Targeting mitochondrial phosphatase PGAM5 alleviates ferroptosis and acute pancreatitis by upregulating NRF2-mediated FSP1 expression

TL;DR

This paper shows that targeting the mitochondrial phosphatase PGAM5 can protect cells from ferroptosis and reduce acute pancreatitis by boosting the antioxidant NRF2-FSP1 pathway.

Contribution

The study reveals PGAM5 as a novel regulator of ferroptosis through its dual role in stabilizing NRF2 and inducing energy stress.

Findings

PGAM5 dysregulation protects against ferroptosis by upregulating NRF2 and FSP1.

PGAM5 inhibition reduces acute pancreatitis in a mouse model.

AMPK activation and energy stress mediate PGAM5's protective effects.

Abstract

Ferroptosis is a regulated necrosis that is driven by iron-dependent lipid peroxidation. Phosphoglycerate mutase 5 (PGAM5), as a mitochondrial signaling hub, modulates mitochondrial dynamics, senses mitochondrial stress, and regulates the anti-oxidative response. However, the function of PGAM5 in ferroptosis remains elusive. Here, we discovered that PGAM5 emerges as a critical regulator of ferroptosis, with both genetic deletion and overexpression conferring protection against ferroptosis by upregulating nuclear factor erythroid 2-related factor 2 (NRF2) mediated ferroptosis suppressor protein 1 (FSP1) expression. On the one hand, dyregulation of PGAM5 upregulates NRF2 expression transcriptionally and inhibits its polyubiquitination. On the other hand, modulating the expression of PGAM5 results in energy stress ([AMP + ADP]/[ATP] ratio increase) and AMP-activated protein kinase (AMPK) activation. AMPK-dependent phosphorylation of NRF2 drives its nuclear accumulation, where it transcriptionally upregulates FSP1 to promote cell survival. Furthermore, pharmacological inhibition of PGAM5 attenuates arginine-induced acute pancreatitis, highlighting its therapeutic potential. Our findings establish PGAM5 as a central node in ferroptosis regulation and implicate its pathogenic role in acute pancreatitis.

The molecular mechanism of alleviation of ferroptosis by dysregulation of PGAM5.

The molecular mechanism of alleviation of ferroptosis by dysregulation of PGAM5.

Figures