Skip to main content

Advertisement

SpringerLink
Log in

Mitochondrial dynamics regulators: implications for therapeutic intervention in cancer

  • Review
  • Published:
Cell Biology and Toxicology Aims and scope Submit manuscript

A Correction to this article was published on 04 March 2022

This article has been updated

Abstract

Regardless of the recent advances in therapeutic developments, cancer is still among the primary causes of death globally, indicating the need for alternative therapeutic strategies. Mitochondria, a dynamic organelle, continuously undergo the fusion and fission processes to meet cell requirements. The balanced fission and fusion processes, referred to as mitochondrial dynamics, coordinate mitochondrial shape, size, number, energy metabolism, cell cycle, mitophagy, and apoptosis. An imbalance between these opposing events alters mitochondrial dynamics, affects the overall mitochondrial shape, and deregulates mitochondrial function. Emerging evidence indicates that alteration of mitochondrial dynamics contributes to various aspects of tumorigenesis and cancer progression. Therefore, targeting the mitochondrial dynamics regulator could be a potential therapeutic approach for cancer treatment. This review will address the role of imbalanced mitochondrial dynamics in mitochondrial dysfunction during cancer progression. We will outline the clinical significance of mitochondrial dynamics regulators in various cancer types with recent updates in cancer stemness and chemoresistance and its therapeutic potential and clinical utility as a predictive biomarker.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Change history

Abbreviations

15D-PGJ2:

15-Deoxy-∆12,14-prostaglandin J2

ADP:

Adenosine diphosphate

Akt:

Protein kinase B or PKB

AMPK:

Adenosine monophosphate-activated protein kinase

ATP:

Adenosine triphosphate

BCL2/BCLXL:

B cell lymphoma2/B cell lymphoma-extra large

BTICs:

Brain tumor-initiating cells

CAMK II:

ca2+/calmodulin-dependent protein kinase II

cAMP:

Cyclic adenosine monophosphate

Cdk-5:

Cyclin-dependent-like kinase 5

CMT2A:

Charcot-Marie-Tooth disease type 2A

COX-2:

Cyclooxygenase-2

CQ:

Chloroquine

CSCs:

Cancer stem cells

DDQ:

Diethyl (3,4-dihydroxyphenethylamino (quinoline-4-yl) methyl phosphonate

Drp1:

Dynamin-related protein 1

EMT:

Epithelial to mesenchymal transition

EPCs:

Endothelial progenitor cells

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinases

ETC:

Electron transport chain

FAO:

Fatty acid oxidation

Fis1:

Mitochondrial fission 1

GTPase:

Guanosine triphosphatase

HCC:

Hepatocellular carcinoma

HIF-1α:

Hypoxia-inducible factor 1

HMGB1:

High mobility group box protein 1

IBM:

Inner boundary membrane

IDH2:

Isocitrate dehydrogenase

IH:

Isorhamnetin

IL-24:

Interleukin 24

IMM:

Inner mitochondrial membrane

IMQ:

Imiquimod

IMS:

Inner membrane space

iPSCs:

Induced pluripotent stem cells

KAP1:

KRAB-associated protein 1

MAM:

Mitochondrial-associated ER membrane

mDivi-1:

Mitochondrial division inhibitor 1

MEFs:

Mouse embryonic fibroblasts

Mff:

Mitochondrial fission factor

Mfn1:

Mitofusin1

Mfn2:

Mitofusin2

MiD49:

Mitochondrial dynamics proteins of 49 kDa

MiD51:

mitochondrial dynamics proteins of 51 kDa

MOAS:

Mitochondria-on-a-string

MSC:

Mesenchymal stem cells

Mst1:

Macrophage stimulating 1

MST1:

Mammalian STE20-like kinase 1

mtDNA:

Mitochondrial DNA

mTORC 1:

Mammalian target for rapamycin complex 1 or mechanistic target for rapamycin complex 1

NAC:

