Plasmalogen Biosynthesis Controls Mitochondrial Fission via Drp1 Recruitment during Aging

Mitochondrial dynamics, governed by balanced fission and fusion events, are critical for cellular homeostasis; however, this process becomes dysregulated during aging. The upstream molecular cues driving this dysfunction remain poorly defined. Here, using Drosophila oenocytes we identify plasmalogens—endogenous ether-linked phospholipids—as key regulators of age-associated mitochondrial fission in Drosophila melanogaster. Loss of Kua (also known as PEDS/TMEM189), the enzyme essential for plasmalogen biosynthesis, leads to inhibition of mitochondrial fission and impaired recruitment of the fission protein Drp1, similar to what is observed during aging. Using biochemical and imaging approaches, we demonstrate that plasmalogens are required for Drp1 localization and proper fission machinery function. Our findings reveal a previously unrecognized lipid-based mechanism that controls mitochondrial fission during aging and position plasmalogens as key effectors linking membrane composition to mitochondrial homeostasis.