Specific patterns of mitochondrial dynamics have been repeatedly reported to promote drug resistance in cancer. However, whether targeting mitochondrial fission- and fusion-related proteins could be leveraged to combat multidrug-resistant pediatric sarcomas is poorly understood. Here, we demonstrated that the expression and activation of the mitochondrial fission mediator DRP1 are affected by chemotherapy exposure in common pediatric sarcomas, namely, rhabdomyosarcoma and osteosarcoma. Unexpectedly, decreasing DRP1 activity through stable DRP1 knockdown neither attenuated sarcoma drug resistance nor affected growth rate or mitochondrial network morphology. The minimal impact on sarcoma cell physiology, along with the up-regulation of fission adaptor proteins (MFF and FIS1) detected in rhabdomyosarcoma cells, suggests an alternative DRP1-independent mitochondrial fission mechanism that may efficiently compensate for the lack of DRP1 activity. By exploring the upstream mitophagy and mitochondrial fission regulator, AMPKα1, we found that markedly reduced AMPKα1 levels are sufficient to maintain AMPK signaling capacity without affecting chemosensitivity. Collectively, our findings challenge the direct involvement of DRP1 in pediatric sarcoma drug resistance and highlight the complexity of yet-to-be-characterized noncanonical regulators of mitochondrial dynamics.

Department of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Zobrazit více v PubMed

Siegel DA, King JB, Lupo PJ, Durbin EB, Tai ER, Mills K, Van Dyne E, Buchanan Lunsford N, Henley SJ, Wilson RJ (2023) Counts, incidence rates, and trends of pediatric cancer in the United States, 2003-2019. J Natl Cancer Inst 115: 1337–1354. 10.1093/jnci/djad115 PubMed DOI PMC

Goedhart LM, Ho VKY, Ploegmakers JJW, van der Geest ICM, van de Sande MAJ, Bramer JA, Stevens M, Jutte PC (2023) Bone sarcoma follow-up; a nationwide analysis of oncological events after initial treatment. J Bone Oncol 38: 100466. 10.1016/j.jbo.2022.100466 PubMed DOI PMC

Zhu L, Sun Y, Wang X, Wang L, Zhang S, Meng Q, Wang X (2020) Survival stratification in childhood rhabdomyosarcoma of the extremities: A derivation and validation study. Sci Rep 10: 5684. 10.1038/s41598-020-62656-x PubMed DOI PMC

Yang L, Takimoto T, Fujimoto J (2014) Prognostic model for predicting overall survival in children and adolescents with rhabdomyosarcoma. BMC Cancer 14: 654. 10.1186/1471-2407-14-654 PubMed DOI PMC

Jin P, Jiang J, Zhou L, Huang Z, Nice EC, Huang C, Fu L (2022) Mitochondrial adaptation in cancer drug resistance: Prevalence, mechanisms, and management. J Hematol Oncol 15: 97. 10.1186/s13045-022-01313-4 PubMed DOI PMC

Mukherjee S, Bhatti GK, Chhabra R, Reddy PH, Bhatti JS (2023) Targeting mitochondria as a potential therapeutic strategy against chemoresistance in cancer. Biomed Pharmacother 160: 114398. 10.1016/j.biopha.2023.114398 PubMed DOI

Chen W, Zhao H, Li Y (2023) Mitochondrial dynamics in health and disease: Mechanisms and potential targets. Signal Transduct Target Ther 8: 333. 10.1038/s41392-023-01547-9 PubMed DOI PMC

Kashatus JA, Nascimento A, Myers LJ, Sher A, Byrne FL, Hoehn KL, Counter CM, Kashatus DF (2015) Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell 57: 537–551. 10.1016/j.molcel.2015.01.002 PubMed DOI PMC

Han Y, Kim B, Cho U, Park IS, Kim SI, Dhanasekaran DN, Tsang BK, Song YS (2019) Mitochondrial fission causes cisplatin resistance under hypoxic conditions via ROS in ovarian cancer cells. Oncogene 38: 7089–7105. 10.1038/s41388-019-0949-5 PubMed DOI