N-Acetylcysteine

NET:

Neutrophil infiltration and neutrophil extracellular traps

NFκB:

Nuclear factor kappa B

NK:

Natural killer

Nrf-1 and 2:

Nuclear respiratory factors 1 and 2

Nrf2:

Nuclear factor erythroid 2-related factor 2

NSC:

Neural stem cells

NSPCs:

Neural stem/progenitor cells

OMM:

Outer mitochondrial membrane

Opa1:

Optic atrophy 1

OxPHOS:

Oxidative phosphorylation

p53:

Tumor antigen p53

PCa:

Prostate cancer

PCNA:

Proliferating cell nuclear antigen

PDAC:

Pancreatic ductal adenocarcinoma

PGC1α:

Peroxisome proliferator-activated receptor γ coactivator-1alpha

Phb1:

Prohibitin 1

PI3K:

Phosphatidylinositol 3-kinases

PIM kinase:

Proto-oncogene serine/threonine-protein kinase

PINK1:

PTEN-induced putative kinase1

PKA:

Protein kinase A

PKCζ:

Protein kinase C zeta

PKM2:

Pyruvate kinase M2

PSCs:

Pluripotent stem cells

PTP:

Permeability transition pores

PYCR1:

Pyrroline-5-carboxylase reductase1

RAGE:

Receptor for the advanced glycation end product

RIN1:

Ras and Rab interactor 1

ROS:

Reactive oxygen species

S6K1:

S6 kinase 1

SIK2:

Salt inducible kinase 2

SIRT1:

Sirtuin 1

Smad2:

Mothers against decapentaplegic homolog 2

TAMs:

Tumor-associated macrophages

TCA:

Tricarboxylic acid

TFAM:

Mitochondrial transcription factor A

TLR7:

Toll-like receptor 7

TME:

Tumor microenvironment

TMZ:

Temozolomide

TNBC:

Triple-negative breast cancer

VDAC1:

Voltage-dependent anion channel-1

Yap:

Yes-associated protein

Ψm:

Membrane potential

References

  • Ahn SY, Li C, Zhang X, Hyun YM. Mitofusin-2 expression is implicated in cervical cancer pathogenesis. Anticancer Res. 2018;38(6):3419–26.

    Article  CAS  PubMed  Google Scholar 

  • Alavi MV, Bette S, Schimpf S, Schuettauf F, Schraermeyer U, et al. A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy. Brain. 2007;130:1029–42.

    Article  PubMed  Google Scholar 

  • Alirol E, James D, Huber D, Marchetto A, Vergani L, et al. The mitochondrial fission protein hFis1 requires the endoplasmic reticulum gateway to induce apoptosis. Molecular Biology of the Cell. 2006;17:4593–935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anand R, Wai T, Baker MJ, Kladt N, Schauss AC, et al. The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J Cell Biol. 2014;204:919–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anderson GR, Wardell SE, Cakir M, Yip C, Ahn YR, et al. Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors. Nat Commun. 2018;9:1677.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Archer SL. Mitochondrial dynamics--mitochondrial fission and fusion in human diseases. N Engl J Med. 2013;369(23):2236–51.

    Article  CAS  PubMed  Google Scholar 

  • Baek SH, Park SJ, Jeong JI, Kim SH, Han J, et al. Inhibition of Drp1 ameliorates synaptic depression, Ab deposition, and cognitive impairment in an Alzheimer’s disease model. J Neurosci. 2017;37(20):5099–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bao D, Zhao J, Zhou X, Yang Q, Chen Y, et al. Mitochondrial fission-induced mtDNA stress promotes tumor-associated macrophage infiltration and HCC progression. Oncogene. 2019;38(25):5007–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bertolini I, Ghosh GC, Kossenkov AV, Mulugu S, et al. Small extracellular vesicle regulation of mitochondrial dynamics reprograms a hypoxic tumor microenvironment. Dev Cell. 2020; 55(2):163-177.e6.

