Ferroptosis and Cancer: Mitochondria Meet the “Iron Maiden” Cell Death

Abstract

Ferroptosis is a new type of oxidative regulated cell death (RCD) driven by iron-dependent lipid peroxidation. As major sites of iron utilization and master regulators of oxidative metabolism, mitochondria are the main source of reactive oxygen species (ROS) and, thus, play a role in this type of RCD. Ferroptosis is, indeed, associated with severe damage in mitochondrial morphology, bioenergetics, and metabolism. Furthermore, dysregulation of mitochondrial metabolism is considered a biochemical feature of neurodegenerative diseases linked to ferroptosis. Whether mitochondrial dysfunction can, per se, initiate ferroptosis and whether mitochondrial function in ferroptosis is context-dependent are still under debate. Cancer cells accumulate high levels of iron and ROS to promote their metabolic activity and growth. Of note, cancer cell metabolic rewiring is often associated with acquired sensitivity to ferroptosis. This strongly suggests that ferroptosis may act as an adaptive response to metabolic imbalance and, thus, may constitute a new promising way to eradicate malignant cells. Here, we review the current literature on the role of mitochondria in ferroptosis, and we discuss opportunities to potentially use mitochondria-mediated ferroptosis as a new strategy for cancer therapy.

Combined lymphocyte/monocyte count, D-dimer and iron status predict COVID-19 course and outcome in a long-term care facility

“…Previous laboratory findings highlighted that a consistent percentage of patients with elevated serum ferritin levels faced a higher probability to experience serious complications from COVID-19 [ 30 , 31 ]. Accordingly, ferroptosis, a novel programmed cell death, has been suggested as an important cause of multiple organ involvement in COVID-19 and it might serve as a new treatment target [ 32 – 36 ].…”

Novel insights into ferroptosis: Implications for age-related diseases

“…Mitochondria are the primary site of iron utilization, play a major role in regulating oxidative metabolism, and are also the main source of ROS 30 . As the most common metal in mitochondria, iron plays an important role in regulating the physiological function of these organelles 31 .…”

Role of Mitofusins and Mitophagy in Life or Death Decisions

“…However, once released from the mitochondria into the cytoplasm, upon cristae opening, these pleiotropic proteins convert into apoptosis initiators, pushing the cell toward a deadly end (Snigirevskaya and Komissarchik, 2019). Besides apoptosis, mitochondria are also recognized by regulating other types of cell death such as necroptosis, ferroptosis, pyroptosis, and mitochondrial-mediated necrosis (Baines, 2010;Baker et al, 2014;Marshall and Baines, 2014;Battaglia et al, 2020;Kai et al, 2020;Wang et al, 2020;Wei et al, 2020). Finally, the IM encloses the mitochondrial matrix, where essential reactions take place, such as iron-sulfur cluster assembly (Cardenas et al, 2018;Lill, 2020) or the tricarboxylic acid (TCA) cycle, which feeds electrons to the respiratory chain and provides amino acid precursors (Mailloux et al, 2007;Martínez-Reyes and Chandel, 2020).…”