Li M, Wang L, Wang Y, Zhang S, Zhou G, Lieshout R, Ma B, Liu J, Qu C, Verstegen MMA, et al. (2020) Mitochondrial fusion via OPA1 and MFN1 supports liver tumor cell metabolism and growth. Cells 9: 121. 10.3390/cells9010121 PubMed DOI PMC

Yu L, Xiao Z, Tu H, Tong B, Chen S (2019) The expression and prognostic significance of Drp1 in lung cancer: A bioinformatics analysis and immunohistochemistry. Medicine (Baltimore) 98: e18228. 10.1097/md.0000000000018228 PubMed DOI PMC

Fang HY, Chen CY, Chiou SH, Wang YT, Lin TY, Chang HW, Chiang IP, Lan KJ, Chow KC (2012) Overexpression of optic atrophy 1 protein increases cisplatin resistance via inactivation of caspase-dependent apoptosis in lung adenocarcinoma cells. Hum Pathol 43: 105–114. 10.1016/j.humpath.2011.04.012 PubMed DOI

Liu B, Fan Y, Song Z, Han B, Meng Y, Cao P, Tan K (2020) Identification of DRP1 as a prognostic factor correlated with immune infiltration in breast cancer. Int Immunopharmacol 89: 107078. 10.1016/j.intimp.2020.107078 PubMed DOI

Zhang L, Zhang X, Liu H, Yang C, Yu J, Zhao W, Guo J, Zhou B, Jiang N (2024) MTFR2-dependent mitochondrial fission promotes HCC progression. J Transl Med 22: 73. 10.1186/s12967-023-04845-6 PubMed DOI PMC

Tian GA, Xu WT, Zhang XL, Zhou YQ, Sun Y, Hu LP, Jiang SH, Nie HZ, Zhang ZG, Zhu L, et al. (2023) CCBE1 promotes mitochondrial fusion by inhibiting the TGFβ-DRP1 axis to prevent the progression of hepatocellular carcinoma. Matrix Biol 117: 31–45. 10.1016/j.matbio.2023.02.007 PubMed DOI

Ashraf R, Kumar S (2022) Mfn2-mediated mitochondrial fusion promotes autophagy and suppresses ovarian cancer progression by reducing ROS through AMPK/mTOR/ERK signaling. Cell Mol Life Sci 79: 573. 10.1007/s00018-022-04595-6 PubMed DOI PMC

Xie L, Shi F, Li Y, Li W, Yu X, Zhao L, Zhou M, Hu J, Luo X, Tang M, et al. (2020) Drp1-dependent remodeling of mitochondrial morphology triggered by EBV-LMP1 increases cisplatin resistance. Signal Transduct Target Ther 5: 56. 10.1038/s41392-020-0151-9 PubMed DOI PMC

Xie Q, Wu Q, Horbinski CM, Flavahan WA, Yang K, Zhou W, Dombrowski SM, Huang Z, Fang X, Shi Y, et al. (2015) Mitochondrial control by DRP1 in brain tumor initiating cells. Nat Neurosci 18: 501–510. 10.1038/nn.3960 PubMed DOI PMC

Civenni G, Bosotti R, Timpanaro A, Vazquez R, Merulla J, Pandit S, Rossi S, Albino D, Allegrini S, Mitra A, et al. (2019) Epigenetic control of mitochondrial fission enables self-renewal of stem-like tumor cells in human prostate cancer. Cell Metab 30: 303–318.e6. 10.1016/j.cmet.2019.05.004 PubMed DOI

Tang M, Yang M, Wu G, Mo S, Wu X, Zhang S, Yu R, Hu Y, Xu Y, Li Z, et al. (2021) Epigenetic induction of mitochondrial fission is required for maintenance of liver cancer-initiating cells. Cancer Res 81: 3835–3848. 10.1158/0008-5472.can-21-0436 PubMed DOI

Liu D, Sun Z, Ye T, Li J, Zeng B, Zhao Q, Wang J, Xing HR (2021) The mitochondrial fission factor FIS1 promotes stemness of human lung cancer stem cells via mitophagy. FEBS Open Bio 11: 1997–2007. 10.1002/2211-5463.13207 PubMed DOI PMC