  • Biel TG, Rao VA. Mitochondrial dysfunction activates lysosomal-dependent mitophagy selectively in cancer cells. Oncotarget. 2018;9:995–1011.

    Article  PubMed  Google Scholar 

  • Bordt EA, Clerc P, Roelofs BA, Saladino AJ, et al. The putative Drp1 inhibitor mdivi-1 is a reversible mitochondrial complex i inhibitor that modulates reactive oxygen species. Dev Cell. 2017; 40:583–594.e6.

  • Brillo V, Chieregato L, Leanza L, Muccioli S, Costa R. Mitochondrial dynamics, ROS, and cell signaling: a Blended Overview. Life. 2021;11:332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buck MD, O’Sullivan D, Geltink RIK, Curtis JD, et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell. 2016; 166: P63-76.

  • Burman JL, Pickles S, Wang C, Sekine S, et al. Mitochondrial fission facilitates the selective mitophagy of protein aggregates. J Cell Biol. 2017;216:3231–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cai J, Wang J, Huang Y, Wu H, et al. ERK/Drp1-dependent mitochondrial fission is involved in the MSC-induced drug resistance of T-cell acute lymphoblastic leukemia cells. Cell Death Dis. 2016;7:e2459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell. 2008;14:193–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chauhan SS, Toth RK, Jensen CC, Casillas AS, Kashatus DF, Warfel NA. PIM kinases alter mitochondrial dynamics and chemosensitivity in Lung Cancer. Oncogene. 2020;39(12):2597–611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen H, Chan DC. Mitochondrial dynamics in regulating the unique phenotypes of cancer and stem cell. Cell Metab. 2017;26:39–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen H, Chomyn A, Chan DC. Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J. Biol. Chem. 2005;280:26185–92.

    Article  CAS  PubMed  Google Scholar 

  • Chen H, Detmer SA, Ewald AJ, Griffin EE, et al. Mitofusins Mfn1 and Mfn2 co-ordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol. 2003;160:189–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen H, McCaffery JM, Chan DC. Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell. 2007;30:548–62.

    Article  CAS  Google Scholar 

  • Chen H, Vermulst M, Wang YE, Chomyn A, et al. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cells. 2010;141:280–9.

    Article  CAS  Google Scholar 

  • Chen L, Zhang J, Lyu Z, Chen Y, Ji X, Cao H, Jin M, et al. Positive feedback loop between mitochondrial fission and Notch signalling promotes surviving-mediated survival of TNBC cells. Cell Death Dis. 2018;9:1050.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Chen S, Liu S, Wang J, Wu Q, Wang A, et al. TBK1-mediated DRP1 targeting confers nucleic acid sensing to reprogram mitochondrial dynamics and physiology. Mol Cell. 2020; 80: 810-827.e7.

  • Cheng C-T, Kuo C-Y, Ouyang C, Li C-F, Chung Y, et al. Metabolic stress-induced phosphorylation of KAP1 Ser473 blocks mitochondrial fusion in breast cancer cells. Cancer Research. 2016;76:5006–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng W-Y, Chow K-C, Chiao M-T, Yang Y-C, Shen C-C. Higher levels of dynamin-related protein 1 are associated with reduced radiation sensitivity of glioblastoma cells. Curr Neurovasc Res. 2020;17:446–63.

    Article  CAS  PubMed  Google Scholar 

  • Chuang K-C, Chang C-R, Chang S-H, Huang S-W, et al. Imiquimod-induced ROS production disrupts the balance of mitochondrial dynamics and increases mitophagy in skin cancer cells. J Dermatol Sci. 2020;98(3):152–62.

    Article  CAS  PubMed  Google Scholar 

  • Civenni G, Carbone GM, Catapano CV. Mitochondrial fission and stemness in prostate cancer. Aging (Albany NY). 2019;11(19):8036–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cogliati S, Frezza C, Soriano ME, Varanita T, et al. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell. 2013;155:P160–71.

