# NDUFS1‐Mediated Mitochondrial Complex I Activity Maintains Pancreatic Cancer Stemness by Promoting PAX2 Hypomethylation

## TL;DR

This study shows that mitochondrial complex I activity, via NDUFS1, helps pancreatic cancer stem cells maintain their stemness by promoting PAX2 hypomethylation.

## Contribution

The novel finding is that NDUFS1-mediated mitochondrial activity supports CSC stemness through a CD147-STAT3-SIRT1-DNMT1 metaboloepigenetic pathway.

## Key findings

- Pancreatic cancer stem cells exhibit active mitochondrial complex I and increased oxidative phosphorylation.
- NDUFS1 promotes CSC stemness by decreasing PAX2 promoter methylation via SIRT1-DNMT1 signaling.
- High CD147 and NDUFS1 co-expression in pancreatic cancer is linked to poor patient survival.

## Abstract

Pancreatic cancer is highly refractory and aggressive, with cancer stem cells (CSCs) being primarily responsible for its metastasis and chemoresistance. Deregulated cellular bioenergetics is a hallmark of cancer cells. However, the influence of bioenergetics on the maintenance of pancreatic CSC stemness and its underlying mechanisms have not been fully elucidated. In this study, pancreatic CSCs, isolated either by sorting ALDH+ subpopulation or enriching serially passaged tumorspheres from pancreatic cancer cells and PDX model, exhibited active mitochondrial complex I activity and increased oxidative phosphorylation. Complex I maintains stemness and tumorigenicity through its core subunit, NDUFS1. NDUFS1‐mediated pancreatic CSC stemness is reinforced by high expression of CD147, which promotes pSTAT3Tyr705‐mediated NDUFS1 transcription. To promote stemness, CD147‐NDUFS1 initiates SIRT1‐DNMT1 metaboloepigenetic signaling, decreasing promoter hypomethylation and increasing the mRNA expression of the stem cell transcript factor PAX2. Moreover, NDUFS1 and CD147 expressions were highly correlated in pancreatic cancer tissues, and their co‐expression was significantly associated with poor patient survival. Taken together, our study provides evidence that mitochondrial complex I functions as a key player in CSC stemness maintenance through NDUFS1‐mediated retrograde metaboloepigenetic signaling. Blocking a key regulator of mitonuclear communication by targeting CD147 may be a novel therapy for pancreatic cancer.

Pancreatic cancer stem cells (CSCs) maintain stemness and tumorigenicity through NDUFS1‐mediated complex I activity, which is transcriptionally upregulated via the CD147‐STAT3 signaling axis. Enhanced oxidative phosphorylation (OXPHOS) and NAD+ production driven by this CD147‐NDUFS1 axis subsequently trigger the SIRT1‐DNMT1 metaboloepigenetic signaling cascade, resulting in PAX2 promoter hypomethylation, increased PAX2 expression, and ultimately reinforcement of the CSC stemness.