Pei S, Minhajuddin M, Adane B, Khan N, Stevens BM, Mack SC, Lai S, Rich JN, Inguva A, Shannon KM, et al. (2018) AMPK/FIS1-Mediated mitophagy is required for self-renewal of human AML stem cells. Cell Stem Cell 23: 86–100.e6. 10.1016/j.stem.2018.05.021 PubMed DOI PMC

Liu K, Lee J, Kim JY, Wang L, Tian Y, Chan ST, Cho C, Machida K, Chen D, Ou JJ (2017) Mitophagy controls the activities of tumor suppressor p53 to regulate hepatic cancer stem cells. Mol Cell 68: 281–292.e5. 10.1016/j.molcel.2017.09.022 PubMed DOI PMC

Fan S, Chen WX, Lv XB, Tang QL, Sun LJ, Liu BD, Zhong JL, Lin ZY, Wang YY, Li QX, et al. (2015) miR-483-5p determines mitochondrial fission and cisplatin sensitivity in tongue squamous cell carcinoma by targeting FIS1. Cancer Lett 362: 183–191. 10.1016/j.canlet.2015.03.045 PubMed DOI

Li X, Wu Q, Ma F, Zhang X, Cai L, Yang X (2022) Mitochondrial fission factor promotes cisplatin resistancein hepatocellular carcinoma. Acta Biochim Biophys Sin (Shanghai) 54: 301–310. 10.3724/abbs.2022007 PubMed DOI PMC

Seo JH, Agarwal E, Chae YC, Lee YG, Garlick DS, Storaci AM, Ferrero S, Gaudioso G, Gianelli U, Vaira V, et al. (2019) Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer. EBioMedicine 48: 353–363. 10.1016/j.ebiom.2019.09.017 PubMed DOI PMC

Romani P, Nirchio N, Arboit M, Barbieri V, Tosi A, Michielin F, Shibuya S, Benoist T, Wu D, Hindmarch CCT, et al. (2022) Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance. Nat Cell Biol 24: 168–180. 10.1038/s41556-022-00843-w PubMed DOI PMC

Zou GP, Yu CX, Shi SL, Li QG, Wang XH, Qu XH, Yang ZJ, Yao WR, Yan DD, Jiang LP, et al. (2021) Mitochondrial dynamics mediated by DRP1 and MFN2 contributes to cisplatin chemoresistance in human ovarian cancer SKOV3 cells. J Cancer 12: 7358–7373. 10.7150/jca.61379 PubMed DOI PMC

Wang WJ, Lai HY, Zhang F, Shen WJ, Chu PY, Liang HY, Liu YB, Wang JM (2021) MCL1 participates in leptin-promoted mitochondrial fusion and contributes to drug resistance in gallbladder cancer. JCI Insight 6: e135438. 10.1172/jci.insight.135438 PubMed DOI PMC

Noguchi M, Kohno S, Pellattiero A, Machida Y, Shibata K, Shintani N, Kohno T, Gotoh N, Takahashi C, Hirao A, et al. (2023) Inhibition of the mitochondria-shaping protein Opa1 restores sensitivity to Gefitinib in a lung adenocarcinomaresistant cell line. Cell Death Dis 14: 241. 10.1038/s41419-023-05768-2 PubMed DOI PMC

Hou D, Zheng X, Cai D, You R, Liu J, Wang X, Liao X, Tan M, Lin L, Wang J, et al. (2023) Interleukin-6 facilitates acute myeloid leukemia chemoresistance via mitofusin 1-mediated mitochondrial fusion. Mol Cancer Res 21: 1366–1378. 10.1158/1541-7786.mcr-23-0382 PubMed DOI

Decker CW, Garcia J, Gatchalian K, Arceneaux D, Choi C, Han D, Hernandez JB (2020) Mitofusin-2 mediates doxorubicin sensitivity and acute resistance in Jurkat leukemia cells. Biochem Biophys Rep 24: 100824. 10.1016/j.bbrep.2020.100824 PubMed DOI PMC

