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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,6,23]]},"abstract":"<jats:p>\n                    Mitochondrial endonuclease G (EndoG) is involved in several important cellular processes and has been implicated in multiple diseases. Accordingly, molecules modulating EndoG activity may have high therapeutic potentials. Searching for compounds affecting paternal mitochondrial elimination (PME) in\n                    <jats:italic toggle=\"yes\">\n                      <jats:italic toggle=\"yes\">Caenorhabditis elegans<\/jats:italic>\n                    <\/jats:italic>\n                    , we have identified resveratrol (RSV), a well-known natural compound, as a PME inhibitor. Interestingly, RSV exists as a mixture of\n                    <jats:italic toggle=\"yes\">trans<\/jats:italic>\n                    - and\n                    <jats:italic toggle=\"yes\">cis<\/jats:italic>\n                    -isomers, which interconvert upon light exposure and, surprisingly, exhibit opposing effects on PME by targeting nematode EndoG. Biochemically,\n                    <jats:italic toggle=\"yes\">trans<\/jats:italic>\n                    -RSV enhances and\n                    <jats:italic toggle=\"yes\">cis<\/jats:italic>\n                    -RSV inhibits endonuclease activity of EndoG through direct binding to EndoG. In cellular thermal shift assays,\n                    <jats:italic toggle=\"yes\">trans<\/jats:italic>\n                    -RSV stabilizes and\n                    <jats:italic toggle=\"yes\">cis<\/jats:italic>\n                    -RSV destabilizes nematode EndoG in vivo, indicating direct physical interactions between RSV isomers and EndoG. Structurally, two\n                    <jats:italic toggle=\"yes\">cis<\/jats:italic>\n                    -RSVs bind to the His-Me finger DNA-binding motifs of the EndoG dimer, obstructing its access to DNA substrates. In contrast,\n                    <jats:italic toggle=\"yes\">trans<\/jats:italic>\n                    -RSV binds to the EndoG dimeric interface to stabilize the EndoG dimer. Functionally,\n                    <jats:italic toggle=\"yes\">trans<\/jats:italic>\n                    -RSV enhances and\n                    <jats:italic toggle=\"yes\">cis<\/jats:italic>\n                    -RSV inhibits dopaminergic (DA) neuronal loss induced by \u03b1-synuclein, consistent with an important role for EndoG in \u03b1-synuclein-induced Parkinsonism. In a mouse model of Parkinson\u2019s disease,\n                    <jats:italic toggle=\"yes\">cis<\/jats:italic>\n                    -RSV treatment inhibited DA neurodegeneration in the substantia nigra and improved motor symptoms of animals. Our study demonstrates unexpected, opposing effects of RSV isomers on EndoG in regulating its nuclease activity and associated biological processes, which could complicate RSV applications and cause unanticipated toxicity and side effects. However, when used properly, RSV isomers hold promise as targeted therapies for EndoG-associated human diseases, including PME-related disorders and neurodegeneration.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2534340123","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T19:02:12Z","timestamp":1781550132000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Resveratrol isomers with opposing activities target endonuclease G to modulate neurodegeneration and mitochondrial elimination"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4526-6059","authenticated-orcid":false,"given":"Jason L. 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