Loss of WIPI4 has been associated with promoting ferroptosis.
In a groundbreaking study published in Nature Cell Biology, researchers have uncovered a novel link between the loss of WIPI4 and ferroptosis, shedding light on the pathogenesis of β-propeller protein-associated neurodegeneration (BPAN). WIPI4, encoded by the WDR45 gene, is known for its role in autophagy, the cellular process responsible for degrading dysfunctional components. During autophagy, WIPI4 binds to phosphatidylinositol-3-phosphate on the phagophore membrane and interacts with autophagy-related protein 2 (ATG2) to transfer phospholipids from the endoplasmic reticulum to the phagophore, promoting autophagosome growth.
The study by Zhu et al. revealed that WIPI4 depletion induces ferroptosis, a form of iron-dependent cell death characterized by lipid peroxidation. Interestingly, disrupting other autophagy-related proteins did not trigger ferroptosis, indicating that WIPI4 regulates this process independently of autophagy. The researchers found that the interaction between WIPI4 and ATG2 was crucial for ferroptosis induction, suggesting that dysregulation of ATG2 function in the absence of WIPI4 may drive cell death.
Further investigations showed that WIPI4 depletion led to mislocalization of ATG2 to mitochondria and endoplasmic reticulum–mitochondria contact sites, promoting lipid peroxidation at mitochondrial membranes. This lipid peroxidation, a hallmark of ferroptosis, was found to be dependent on the lipid transfer activity of ATG2. The researchers also discovered that reducing mitochondrial lipid peroxidation prevented cell death caused by WIPI4 depletion or ATG2 overexpression.
By delving into the lipid dynamics involved, the team elucidated that WIPI4 disruption altered the lipid composition of mitochondrial membranes, increasing levels of phosphatidylethanolamine (PE) and polyunsaturated fatty acids. This effect was mediated by the lipid transfer activity of ATG2, ultimately leading to lipid peroxidation and ferroptosis initiation. Inhibition of phosphatidylserine decarboxylase (PISD), an enzyme involved in PE synthesis at mitochondria, rescued cell death induced by WIPI4 depletion, highlighting the potential therapeutic target for diseases associated with excessive ferroptosis.
This study unveils a non-autophagic role for WIPI4 in preventing ferroptosis, offering insights into the mechanisms underlying neurodegeneration in BPAN. The findings underscore the significance of phospholipid dynamics in ferroptosis regulation and propose targeting PISD as a promising therapeutic strategy for BPAN and other ferroptosis-related diseases.
By unraveling the complex interplay between WIPI4, ATG2, and lipid metabolism, this research paves the way for a deeper understanding of cell death mechanisms and opens up new avenues for developing targeted therapies for neurodegenerative disorders.
Source: https://www.nature.com/articles/s41556-024-01359-1
The study by Zhu et al. revealed that WIPI4 depletion induces ferroptosis, a form of iron-dependent cell death characterized by lipid peroxidation. Interestingly, disrupting other autophagy-related proteins did not trigger ferroptosis, indicating that WIPI4 regulates this process independently of autophagy. The researchers found that the interaction between WIPI4 and ATG2 was crucial for ferroptosis induction, suggesting that dysregulation of ATG2 function in the absence of WIPI4 may drive cell death.
Further investigations showed that WIPI4 depletion led to mislocalization of ATG2 to mitochondria and endoplasmic reticulum–mitochondria contact sites, promoting lipid peroxidation at mitochondrial membranes. This lipid peroxidation, a hallmark of ferroptosis, was found to be dependent on the lipid transfer activity of ATG2. The researchers also discovered that reducing mitochondrial lipid peroxidation prevented cell death caused by WIPI4 depletion or ATG2 overexpression.
By delving into the lipid dynamics involved, the team elucidated that WIPI4 disruption altered the lipid composition of mitochondrial membranes, increasing levels of phosphatidylethanolamine (PE) and polyunsaturated fatty acids. This effect was mediated by the lipid transfer activity of ATG2, ultimately leading to lipid peroxidation and ferroptosis initiation. Inhibition of phosphatidylserine decarboxylase (PISD), an enzyme involved in PE synthesis at mitochondria, rescued cell death induced by WIPI4 depletion, highlighting the potential therapeutic target for diseases associated with excessive ferroptosis.
This study unveils a non-autophagic role for WIPI4 in preventing ferroptosis, offering insights into the mechanisms underlying neurodegeneration in BPAN. The findings underscore the significance of phospholipid dynamics in ferroptosis regulation and propose targeting PISD as a promising therapeutic strategy for BPAN and other ferroptosis-related diseases.
By unraveling the complex interplay between WIPI4, ATG2, and lipid metabolism, this research paves the way for a deeper understanding of cell death mechanisms and opens up new avenues for developing targeted therapies for neurodegenerative disorders.
Source: https://www.nature.com/articles/s41556-024-01359-1
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