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

Abstract

Fuchs endothelial corneal dystrophy (FECD) is characterized by an accelerated loss of corneal endothelial cells. Since the function of these cells is to maintain the cornea in a state of deturgescence necessary for its transparency, the depletion of corneal endothelial cells ultimately causes corneal edema and irreversible loss of vision. Evidence is accumulating regarding the central involvement of mitochondria in FECD. As we have previously shown, when endothelial cells die and are not replaced, the mitochondria of surviving cells must provide more energy to compensate, leading to a phenomenon we have called mitochondrial burnout. This burnout causes cell death, thus exacerbating an irreversible vicious circle responsible for FECD progression. Corneal transplantation, for which the transplant supply is insufficient, is the only curative alternative for FECD. It thus becomes imperative to find other avenues of treatment. In this article, we tested whether incorporating healthy mitochondria into FECD cells would improve pathological molecular markers of the disease. Using corneal endothelium explants from FECD patients, we demonstrated that incorporation of exogenous mitochondria into FECD cells by co-incubation reduces oxidative stress, increases mitochondrial membrane potential, and reduces mitophagy. In addition, internalization of exogenous mitochondria significantly reduces apoptosis (57% in FECD vs 12% in FECD with internalized mitochondria). Taken together, these results suggest that the internalization of exogenous mitochondria reverses the vicious circle involved in FECD, thus revealing a much-needed novel treatment alternative for FECD.

Mitochondria Transplantation Promotes Corneal Epithelial Wound Healing

“…Although the precise molecular mechanisms that underlie the effects of mitochondrial transfer are not fully defined, mitochondrial transfer was shown to restore cellular bioenergetics and alter the metabolic state of recipient cells. 10 , 13 , 14 , 17 , 39 – 49 In CECs, transfer of mitochondria from MSCs via tunneling nanotubes was shown to improve cell survival under conditions of oxidative stress. Mechanistically, the effect of the transferred mitochondria was correlated to increased respiration and reduced oxidative stress signaling such as NFkB.…”