# Antitumor natural products targeting mitochondrial NADH: ubiquinone oxidoreductase (complex I): a review

## TL;DR

This review explores natural compounds that fight cancer by targeting a key mitochondrial enzyme, complex I, and highlights their potential for drug development.

## Contribution

The paper provides a structured analysis of natural products targeting complex I, linking their structures to mechanisms of action.

## Key findings

- Natural products like alkaloids and acetogenins inhibit complex I, causing metabolic stress in cancer cells.
- Compounds are categorized by their binding modes, such as 'deep tunnel blockers' or 'shallow pocket binders'.
- The review identifies a gap in understanding how chemical structures relate to specific antitumor mechanisms.

## Abstract

Mitochondrial complex I (NADH:ubiquinone oxidoreductase) is a critical hub for bioenergetics and redox signaling. Beyond its canonical role in oxidative phosphorylation and ATP synthesis, complex I regulates the intracellular NADH/NAD+ balance and reactive oxygen species (ROS) production, both of which are vital for tumor survival. Consequently, targeting complex I has emerged as a promising therapeutic strategy. Increasing evidence shows that diverse natural products—ranging from alkaloids to annonaceous acetogenins—exert potent antitumor effects by inhibiting complex I. These compounds disrupt mitochondrial function, inducing metabolic stress and cancer cell death. However, a systematic overview linking their chemical structures to specific binding modes and antitumor mechanisms is currently lacking. In this review, we summarize recent advances in natural products targeting mitochondrial complex I. We categorize these agents based on their structural characteristics and discuss their distinct mechanisms, such as acting as “deep tunnel blockers” versus “shallow pocket binders.” This work aims to provide a theoretical foundation for the rational development of novel complex I-targeted antitumor drugs.