

Posttranslational modifications of proteins in diseased retina

“…Recent developments in proteomic research have made it possible to identify a set of proteins differentially posttranslationally modified in diseased retinas ( Garcia-Quintanilla et al, 2022 ; Lam et al, 2022 ; Lee et al, 2022 ; Nattinen et al, 2022 ; Smyczynska et al, 2022 ; Zhou H. et al, 2022 ). However, despite advancements in molecular knowledge regarding the retinal pathobiology of ocular diseases, the question of whether the differential expression of proteins associates with altered activity remains unaddressed.…”