# Mitochondrial Iron Handling and Lipid Peroxidation as Drivers of Ferroptosis

## TL;DR

This review explains how mitochondrial iron metabolism and lipid peroxidation drive ferroptosis, a type of cell death linked to metabolic and neurodegenerative diseases.

## Contribution

The paper highlights the role of mitochondrial iron handling and Fe-S cluster stability in regulating ferroptosis, beyond cytosolic mechanisms.

## Key findings

- Disruption of mitochondrial Fe-S clusters and heme metabolism can trigger ferroptosis through mtROS overproduction.
- Cardiolipin oxidation via the Fenton reaction destabilizes mitochondria and contributes to cell death in metabolic diseases.
- Dysregulation of iron transporters and glutathione homeostasis is linked to ferroptosis in obesity and Alzheimer’s disease.

## Abstract

Mitochondria are a key organelle in maintaining metabolic homeostasis. It not only generates most of the cell’s energy through oxidative phosphorylation but also acts as a complex sensor of the redox state and oxygen in the cell. This review thoroughly analyzes the interactions among mitochondrial iron metabolism, mitochondrial reactive oxygen species (mtROS), and lipid peroxidation (LPO), the triggering factors of ferroptosis, an iron-dependent form of programmed cell death. We point out research showing that intrinsic mitochondrial machinery, such as iron–sulfur (Fe-S) cluster assembly and heme metabolism, is both an important cofactor and a master regulator. If these processes are disrupted, they can lead to ferroptosis. Unlike views that focus on the cytosol, we explain that the stability of Fe-S clusters in complexes such as aconitase and respiratory Complex I is crucial for preventing electron leakage and excessive mtROS formation. The Fenton reaction and its direct effect on cardiolipin (CL) oxidation in the inner membrane of mitochondria is a central event in cardiometabolic diseases. Its peroxidation and breakdown make the organelle very unstable and lead to cell death though Ca2+ overload and a significantly decreased reduced/oxidized glutathione ratio. Additionally, the functions of essential iron transporters and glutathione homeostasis are examined, and their dysregulation is correlated with ferroptosis-associated progression of cardiometabolic and neurodegenerative disorders, such as obesity and Alzheimer’s disease. This review focused on the need to revisit the classic bioenergetic core of the mitochondria as a key player in the pathophysiology of metabolic and neurodegenerative diseases.