Modulating Ubiquinone Biosynthesis Rescues Mitochondrial Dysfunction by Genetic Interaction in a Phosphatidylethanolamine (PE)-Deficient Disease Model

Mitochondrial dysfunctions are often associated with cellular aging as well as metabolic disorders. Therapeutic strategies for rewiring mitochondrial stress signaling in a disease context could be beneficial. New evidence indicates that mitochondrial membrane lipids actively regulate mitochondrial signaling pathways that influence cellular health, stress responses, and longevity. Phosphatidylethanolamine (PE), the non-bilayer-forming phospholipid, plays major roles in mitochondrial morphology and ETC function. The biosynthesis of PE takes place within the inner mitochondrial membrane and is catalyzed by the enzyme phosphatidylserine decarboxylase-1 (PSD-1), which converts phosphatidylserine (PS) to PE. While the biochemical role of PSD-1 in PE biosynthesis is well established, how its dysfunction translates into mitochondrial pathology remains poorly understood. In this work, we describe the physiological implications of PSD-1 function and validate a novel disease model for human PISD (the ortholog of C. elegans psd-1) by undertaking targeted gene knockdown using RNA interference (RNAi) in Caenorhabditis elegans. We show that psd-1 deficiency causes several physiological defects in C. elegans, demonstrating that PE biosynthesis via PSD-1 is critical for mitochondrial activity and organismal development (mitochondrial PE levels were reduced by 69.51% in psd-1 knockdown worms compared to controls). These findings establish psd-1 knockdown worms as a reliable model for studying human PISD-related disease. Surprisingly, co-knockdown of psd-1 along with the ETC component clk-1 rescued physiological defects such as restoring the lifespan of from 13.48 ± 0.51 days psd-1 RNAi worms to 17.36 ± 0.44 days in psd-1; clk-1 double-knockdown worms and normalizing oxygen consumption rate, suggesting that ETC-mediated retrograde signaling, rather than phospholipid depletion alone, is the primary driver of the observed pathology.