Yan C, Luo L, Guo CY, Goto S, Urata Y, Shao JH, Li TS (2017) Doxorubicin-induced mitophagy contributes to drug resistance in cancer stem cells from HCT8 human colorectal cancer cells. Cancer Lett 388: 34–42. 10.1016/j.canlet.2016.11.018 PubMed DOI

Wang H, Liang Y, Zhang T, Yu X, Song X, Chen Y, Mao Q, Xia W, Chen B, Xu L, et al. (2023) C-IGF1R encoded by cIGF1R acts as a molecular switch to restrict mitophagy of drug-tolerant persister tumour cells in non-small cell lung cancer. Cell Death Differ 30: 2365–2381. 10.1038/s41418-023-01222-0 PubMed DOI PMC

Xie XQ, Yang Y, Wang Q, Liu HF, Fang XY, Li CL, Jiang YZ, Wang S, Zhao HY, Miao JY, et al. (2023) Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria. Cell Res 33: 215–228. 10.1038/s41422-022-00766-z PubMed DOI PMC

Zhou J, Li G, Zheng Y, Shen HM, Hu X, Ming QL, Huang C, Li P, Gao N (2015) A novel autophagy/mitophagy inhibitor liensinine sensitizes breast cancer cells to chemotherapy through DNM1L-mediated mitochondrial fission. Autophagy 11: 1259–1279. 10.1080/15548627.2015.1056970 PubMed DOI PMC

Quintana-Cabrera R, Scorrano L (2023) Determinants and outcomes of mitochondrial dynamics. Mol Cell 83: 857–876. 10.1016/j.molcel.2023.02.012 PubMed DOI

Williamson D, Missiaglia E, de Reyniès A, Pierron G, Thuille B, Palenzuela G, Thway K, Orbach D, Laé M, Fréneaux P, et al. (2010) Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol 28: 2151–2158. 10.1200/JCO.2009.26.3814 PubMed DOI

Kuijjer M, Rydbeck H, Kresse S, Buddingh E, Lid A, Roelofs H, Bürger H, Myklebost O, Hogendoorn P, Meza-Zepeda L, et al. (2012) Identification of osteosarcoma driver genes by integrative analysis of copy number and gene expression data. Genes Chromosomes Cancer 51: 696–706. 10.1002/gcc.21956 PubMed DOI

Kraus F, Roy K, Pucadyil TJ, Ryan MT (2021) Function and regulation of the divisome for mitochondrial fission. Nature 590: 57–66. 10.1038/s41586-021-03214-x PubMed DOI

Tong M, Zablocki D, Sadoshima J (2020) The role of Drp1 in mitophagy and cell death in the heart. J Mol Cell Cardiol 142: 138–145. 10.1016/j.yjmcc.2020.04.015 PubMed DOI PMC

Pápai Z, Bodoky G, Szántó J, Poller I, Rahóty P, Eckhardt S, Láng I, Szendröi M (2000) The efficacy of a combination of etoposide, ifosfamide, and cisplatin in the treatment of patients with soft tissue sarcoma. Cancer 89: 177–180. 10.1002/1097-0142(20000701)89:1<177::aid-cncr23>3.3.co;2-v PubMed DOI

Isakoff MS, Bielack SS, Meltzer P, Gorlick R (2015) Osteosarcoma: Current treatment and a collaborative pathway to success. J Clin Oncol 33: 3029–3035. 10.1200/jco.2014.59.4895 PubMed DOI PMC

Bisogno G, Ferrari A, Bergeron C, Scagnellato A, Prete A, Alaggio R, Casanova M, D’Angelo P, Di Cataldo A, Carli M (2005) The IVADo regimen-a pilot study with ifosfamide, vincristine, actinomycin D, and doxorubicin in children with metastatic soft tissue sarcoma: A pilot study of behalf of the European pediatric soft tissue sarcoma study group. Cancer 103: 1719–1724. 10.1002/cncr.20928 PubMed DOI

Seibel NL, Krailo M, Chen Z, Healey J, Breitfeld PP, Drachtman R, Greffe B, Nachman J, Nadel H, Sato JK, et al. (2007) Upfront window trial of topotecan in previously untreated children and adolescents with poor prognosis metastatic osteosarcoma: Children’s cancer group (CCG) 7943. Cancer 109: 1646–1653. 10.1002/cncr.22553 PubMed DOI

