Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria

Abstract

Ferroptosis is a recently described form of regulated cell death characterized by intracellular iron accumulation and severe lipid peroxidation due to an impaired cysteine-glutathione-glutathione peroxidase 4 antioxidant defence axis. One of the hallmarks of ferroptosis is a specific morphological phenotype characterized by extensive ultrastructural changes of mitochondria. Increasing evidence suggests that mitochondria play a significant role in the induction and execution of ferroptosis. The present review summarizes existing knowledge about the mitochondrial impact on ferroptosis in different pathological states, primarily cancer, cardiovascular diseases, and neurodegenerative diseases. Additionally, we highlight pathologies in which the ferroptosis/mitochondria relation remains to be investigated, where the process of ferroptosis has been confirmed (such as liver- and kidney-related pathologies) and those in which ferroptosis has not been studied yet, such as diabetes. We will bring attention to avenues that could be followed in future research, based on the use of mitochondria-targeted approaches as anti- and proferroptotic strategies and directed to the improvement of existing and the development of novel therapeutic strategies.

Ferroptosis as a Novel Determinant of β-Cell Death in Diabetic Conditions

“…Ferroptosis has been suggested to contribute to pancreatic β -cell loss and dysfunction [ 8 , 25 , 26 ]. However, the data connecting HG, lipids, cytokines, and/or ROS levels with ferroptosis of β -cells are still obscure.…”

“…In addition, targeting β-cell death has also emerged as an important potential approach in diabetes treatment. Till date, several types of death of β-cells have been described in diabetic conditions including necrosis, apoptosis, and autophagy [5][6][7][8]. The connecting link between them is the disturbance of the redox state, suggesting that manipulation of the reactive species production/removal can have great therapeutic potential for the regulation of β-cell mass.…”

“…When compared to the liver, pancreatic islets have significantly lower catalase, glutathione peroxidase (GPX), and superoxide dismutase 1 (SOD1) expression levels and activities [10][11][12]. What makes the situation even worse in the diabetic state is the suppression of antioxidant capacity along with the increase in the production of ROS in many tissues, including the pancreas [8,13,14].…”

Targeting ferroptosis in acute kidney injury

“…Morphologically, ferroptosis mainly manifests as shrinkage of mitochondria with the rupture of mitochondria membrane, enhanced membrane density, and reduction or disappearance of the mitochondrial crest [ 18 ]. Based on the morphological particularity of ferroptosis, transmission electron microscopy (TEM) is widely applied to observe ultrastructural changes [ 19 ].…”

Construction of a Novel Ferroptosis-Related Gene Signature of Atherosclerosis

“…Since ferroptosis is always accompanied by mitochondrial dysfunction ( Battaglia et al, 2020 ; Otasevic et al, 2021 ), the relationship between hub genes and MFRGs was analyzed. Among the 1,262 MFRGs, 505 genes were eventually classified as DE-MFRGs ( Supplementary Figure S1A ).…”