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Fig. 1. Loss of CISD2 appears to be an important aspect in the pathogenesis of corneal An early consequence of ageing in humans is a decline in vision. Usually, this is limited to presbyopia starting at the age of forty. However, at later age, more severe age-related eye disease can occur, possibly resulting in blindness. Proper corneal epithelium maintenance is indispensable for corneal clarity and good vision quality. A major culprit of blindness associated with corneal epithelium defects is the formation of corneal scars. These scars are the outcome of a wound healing process initiated by re-epithelialisation and further driven by activated keratocytes, which help to re-establish the integrity of the tissue but fail to restore optical properties. A protein key to healthy ageing in mammalian organisms is CDGSH Iron Sulfur Domain 2 (CISD2) [1]. CISD2-protein levels are dynamically regulated whereby adequate levels of CISD2 prevent early ageing and prolongs lifespan. Moreover, loss-of-function mutations in the CISD2 gene cause Wolfram syndrome 2, a rare genetic disease [2]. From a biochemical perspective, CISD2 is an iron-sulfur cluster-binding protein affecting reactive oxygen species (ROS) formation. From a cell physiological perspective, CISD2 is strategically located at the endoplasmic reticulum (ER) and mitochondria interface, key organelles for protein folding, Ca signalling, bioenergetics and cell survival. Thus, given the crucial role of ER-mitochondrial Ca + signalling in health and disease, CISD2 is uniquely positioned to impact cellular fitness. However, the exact mechanisms by which CISD2 influences intracellular Ca-transport systems remain unclear. Inspired by their previous findings in CISD2-deficient mice suffering from blindness due to corneal damage [3] and resembling clinical manifestations associated with corneal limbal stem cell (CLSC) deficiency, Tsai et al. studied CISD2 levels in the corneal tissues taken from patients undergoing corneal transplantation procedures [4] (see Fig. 1). Notably, CISD2 was decreased in the corneal epithelium derived from patients with corneal epithelium deficits but not from those with corneal defects stemming from endothelial problems. Vice versa, CISD2-deficient mice displayed corneal epithelium deficits due to a vicious cycle of inflammation and continuous loss of epithelial cells, further aggravated by impaired renewal and differentiation of epithelial cells from CLSC. Comparing young versus old mice, the