Compostella A, Affinita MC, Casanova M, Milano GM, Scagnellato A, Dall’Igna P, Chiaravalli S, Pierobon M, Manzitti C, Zanetti I, et al. (2019) Topotecan/carboplatin regimen for refractory/recurrent rhabdomyosarcoma in children: Report from the AIEOP Soft Tissue Sarcoma Committee. Tumori 105: 138–143. 10.1177/0300891618792479 PubMed DOI

Defachelles AS, Bogart E, Casanova M, Merks JHM, Bisogno G, Calareso G, Gallego Melcon S, Gatz SA, Le Deley MC, McHugh K, et al. (2021) Randomized phase II trial of vincristine-irinotecan with or without temozolomide, in children and adults with relapsed or refractory rhabdomyosarcoma: A European paediatric soft tissue sarcoma study group and innovative therapies for children with cancer trial. J Clin Oncol 39: 2979–2990. 10.1200/jco.21.00124 PubMed DOI

Herzig S, Shaw RJ (2018) AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19: 121–135. 10.1038/nrm.2017.95 PubMed DOI PMC

Abdrakhmanov A, Kulikov AV, Luchkina EA, Zhivotovsky B, Gogvadze V (2019) Involvement of mitophagy in cisplatin-induced cell death regulation. Biol Chem 400: 161–170. 10.1515/hsz-2018-0210 PubMed DOI

Lin Q, Li S, Jin H, Cai H, Zhu X, Yang Y, Wu J, Qi C, Shao X, Li J, et al. (2023) Mitophagy alleviates cisplatin-induced renal tubular epithelial cell ferroptosis through ROS/HO-1/GPX4 axis. Int J Biol Sci 19: 1192–1210. 10.7150/ijbs.80775 PubMed DOI PMC

Park JM, Jung CH, Seo M, Otto NM, Grunwald D, Kim KH, Moriarity B, Kim YM, Starker C, Nho RS, et al. (2016) The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14. Autophagy 12: 547–564. 10.1080/15548627.2016.1140293 PubMed DOI PMC

Rivera-Mejías P, Narbona-Pérez AJ, Hasberg L, Kroczek L, Bahat A, Lawo S, Folz-Donahue K, Schumacher AL, Ahola S, Mayer FC, et al. (2023) The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage. Cell Rep 42: 112332. 10.1016/j.celrep.2023.112332 PubMed DOI

Yu R, Jin SB, Lendahl U, Nistér M, Zhao J (2019) Human Fis1 regulates mitochondrial dynamics through inhibition of the fusion machinery. EMBO J 38: e99748. 10.15252/embj.201899748 PubMed DOI PMC

Vara-Ciruelos D, Dandapani M, Hardie DG (2020) AMP-activated protein kinase: Friend or foe in cancer? Annu Rev Cancer Biol 4: 1–16. 10.1146/annurev-cancerbio-030419-033619 DOI

Monteverde T, Muthalagu N, Port J, Murphy DJ (2015) Evidence of cancer-promoting roles for AMPK and related kinases. FEBS J 282: 4658–4671. 10.1111/febs.13534 PubMed DOI

Vara-Ciruelos D, Dandapani M, Gray A, Egbani EO, Evans AM, Hardie DG (2018) Genotoxic damage activates the AMPK-α1 isoform in the nucleus via Ca2+/CaMKK2 signaling to enhance tumor cell survival. Mol Cancer Res 16: 345–357. 10.1158/1541-7786.mcr-17-0323 PubMed DOI

Cheratta AR, Thayyullathil F, Hawley SA, Ross FA, Atrih A, Lamont DJ, Pallichankandy S, Subburayan K, Alakkal A, Rezgui R, et al. (2022) Caspase cleavage and nuclear retention of the energy sensor AMPK-⍺1 during apoptosis. Cell Rep 39: 110761. 10.1016/j.celrep.2022.110761 PubMed DOI PMC

