# Caspase-2 inhibits mitochondrial respiration in colorectal adenocarcinoma cells

## TL;DR

Caspase-2 limits mitochondrial respiration in colorectal cancer cells by suppressing key mitochondrial genes, potentially slowing tumor growth.

## Contribution

Caspase-2's novel role in regulating mitochondrial respiration and tumor suppression through gene suppression is revealed.

## Key findings

- Caspase-2 knockout increases mitochondrial oxygen consumption and oxidative stress in colorectal adenocarcinoma cells.
- Caspase-2 suppresses SDHB, TOMM, and TIMM gene transcription, reducing mitochondrial respiration.
- Caspase-2 knockout elevates p53 and c-Jun, which regulate mitochondria-related genes.

## Abstract

Knockout of caspase-2 in colorectal adenocarcinoma cells enhances mitochondrial oxygen consumption supported by succinate, a substrate of complex II. Additionally, caspase-2 knockout stimulates oxidative stress and promotes cell proliferation. The restriction of oxygen consumption by caspase-2 was attributed to the suppression of transcription of succinate dehydrogenase subunit B (SDHB), translocase of the outer mitochondrial membrane (TOMM), and the translocase of the inner mitochondrial membrane (TIMM). Caspase-2 knockout also increased the expression of the transcription factors p53 and c-Jun, which regulate the expression of mitochondria-related genes. Importantly, the catalytic activity of caspase-2 was dispensable for controlling mitochondrial respiration. In caspase-2 knockout mice, SDHA content remained unchanged, while SDHB and TIMM23 levels tended to increase, with TOMM20 showing the most prominent upregulation. Collectively, our findings uncover a novel molecular signaling pathway regulated by caspase-2 that may contribute to tumor growth suppression.

The online version contains supplementary material available at 10.1186/s12964-026-02671-z.