Mitochondrial phosphatase PGAM5 negatively regulates IL-4-induced anti-inflammatory responses and metabolic reprogramming of macrophages by controlling JAK

Zheng et al. identify a PGAM5-driven harmful stress response inside mitochondria as a shared pathological feature of amyotrophic lateral sclerosis and demonstrate that targeting PGAM5 reduces this stress and ameliorates disease pathology across ALS subtypes.

Aberrant release of mitochondrial reactive oxygen species (mtROS) in response to cellular stress is well known for promoting cancer progression. However, precise molecular mechanism by which mtROS contribute to epithelial cancer progression remains only partially understood. Here, using colorectal cancer (CRC) models, we show that upon sensing excessive mtROS, phosphatase PGAM5, which normally localizes to the mitochondria, undergoes aberrant cleavage by presenilin-associated rhomboid-like protein (PARL), becoming released into the cytoplasm. Cytosolic PGAM5 then directly binds to and dephosphorylates MST3 kinase. This, in turn, prevents STK25-mediated LATS1/2 phosphorylation, leading to YAP activation and CRC progression. Importantly, depletion of MST3 reciprocally promotes accumulation of cytosolic PGAM5 by inducing mitochondrial damage. Taken together, these findings demonstrate how mtROS promotes CRC progression by activating YAP via a post-transcriptional positive feedback loop be

Read the full paper: Targeting PGAM5-driven mitochondrial integrated stress response slows ALS progression across subtypes

Read the full paper: Butyrylated PGAM5-Triggered and GSH-Responsive Cysteine Polymer Nanoparticles for CBL0137 Delivery to Enhance Necroptosis in Prostate Cancer

As a member of the δ-coronavirus family, porcine deltacoronavirus (PDCoV) is a vital reason for diarrhea in piglets, which can contribute to high morbidity and mortality rates. Initially identified i...

Scientific Reports - Unveiling the novel role of PGAM5 in rewiring metabolism through PI3K/AKT/mTOR signaling in acute myelogenous leukemia

Key Highlights • Researchers have identified a harmful stress response inside mitochondria, driven by a protein called PGAM5, as a common feature in amyotrophic lateral sclerosis (ALS). Targeting PGAM5 reduces this stress and improves disease pathology across different ALS subtypes, offering a promising new therapeutic strategy. Source → • Scientists have deconstructed a fear memory in the brain, identifying distinct groups of neurons that were active during specific moments of learning.

Targeting a Cellular Pathway to Protect the Lungs from Inflammatory Damage A recent study published in Cell Death & Disease reveals a novel molecular strategy for mitigating acute lung injury. The research demonstrates that inhibiting the mitochondrial phosphatase PGAM5 can alleviate ferroptosis, a specific type of inflammatory cell death, in models of acute pancreatitis. This protective effect is achieved by upregulating the NRF2-mediated expression of FSP1, a key anti-ferroptotic protein.