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In this study, we explored whether mitochondrial transfer is influenced by genetic and environmental factors and whether dysfunction in this process is one of the mechanisms of the pathogenic\n                      <jats:italic>LRRK2<\/jats:italic>\n                      G2019S mutation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      DA neurons and astrocytes were differentiated from induced pluripotent stem cells generated from the peripheral blood of a healthy individual and a PD patient carrying the\n                      <jats:italic>LRRK2<\/jats:italic>\n                      G2019S mutation. A coculture system of astrocytes and DA neurons was established to explore the pathogenic mechanisms of\n                      <jats:italic>LRRK2<\/jats:italic>\n                      G2019S.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Exposure to the environmental toxin rotenone impaired mitochondrial transfer from astrocytes to DA\u00a0neurons. Compared with the co-culture system from the healthy participant, the co-culture system harboring the\n                      <jats:italic>LRRK2<\/jats:italic>\n                      G2019S mutation experienced more pronounced damage. Specifically, STX17 was colocalized with the mitochondrial outer membrane marker TOM20, and its knockdown caused damage to mitochondrial transfer. Drp1 interacted with STX17.\n                      <jats:italic>LRRK2<\/jats:italic>\n                      G2019S-mutant astrocytes exhibited markedly increased phosphorylation of Drp1 at Ser616 upon rotenone exposure. Moreover, the degree of colocalization of STX17 with TOM20 decreased. The Drp1 phosphorylation inhibitor DUSP6 restored the colocalization of STX17 and TOM20, as well as the\u00a0mitochondrial transfer efficiency and neuronal survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The impairment of mitochondrial transfer is a potential pathogenic mechanism associated with\n                      <jats:italic>LRRK2<\/jats:italic>\n                      G2019S mutation. The molecular mechanisms of mitochondrial transfer were observed to occur through a Drp1-STX17-dependent pathway. Notably, inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through mitigating mitochondrial transfer impairments. This study provides novel insights into the pathogenesis of PD and the development of new therapeutic targets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s40035-025-00525-1","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T03:11:51Z","timestamp":1765163511000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["LRRK2 G2019S mutation contributes to mitochondrial transfer dysfunction in a Drp1-STX17-dependent manner"],"prefix":"10.1186","volume":"14","author":[{"given":"Mei","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan-Lan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Wan","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Yi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Xia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Ru","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Jie","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Kang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8364-0219","authenticated-orcid":false,"given":"Chun-Feng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yu","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"issue":"6","key":"525_CR1","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1007\/s11910-024-01339-w","volume":"24","author":"JR Deliz","year":"2024","unstructured":"Deliz JR, Tanner CM, Gonzalez-Latapi P. 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