Chen L, Zhang J, Lyu Z, Chen Y, Ji X, Cao H, Jin M, Zhu J, Yang J, Ling R, et al. (2018) Positive feedback loop between mitochondrial fission and Notch signaling promotes survivin-mediated survival of TNBC cells. Cell Death Dis 9: 1050. 10.1038/s41419-018-1083-y PubMed DOI PMC

Lin XH, Qiu BQ, Ma M, Zhang R, Hsu SJ, Liu HH, Chen J, Gao DM, Cui JF, Ren ZG, et al. (2020) Suppressing DRP1-mediated mitochondrial fission and mitophagy increases mitochondrial apoptosis of hepatocellular carcinoma cells in the setting of hypoxia. Oncogenesis 9: 67. 10.1038/s41389-020-00251-5 PubMed DOI PMC

Huang Q, Zhan L, Cao H, Li J, Lyu Y, Guo X, Zhang J, Ji L, Ren T, An J, et al. (2016) Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy 12: 999–1014. 10.1080/15548627.2016.1166318 PubMed DOI PMC

Fan S, Liu B, Sun L, Lv XB, Lin Z, Chen W, Chen W, Tang Q, Wang Y, Su Y, et al. (2015) Mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma through the BRCA1-miR-593-5p-MFF axis. Oncotarget 6: 14885–14904. 10.18632/oncotarget.3659 PubMed DOI PMC

Soares CD, Morais TML, Carlos R, de Almeida OP, Mariano FV, Altemani A, de Carvalho MGF, Corrêa MB, dos Reis RRD, Amorim LS, et al. (2019) Prognostic importance of mitochondrial markers in mucosal and cutaneous head and neck melanomas. Hum Pathol 85: 279–289. 10.1016/j.humpath.2018.11.009 PubMed DOI

Baek ML, Lee J, Pendleton KE, Berner MJ, Goff EB, Tan L, Martinez SA, Mahmud I, Wang T, Meyer MD, et al. (2023) Mitochondrial structure and function adaptation in residual triple negative breast cancer cells surviving chemotherapy treatment. Oncogene 42: 1117–1131. 10.1038/s41388-023-02596-8 PubMed DOI PMC

Ding M, Shi R, Cheng S, Li M, De D, Liu C, Gu X, Li J, Zhang S, Jia M, et al. (2022) Mfn2-mediated mitochondrial fusion alleviates doxorubicin-induced cardiotoxicity with enhancing its anticancer activity through metabolic switch. Redox Biol 52: 102311. 10.1016/j.redox.2022.102311 PubMed DOI PMC

Serasinghe MN, Wieder SY, Renault TT, Elkholi R, Asciolla JJ, Yao JL, Jabado O, Hoehn K, Kageyama Y, Sesaki H, et al. (2015) Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Mol Cell 57: 521–536. 10.1016/j.molcel.2015.01.003 PubMed DOI PMC

Ma R, Ma L, Weng W, Wang Y, Liu H, Guo R, Gao Y, Tu J, Xu TL, Cheng J, et al. (2020) DUSP6 SUMOylation protects cells from oxidative damage via direct regulation of Drp1 dephosphorylation. Sci Adv 6: eaaz0361. 10.1126/sciadv.aaz0361 PubMed DOI PMC

Huang J, Xie P, Dong Y, An W (2021) Inhibition of Drp1 SUMOylation by ALR protects the liver from ischemia-reperfusion injury. Cell Death Differ 28: 1174–1192. 10.1038/s41418-020-00641-7 PubMed DOI PMC

Karbowski M, Neutzner A, Youle RJ (2007) The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division. J Cell Biol 178: 71–84. 10.1083/jcb.200611064 PubMed DOI PMC

Valera-Alberni M, Joffraud M, Miro-Blanch J, Capellades J, Junza A, Dayon L, Núñez Galindo A, Sanchez-Garcia JL, Valsesia A, Cercillieux A, et al. (2021) Crosstalk between Drp1 phosphorylation sites during mitochondrial remodeling and their impact on metabolic adaptation. Cell Rep 36: 109565. 10.1016/j.celrep.2021.109565 PubMed DOI PMC

Chang CR, Blackstone C (2007) Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem 282: 21583–21587. 10.1074/jbc.C700083200 PubMed DOI

