Mitochondria as multifaceted regulators of ferroptosis

Abstract

Mitochondria are well known to be ‘energy factories’ of the cell as they provide intracellular ATP via oxidative phosphorylation. Interestingly, they also function as a ‘cellular suicidal weapon store’ by acting as a key mediator of various forms of regulated cell death, including apoptosis, pyroptosis, necroptosis and ferroptosis. Ferroptosis, distinct from the other types of regulated cell death, is characterized by iron-dependent lipid peroxidation and subsequent plasma membrane rupture. Growing evidence suggests that an impaired ferroptotic response is implicated in various diseases and pathological conditions, and this impaired response is associated with dramatic changes in mitochondrial morphology and function. Mitochondria are the center of iron metabolism and energy production, leading to altered lipid peroxidation sensitivity. Although a growing number of studies have explored the inextricable link between mitochondria and ferroptosis, the role of this organelle in regulating ferroptosis remains unclear. Here, we review recent advances in our understanding of the role of mitochondrial in ferroptosis and summarize the characteristics of this novel iron-based cellular suicide weapon and its arsenal. We also discuss the importance of ferroptosis in pathophysiology, including the need for a further understanding of the relationship between mitochondria and ferroptosis to identify combinatorial targets that are essential for the development of successful drug discovery.

Ferroptosis and its role in gastric and colorectal cancers

“…These iron-sulphur clusters are essential cofactors in various cellular processes, including the TCA cycle, respiratory chain complexes, and cytoplasmic enzymes. Furthermore, mitochondria contain iron storage proteins similar to cytoplasmic ferritin, known as mitochondrial ferritin (FtMt), which interacts with NCOA4 to promote the release of iron from mitochondrial autophagy when iron levels in mitochondria are decreased [ 74 ].…”

Molecular mechanisms of mitochondria-mediated ferroptosis: a potential target for antimalarial interventions

“…The induction of ferroptosis with RAS selective lethal 3 (RSL3) resulted in modifications in the morphology of the mitochondria as well as the clustering of fragmented mitochondria around the nucleus ( Wang et al, 2020a ). In addition, the oxidation of lipids takes place on the plasma membrane and the membranes of various organelles with the inclusion of mitochondria ( Chen et al, 2021 ; Guo et al, 2022 ).…”

“…Phospholipids, sterols, and sphingolipids make up the major constituents of the membrane lipids ( Klug and Daum, 2014 ). Phospholipids are naturally amphipathic, with a hydrophobic chain (constituted of a saturated or unsaturated fatty acyl group) at one end and a hydrophilic chain (containing phosphatidylethanolamine and phosphatidylcholine) at the other end, particularly the head ( Guo et al, 2022 ). Polyunsaturated fatty acids (PUFAs) are the preferential candidates for oxidative degradation during ferroptosis ( Rodencal and Dixon, 2023 ).…”

“…This oxidative degradation of the phospholipids of PUFA leads to alterations in their membrane structure and fluidity and possibly forming pores (water-loving) that alter the plasma membrane barrier ( Boonnoy et al, 2017 ). Mitochondria are composed of elevated amounts of phosphatidylethanolamine, and there is a possibility of the foremost occurrence of lipid peroxidation on the outer or inner mitochondrial membrane ( Guo et al, 2022 ). Various mitochondrial enzyme systems are involved in lipid metabolism, including acyl-coA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), which are leading factors in ferroptosis.…”

A large Stokes shift NIR fluorescent probe for visual monitoring of mitochondrial peroxynitrite during inflammation and ferroptosis and in an Alzheimer's disease model

“…[6][7][8] Studies have indicated that the excessive formation and accumulation of the reactive oxygen species (ROS) in mitochondria make cells prone to ferroptosis. [9][10][11][12] Ferroptosis is a type of programmed cell death, which is different from autophagy, necrosis, and apoptosis. It underlies the pathogenesis of a broad range of disorders, 13 such as cancer, anemia, and Alzheimer's disease (AD).…”