# Alkyltriphenylphosphonium Binding to Cardiolipin Triggers Oncosis in Cancer Cells

## TL;DR

A compound called TPP+‐C14 targets mitochondria in cancer cells, causing cell death through a unique process called oncosis.

## Contribution

The study reveals a novel mechanism where alkylated TPP+ derivatives selectively bind to cardiolipin, inducing oncosis rather than apoptosis or autophagy.

## Key findings

- TPP+‐C14 selectively binds to cardiolipin in mitochondria, impairing its function.
- TPP+‐C14 induces oncosis in cancer cells by activating endoplasmic reticulum stress.
- TPP+‐C14 causes mitochondrial dysfunction through ATP depletion and membrane potential collapse.

## Abstract

Mitochondria, pivotal for cellular bioenergetics and signaling, are attractive targets for cancer therapy. Triphenylphosphonium (TPP+) is a widely used mitochondrial‐targeting ligand, yet its intrinsic bioactivity and mechanism remain underexplored. Here we demonstrate that alkylated TPP+ derivatives exhibit chain length‐dependent anticancer activity, with TPP+‐C14 showing superior efficacy both in vitro and in vivo. Mechanistically, TPP+‐C14 selectively binds to cardiolipin, a key phospholipid in the inner mitochondrial membrane, through electrostatic and hydrophobic interactions, as validated by biolayer interferometry, competitive binding assays, and molecular dynamics simulations. This binding impairs cardiolipin function, leading to mitochondrial membrane potential collapse, adenosine triphosphate depletion, metabolic reprogramming, and ultimately mitochondrial dysfunction. Intriguingly, TPP+‐C14 induces oncosis in cancer cells, rather than apoptosis or autophagy, by activating the endoplasmic reticulum stress pathway. These findings reveal a novel bioactive mechanism for TPP+ beyond its intrinsic mitochondrial targeting property, providing a foundation for next‐generation mitochondrial‐targeted anticancer strategies that could precisely modulate mitochondrial functions.

Alkyltriphenylphosphonium, exemplified by TPP+‐C14, preferentially accumulates in mitochondria and selectively binds to cardiolipin, a key phospholipid of the inner mitochondrial membrane, causing loss of mitochondrial membrane potential, severe cellular ATP depletion, and calcium imbalance. These disruptions lead to mitochondrial dysfunction and trigger endoplasmic reticulum stress, ultimately inducing oncosis in cancer cells.