# Mito-Genipin, a Novel Mitochondria-Targeted Genipin Derivative Modulates Oxidative Stress and Inflammation in Macrophages

## TL;DR

A new mitochondria-targeted version of genipin increases oxidative stress and inflammation in macrophages, likely by inhibiting UCP2.

## Contribution

Mito-genipin is a novel mitochondria-targeted genipin derivative with enhanced efficacy and UCP2 inhibition.

## Key findings

- Mito-genipin induces mitochondrial hyperpolarization and increases ROS production in macrophages.
- Mito-genipin amplifies pro-inflammatory cytokine expression compared to genipin or control.
- Mito-genipin's effects on ROS are UCP2-dependent, as they are absent in UCP2-deficient cells.

## Abstract

Genipin, a natural compound derived from Gardenia jasminoides, is widely used as an inhibitor of uncoupling protein 2 (UCP2), a protein located in the inner mitochondrial membrane (IMM) that plays a crucial role in regulating oxidative stress and cellular metabolism. Pharmacological inhibition of UCP2 has been explored as a strategy to modulate reactive oxygen species (ROS) and inflammatory responses. However, the utility of genipin is limited by its relatively low bioavailability and dose-dependent toxicity. To address these limitations, we developed mito-genipin, a mitochondria-targeted genipin derivative incorporating a triphenylphosphonium (TPP+) moiety, designed to enhance mitochondrial accumulation and thereby increase efficacy. In macrophages, mito-genipin induced mitochondrial hyperpolarization, elevated ROS production, and amplified pro-inflammatory cytokine expression compared with control or genipin treatment. In cells lacking UCP2, mito-genipin did not enhance ROS production. Our data identify mito-genipin as an effective modulator of oxidative stress and inflammation, supporting a putative link to UCP2 inhibition and highlighting potential implications in redox biology and immunomodulation.