Chronology of cellular events related to mitochondrial burnout leading to cell death in Fuchs endothelial corneal dystrophy

Abstract

fuchs endothelial corneal dystrophy (fecD) is a degenerative eye disease characterized by corneal endothelial cell (CEC) death and the formation of guttae, an abnormal thickening of CEC's basement membrane. At the tissue level, an oxidative stress causing mitochondrial damage and CEC death have been described to explain FECD pathogenesis. At the cellular level, our group has previously observed significant variability in the mitochondrial mass of FECD CECs. This led us to hypothesize that mitochondrial mass variability might play a key role in the chronology of events eventually leading to CEC death in FECD. We thus used different fluorescent markers to assess mitochondrial health and functionality as a function of mitochondrial mass in FECD corneal endothelial explants, namely, intramitochondrial calcium, mitochondrial membrane potential, oxidation level and apoptosis. This has led us to describe for the first time a sequence of events leading to what we referred to as a mitochondrial burnout, and which goes as follow. FECD CECs initially compensate for endothelial cell losses by incorporating mitochondrial calcium to help generating more ATP, but this leads to increased oxidation. CECs then resist the sustained need for more ATP by increasing their mitochondrial mass, mitochondrial calcium and mitochondrial membrane potential. At this stage, CECs reach their maximum capacity and start to cope with irreversible oxidative damage, which leads to mitochondrial burnout. This burnout is accompanied by a dissipation of the membrane potential and a release of mitochondrial calcium, which in turn leads to cell death by apoptosis. The cornea is composed of three cellular layers, i.e. the epithelium, the stroma and the endothelium 1. The stroma needs to be maintained partially dehydrated to allow for the optimal arrangement of its collagen fibrils necessary to ensure its transparency 2. This ATP-demanding function is achieved mainly by the corneal endothelium, a leaky cell monolayer that pumps fluid out of the stroma, into the anterior chamber, maintaining the proper hydration of the corneal stroma 2,3. Fuchs endothelial corneal dystrophy (FECD) is characterized by a loss of corneal endothelial cells (CECs), abnormal extracellular matrix deposition on its basal membrane (Descemet's membrane) leading to the formation of excrescences called guttae, and changes in cellular morphology 4. The loss of CECs ultimately compromises the role of the endothelium to preserve corneal deturgescence. This leads to corneal edema and vision loss 4. FECD affects 4 percent of the US populations over 40 years old 5 and the only treatment currently available for FECD is corneal transplantation 6,7. Although the exact cause of FECD is not yet determined, there is growing evidence that oxidative stress and mitochondria are major contributors 8,9. The mechanism and the sequence of events leading to mitochondrial dysfunction and cell loss still remain to be elucidated. Manifestations of cumulative oxidative damage and mitochondrial dysfunction in ...

Mitochondrial Dysfunction and Mitophagy in Fuchs Endothelial Corneal Dystrophy

“…Mitochondrial dynamics consists of a coordinated cycle of mitochondrial fusion and fission to maintain its shape and size. Abnormal mitochondrial dynamics in FECD comprises aberrant mitochondrial fusion including decline in mitofusin 2, loss of mitochondrial mass [15,16], and fission including increased mitochondrial fission proteins indicative of fragmentation [18], and activation of mitochondrial-mediated intrinsic apoptosis pathway [11].…”

“…In FECD, CEnCs exhibits stress-induced senescence [8], oxidant-antioxidant imbalance [9], mitochondrial DNA damage [10] and dysfunction [11], sustained unfolded protein response (UPR) [12,13], and endoplasmic reticulum (ER) stress [14]. Among these factors, mitochondrial stress [15][16][17][18] plays an important role in FECD pathogenesis. Maintaining functional mitochondria is the key to the ion pump function in CEnCs.…”

Effect of diagnostic ultrasound on corneal apoptosis in rats

“…Some studies have shown that the mechanism of ultrasonic diagnosis may be related to the changes of nuclear size and acoustic characteristics, which are related to cell death, especially the form of apoptosis [10] . Through the preliminary study of the effect of apoptosis on corneal cells caused by ultrasound irradiation time, this experiment preliminarily shows the role of apoptosis in the metabolism of normal cornea and the occurrence and development of some keratopathy, and attempts to study the changes of corneal cell apoptosis after diagnostic ultrasound irradiation in rats in order to find the safe range of diagnostic ultrasound examination.…”

Rescuing cellular function in Fuchs endothelial corneal dystrophy by healthy exogenous mitochondrial internalization

“…The exact cause of FECD is yet to be determined but evidence has shown that oxidative stress and mitochondrial dysfunction are implicated 8 , 9 . In a previous study, we have shown that oxidative stress and mitochondrial dysfunction are linked in a mitochondrial overuse vicious cycle we called mitochondrial burnout cycle 10 . In this cycle, cells are progressing through different stages that can be sorted using mitochondrial mass.…”

“…To respond to the increased energetic demand, these cells increase their mitochondrial mass, which leads to an increased production of reactive oxygen species (ROS). These ROS further damage the cells that will eventually trigger mitophagy and apoptosis 10 .…”