The mystery of phospho-Drp1 with four adaptors in cell cycle: when mitochondrial fission couples to cell fate decisions

ABSTRACTRecent study had deepened our knowledge of the mitochondrial dynamics to classify mitochondrial fission into two types. To further clarify the relationship between the two distinct fission machinery and the four major adaptors of Drp1, we propose a model of mechanism elucidating the multiple functions of phospho-Drp1 with its adaptors during cell cycle and providing in-depth insights into the molecular basis and evolutionary implications in depth. The model highlights not only the clustering characteristics of different phospho-Drp1 with respective subsets of mitochondrial pro-fission adaptors but also the correlation, crosstalk and shifting between different clustering of phosphorylated Drp1-adaptors during different key fission situations. Particularly, phospho-Drp1 (Ser616) couples with Mff/MiD51 to exert mitochondrial division and phospho-Drp1 (Ser637) couples with MiD49/Fis1 to execute mitophagy in M-phase. We then apply the model to address the relationship of mitochondrial dynamics to Parkinson’s disease (PD) and carcinogenesis. Our proposed model is indeed compatible with current research results and pathological observations, providing promising directions for future treatment design.KEYWORDS: Drp1phosphorylationMitochondrial Adaptorsmitophagycell cycle Disclosure statementNo potential conflict of interest was reported by the author(s).Data availability statementAll data generated or analyzed in this study are included in this published article.Author contributionConceptualization: Nian-Siou Wu, I-Chu Ma, Yi-Fan Lin; Writing – original draft: Nian-Siou Wu, I-Chu Ma, Yi-Fan Lin; Methodology and Investigation: Huey-Jiun Ko, Yi-Ren Hong; Project Administration: Yi-Ren Hong, Joon-Khim Loh; Writing – review & editing: Yi-Ren Hong, Joon-Khim Loh.Supplementary materialSupplemental data for this article can be accessed online at https://doi.org/10.1080/15384101.2023.2289753Additional informationFundingThis work was supported by the National Science and Technology Council (NSTC), Taiwan, 110-2320-B-037-029, 111-2320-B-037–028, 112-2622-B-037-002 (awarded to YRH), 112-2314-B-037-107 (awarded to JKL); NSYSU-KMU Joint Research Project, Taiwan NSYSUKMU110-P009 (awarded to YRH); Kaohsiung Medical University Grant No. KMU-DK(A)112007 (awarded to YRH).