Yu R, Liu T, Ning C, Tan F, Jin S, Lendahl U, Zhao J, Nistér M (2019) The phosphorylation status of Ser-637 in dynamin-related protein 1 (Drp1) does not determine Drp1 recruitment to mitochondria. J Biol Chem 294: 17262–17277. 10.1074/jbc.RA119.008202 PubMed DOI PMC

Kalia R, Wang R, Yusuf A, Thomas P, Agard D, Shaw J, Frost A (2018) Structural basis of mitochondrial receptor binding and constriction by DRP1. Nature 558: 401–405. 10.1038/s41586-018-0211-2 PubMed DOI PMC

Milani M, Beckett AJ, Al-Zebeeby A, Luo X, Prior IA, Cohen GM, Varadarajan S (2019) DRP-1 functions independently of mitochondrial structural perturbations to facilitate BH3 mimetic-mediated apoptosis. Cell Death Discov 5: 117. 10.1038/s41420-019-0199-x PubMed DOI PMC

Kim DI, Lee KH, Gabr AA, Choi GE, Kim JS, Ko SH, Han HJ (2016) Aβ-Induced Drp1 phosphorylation through Akt activation promotes excessive mitochondrial fission leading to neuronal apoptosis. Biochim Biophys Acta 1863: 2820–2834. 10.1016/j.bbamcr.2016.09.003 PubMed DOI

Westrate LM, Sayfie AD, Burgenske DM, MacKeigan JP (2014) Persistent mitochondrial hyperfusion promotes G2/M accumulation and caspase-dependent cell death. PLoS One 9: e91911. 10.1371/journal.pone.0091911 PubMed DOI PMC

Tanwar DK, Parker DJ, Gupta P, Spurlock B, Alvarez RD, Basu MK, Mitra K (2016) Crosstalk between the mitochondrial fission protein, Drp1, and the cell cycle is identified across various cancer types and can impact survival of epithelial ovarian cancer patients. Oncotarget 7: 60021–60037. 10.18632/oncotarget.11047 PubMed DOI PMC

Zhou TJ, Zhang SL, He CY, Zhuang QY, Han PY, Jiang SW, Yao H, Huang YJ, Ling WH, Lin YC, et al. (2017) Downregulation of mitochondrial cyclooxygenase-2 inhibits the stemness of nasopharyngeal carcinoma by decreasing the activity of dynamin-related protein 1. Theranostics 7: 1389–1406. 10.7150/thno.17647 PubMed DOI PMC

Yu M, Nguyen ND, Huang Y, Lin D, Fujimoto TN, Molkentine JM, Deorukhkar A, Kang Y, San Lucas FA, Fernandes CJ, et al. (2019) Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer. JCI Insight 5: e126915. 10.1172/jci.insight.126915 PubMed DOI PMC

Fonseca TB, Sánchez-Guerrero A, Milosevic I, Raimundo N (2019) Mitochondrial fission requires DRP1 but not dynamins. Nature 570: E34–E42. 10.1038/s41586-019-1296-y PubMed DOI

Kamerkar SC, Kraus F, Sharpe AJ, Pucadyil TJ, Ryan MT (2018) Dynamin-related protein 1 has membrane constricting and severing abilities sufficient for mitochondrial and peroxisomal fission. Nat Commun 9: 5239. 10.1038/s41467-018-07543-w PubMed DOI PMC

Lee JE, Westrate LM, Wu H, Page C, Voeltz GK (2016) Multiple dynamin family members collaborate to drive mitochondrial division. Nature 540: 139–143. 10.1038/nature20555 PubMed DOI PMC

Young L, Sung J, Stacey G, Masters JR (2010) Detection of Mycoplasma in cell cultures. Nat Protoc 5: 929–934. 10.1038/nprot.2010.43 PubMed DOI

Chaudhry A, Shi R, Luciani DS (2020) A pipeline for multidimensional confocal analysis of mitochondrial morphology, function, and dynamics in pancreatic β-cells. Am J Physiol Endocrinol Metab 318: E87–E101. 10.1152/ajpendo.00457.2019 PubMed DOI PMC