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The dynamin\u2010related GTPase Optic Atrophy 1 (OPA1) is essential for inner mitochondrial membrane fusion and cristae structure maintenance. While post\u2010translational modifications, particularly lysine acetylation, are emerging as critical regulators of mitochondrial protein function, their impact on OPA1 remains poorly characterized. In this study, we explored the effects of lysine acetylation on the short form of OPA1 (s\u2010OPA1) using acetylation and deacetylation mimetic mutations. Through a combination of in silico analyses and functional assays, we identified lysine residues in s\u2010OPA1 that are conserved across species and significantly influence protein stability, GTPase activity, and oligomeric assembly upon acetylation or deacetylation. Our findings reveal that acetylation at K328 and deacetylation at K342 within the G domain enhance the GTPase activity of s\u2010OPA1 upon lipid membrane binding, whereas deacetylation at K772 abolishes membrane binding\u2010induced GTPase activity. Negative\u2010stain transmission electron microscopy indicated that while lysine acetylation does not alter the ability of s\u2010OPA1 to bind and tubulate liposomes, it significantly impacts higher\u2010order filament formation. These findings provide novel insights into how acetylation modulates s\u2010OPA1 function, highlighting a potential mechanism for post\u2010translational regulation of mitochondrial dynamics. Our study contributes to the understanding of how molecular changes influence broader cellular processes, with implications for mitochondrial function and related disorders.<\/jats:p>","DOI":"10.1002\/pro.70179","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T08:04:58Z","timestamp":1748505898000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Lysine acetylation modulates s\u2010<scp>OPA1 GTPase<\/scp> activity and oligomerization in mitochondrial membrane remodeling"],"prefix":"10.1002","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8217-3412","authenticated-orcid":false,"given":"Javaid","family":"Jabbar","sequence":"first","affiliation":[{"name":"Department of Biochemistry &amp; Pharmacology Bio21 Molecular Science and Biotechnology Institute, University of Melbourne  Parkville Victoria Australia"},{"name":"ARC Centre for Cryo\u2010electron Microscopy of Membrane Proteins  Parkville Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bakht","family":"Afroze","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Pharmacology Bio21 Molecular Science and Biotechnology Institute, University of Melbourne  Parkville Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi X. 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