{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:57:26Z","timestamp":1792789046937,"version":"4.5.0"},"reference-count":42,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SRM University-AP","award":["SRMAP\/URG\/GENERAL\/2024-25\/004"],"award-info":[{"award-number":["SRMAP\/URG\/GENERAL\/2024-25\/004"]}],"id":[{"id":"https:\/\/ror.org\/037skf023","id-type":"ROR","asserted-by":"crossref"}]},{"award":["SRMAP\/URG\/GENERAL\/2024-25\/004"],"award-info":[{"award-number":["SRMAP\/URG\/GENERAL\/2024-25\/004"]}],"id":[{"id":"https:\/\/ror.org\/037skf023","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>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 \u00b1 0.51 days psd-1 RNAi worms to 17.36 \u00b1 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.<\/jats:p>","DOI":"10.3390\/antiox15091212","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:03:47Z","timestamp":1789977827000},"page":"1212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modulating Ubiquinone Biosynthesis Rescues Mitochondrial Dysfunction by Genetic Interaction in a Phosphatidylethanolamine (PE)-Deficient Disease Model"],"prefix":"10.3390","volume":"15","author":[{"given":"Lavanya","family":"Vadupu","sequence":"first","affiliation":[{"name":"Mitochondrial Biogenesis Lab, Department of Biological Sciences, School of Engineering and Sciences, SRM University-AP, Amaravati 522240, Andhra Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay Aditya","family":"Mavuduru","sequence":"additional","affiliation":[{"name":"Mitochondrial Biogenesis Lab, Department of Biological Sciences, School of Engineering and Sciences, SRM University-AP, Amaravati 522240, Andhra Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7678-126X","authenticated-orcid":false,"given":"Writoban","family":"Basu Ball","sequence":"additional","affiliation":[{"name":"Mitochondrial Biogenesis Lab, Department of Biological Sciences, School of Engineering and Sciences, SRM University-AP, Amaravati 522240, Andhra Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.cmet.2015.05.013","article-title":"Evolution of Mitochondria as Signaling Organelles","volume":"22","author":"Chandel","year":"2015","journal-title":"Cell Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1186\/s12967-026-07783-1","article-title":"The importance of mitochondria and mitochondrial calcium signaling in health and disease: An updated outlook on inflammation","volume":"24","author":"Morciano","year":"2026","journal-title":"J. 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