Abstract:  Peroxisomes, recently recognized as vital regulators in the aging process, undergo functional changes with age, affecting lipid metabolism and the dynamics of mitochondria, the powerhouse of the cell. Our research explores the intricate relationship between peroxisomes and mitochondria, critical for maintaining cellular homeostasis. Expanding on previous studies, we have identified the plasmalogen ether phospholipid biosynthesis pathway as crucial for communication between these organelles. Notably, we found that levels of plasmalogens decline with age, particularly within mitochondria, indicating their essential role in cellular function. However, a comprehensive analysis of the regulators and effectors for this phospholipid has not been fully achieved.

To investigate further, we used a proteomic approach with mouse heart tissue. Utilizing biotinylated plasmalogens, we conducted a pulldown assay followed by TMT mass spectrometry, revealing a complex protein interaction network surrounding plasmalogens. We identified 70 enriched proteins, with a surprisingly significant portion 75% localized to mitochondrial membranes, primarily associated with mitochondrial respiratory function and membrane structure. These discoveries highlight the profound impact of plasmalogens on the structural integrity of mitochondria, shedding light on their pivotal role in cellular health. Furthermore, our screening for disease-associated genes and variants revealed significant (more than 60% of enriched proteins) connections with conditions such as Diabetic cardiomyopathy and neurodegenerative diseases.

Our comprehensive study not only deepens our understanding of the intricate crosstalk between peroxisomes and mitochondria-mediated by plasmalogens but also unveils their involvement in metabolic pathways and diseases. These insights pave the way for potential therapeutic strategies aimed at preserving cellular health and combating age-related health issues.