    Article  CAS  Google Scholar 

  • Courtois S, de Luxán-Delgado B, Penin-Peyta L, Royo-García A, Parejo-Alonso B, et al. Inhibition of mitochondrial dynamics preferentially targets pancreatic cancer cells with enhanced tumorigenic and invasive potential. Cancers. 2021;13(4):698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dabrowska A, Venero JL, Iwasawa R, Hankir MK, Rahman S, et al. PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity. Aging (Albany NY). 2015;7(9):629–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davies VJ, Hollins AJ, Piechota MJ, Yip W, Davies JR, et al. Opa1 deficiency in a mouse model of Autosomal Dominant Optic Atrophy impairs mitochondrial morphology, optic nerve structure and visual function. Hum Mol Genet. 2007;16:1307–18.

    Article  CAS  PubMed  Google Scholar 

  • Decker CW, Garcia J, Gatchalian K, Arceneaux D, Choi C, et al. Mitofusin-2 mediates doxorubicin sensitivity and acute resistance in Jurkat leukaemia cells. Biochem Biophys Rep. 2020;100824.

  • Delierneux C, Kouba S, Shanmughapriya S, Potier-Cartereau M, Trebak M, Hempel N. Mitochondrial calcium regulation of redox signaling in cancer. Cells. 2020;9:432.

    Article  CAS  PubMed Central  Google Scholar 

  • Deng X, Liu J, Liu L, Sun X, Huang J, Dong J. Drp1-mediated mitochondrial fission contributes to baicalein-induced apoptosis and autophagy in lung cancer via activation of AMPK signaling pathway. Int J Biol Sci. 2020;16(8):1403–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Distelmaier F, Valsecchi F, Liemburg-Apers DC, Lebiedzinska M, Rodenburg RJ, et al. Mitochondrial dysfunction in primary human fibroblasts triggers an adaptive cell survival program that requires AMPK-α. Biochim Biophys Acta. 1852;2015:529–40.

    Article  CAS  PubMed  Google Scholar 

  • Duvezin-Caubet S, Jagasia R, Wagener J, Hofmann S, et al. Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology. J Biol Chem. 2006;281:37972–9.

    Article  CAS  PubMed  Google Scholar 

  • Fang CL, Sun DP, Chen HK, Lin CC, Hung ST, et al. Overexpression of mitochondrial GTPase MFN2 represents a negative prognostic marker in human gastric cancer and its inhibition exerts anti-cancer effects. J Cancer. 2017;8:1153–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Favaro G, Romanello V, Varanita T, et al. DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass. Nat Commun. 2019;10:2576.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ferreira-da-Silva A, Valacca C, Rios E, Populo H, Soares P, et al. Mitochondrial dynamics protein Drp1 Is overexpressed in oncocytic thyroid tumors and regulates cancer cell migration. PLoS One. 2015;10(3):e0122308.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Filichia E, Hoffer B, Qi X, Luo Y. Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson’s disease model induced by MPTP. Sci Rep. 2016;6(1):32656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friedman JR, Nunnari J. Mitochondrial form and function. Nature. 2014;505:335–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu W, Liu Y, Yin H. Mitochondrial dynamics: biogenesis, fission, fusion, and mitophagy in the regulation of stem cell behaviours. Stem Cells Int. 2019;2019:9757201.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gao D, Zhang L, Dhillon R, Hong TT, Shaw RM, Zhu J. Dynasore protects mitochondria and improves cardiac lusitropy in Langendorff perfused mouse heart. PloS One. 2013;8(4):e60967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao T, Zhang X, Zhao J, Zhou F, Wang Y, et al. SIK2 promotes reprogramming of glucose metabolism through PI3K/AKT/HIF-1α pathway and Drp1-mediated mitochondrial fission in ovarian cancer. Cancer Letters. 2020;469:89–101.

