Mitochondrial Strategies in Ferroptotic Cell Death

Introduction

Mitochondria serve as the epicenter of cellular metabolism. Their dynamic communication with other compartments within the cell ensures proper cellular function. My recent work reveals how mitochondria communicate with the plasma membrane (PM) to transport a redox-active lipid Coenzyme Q (Ubiquinone or CoQ).

Importance of Coenzyme Q

This communication is crucial for inhibiting a form of iron-mediated cell death called ferroptosis. Notably, CoQ is exclusively synthesized within the mitochondria and plays a pivotal role in maintaining the mitochondrial respiratory chain, as well as other metabolic pathways, such as:

1. Pyrimidine synthesis
2. Fatty acid oxidation
3. Proline metabolism

My work highlights that cellular defense is primarily orchestrated from the mitochondria and surprisingly dependent on a molecule—CoQ—that is indispensable for mitochondrial function.

Mitochondrial Defense Mechanisms

This work shows that mitochondria—known as cell death inducers—protect cells from ferroptosis and opens several key questions that I will address in Mito-FerroQuest, including:

i) Which proteins and metabolic pathways within the mitochondria dictate whether CoQ should be exported or retained within the mitochondria?
ii) Do mitochondria have other ways to defend against ferroptosis, or is CoQ export their only defense?
iii) Does mitochondrial communication extend beyond the PM and involve interactions with other organelles, such as the endoplasmic reticulum (ER), in protecting cells against ferroptosis?

Future Implications

Answers to these questions will enhance our understanding of mitochondrial strategies in ferroptosis, potentially paving the way for new therapies in conditions where ferroptosis is implicated, like neurodegenerative disorders.

Research Goals

Mito-FerroQuest sets the stage for my overarching goal of exploring ferroptosis in diseases with compromised mitochondrial function, such as Leigh syndrome, with the aim to assess its potential as a therapeutic target.