Targeting Mitochondrial Dysfunction and Oxidative Stress to Prevent the Neurodegeneration of Retinal Ganglion Cells

Abstract

The imbalance of redox homeostasis contributes to neurodegeneration, including that related to the visual system. Mitochondria, essential in providing energy and responsible for several cell functions, are a significant source of reactive oxygen and/or nitrogen species, and they are, in turn, sensitive to free radical imbalance. Dysfunctional mitochondria are implicated in the development and progression of retinal pathologies and are directly involved in retinal neuronal degeneration. Retinal ganglion cells (RGCs) are higher energy consumers susceptible to mitochondrial dysfunctions that ultimately cause RGC loss. Proper redox balance and mitochondrial homeostasis are essential for maintaining healthy retinal conditions and inducing neuroprotection. In this respect, the antioxidant treatment approach is effective against neuronal oxidative damage and represents a challenge for retinal diseases. Here, we highlighted the latest findings about mitochondrial dysfunction in retinal pathologies linked to RGC degeneration and discussed redox-related strategies with potential neuroprotective properties.

Keywords: ganglion cells; mitochondria; neurodegeneration; redox homeostasis; retina.

Figure 1

Measurements of mitochondrial activity with MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay absorbance in adult D. melanogaster head extracts after ten days of feeding with a standard diet (STD, 5–9% sucrose), a high sucrose diet (HSD) of 30%, and a very HSD of 40%, according to the method previously published [43]. Data representing ca. 100 heads were obtained from at least 5 independent experiments. The statistical significance was evaluated using a one-way ANOVA followed by the Tukey post-test. The results were expressed as means ± SEM. a.u.: arbitrary units. *** p < 0.0001 vs. STD, and § p < 0.01 vs. HSD 30%.

Figure 2

Latest findings about mitochondrial dysfunction causing retinal ganglion cell (RGC) degeneration and the main factors involved. Reactive oxygen species (ROS); diabetic retinopathy (DR); familial dysautonomia (FD); Leber’s hereditary optic neuropathy (LHON); inhibitor of kappa light polypeptide gene enhancer in b cells; kinase complex-associated protein/elongator acetyltransferase complex; subunit 1 (IKBKAP/ELP1); mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4 (MT-ND4); optineurin dominant mutation (E50K); sirtuin 3 (SIRT3); manganese superoxide dismutase (MnSOD); glutathione (GSH); nuclear factor-erythroid-2-related factor 2 (Nrf2); mitochondrial DNA (mtDNA); kinesin family member 5A (KIF5A); phospho-dynamin-related protein 1 (p-Drp1); apolipoprotein A-I-binding protein (AIBP); A-Kinase-anchoring protein 1 (AKAP1); oxidative phosphorylation (OXPHOS); superoxide dismutase 2 (SOD2); glutathione-S-transferase (GstD1); kelch-like ECH-associated protein 1 (Keap1); activating transcription factor 4 (ATF4); heat shock protein 70 (HSP70); and extracellular signal-regulated kinase 1/2 (ERK 1/2).

Figure 3

Oxidative stress is a hallmark of neurodegenerative retinal diseases. Reactive oxygen species (ROS) accumulation affects mitochondria that undergo dynamic dysregulation and dysfunction. Retinal ganglion cells (RGCs) are high-energy consumers and are particularly sensitive to oxidative stress damage and mitochondrial impairment.