    Article  CAS  PubMed  Google Scholar 

  • García-Heredia JM, Carnero A. Role of Mitochondria in Cancer Stem Cell Resistance. Cells. 2020;9(7):1693.

    Article  CAS  PubMed Central  Google Scholar 

  • Gaude E, Frezza C. Defects in mitochondrial metabolism and cancer. Cancer & Metab. 2014;2:10.

    Article  Google Scholar 

  • Giacomello M, Pyakurel A, Glytsou C, Scorrano L. The cell biology of mitochondrial membrane dynamics. Nature Reviews Molecular Cell Biology. 2020;21:204–24.

    Article  CAS  PubMed  Google Scholar 

  • Gilkerson RW, Selker JML, Capaldi RA. The cristal membrane of mitochondria is the principal site of oxidative phosphorylation. FEBS Lett. 2003;546:355–8.

    Article  CAS  PubMed  Google Scholar 

  • Groß CJ, Mishra R, Schneider KS, Medard G, Wettmarshausen J, et al. K (+) efflux-independent NLRP3 inflammasome activation by small molecules targeting mitochondria. Immunity. 2016;45(4):761–73.

    Article  PubMed  CAS  Google Scholar 

  • Guido C, Whitaker-Menezes D, Lin Z, Pestell RG, Howell A, et al. Mitochondrial fission induces glycolytic reprogramming in cancer-associated myofibroblasts, driving stromal lactate production, and early tumor growth. Oncotarget. 2012;3(8):798–810.

    Article  PubMed  PubMed Central  Google Scholar 

  • Guièze R, Liu VM, Rosebrock D, Jourdian AA, et al. Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies. Cancer Cell. 2019; 36(4):369-384.e13.

  • Gundamaraju R, Lu W, Manikam R. Revisiting mitochondria scored cancer progression and metastasis. Cancers. 2021;13:432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo J, Ye F, Jiang X, Guo H, Xie W, et al. Drp1 mediates high glucose-induced mitochondrial dysfunction and epithelial-mesenchymal transition in endometrial cancer cells. Exp Cell Res. 2020a;389(1):111880.

    Article  CAS  PubMed  Google Scholar 

  • Guo L, Cui C, Wang J, Yuan J, Yang Q, et al. PINCH-1 regulates mitochondrial dynamics to promote proline synthesis and tumor growth. Nat Commun. 2020b;11:4913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han X-J, Shi S-L, Wei Y-F, Jiang L-P, Guo M-Y, et al. Involvement of mitochondrial dynamics in the antineoplastic activity of cisplatin in murine leukemia L1210 cells. Oncol Rep. 2017;38:985–92.

    Article  CAS  PubMed  Google Scholar 

  • Han Y, Cho U, Kim S, Park IS, et al. Tumour microenvironment on mitochondrial dynamics and chemoresistance in cancer. Free Radic Res. 2018;52(11-12):1271–87.

    Article  CAS  PubMed  Google Scholar 

  • Han Y, Kim B, Cho U, Parkho IS, Kimho SL, et al. Mitochondrial fission causes cisplatin resistance under hypoxic conditions via ROS in ovarian cancer cells. Oncogene. 2019; 38: 7089–7105.

  • Herkenne S, Ek O, Zamberlan N, et al. Developmental and tumor angiogenesis requires the mitochondria-shaping protein Opa1. Cell Metabolism. 2020;31:987–1003.

    Article  CAS  PubMed  Google Scholar 

  • Herkenne S, Scorrano L. OPA1, a new mitochondrial target in cancer therapy. Aging (Albany NY). 2020;12(21):20931–3.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hsu C-C, Tseng L-M, Lee H-C. Role of mitochondrial dysfunction in cancer progression. Exp Biol Med (Maywood). 2016;241(12):1281–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu J, Zhang Y, Jiang X, Zhang H, Gao Z, et al. ROS-mediated activation and mitochondrial translocation of CaMKII contributes to Drp1-dependent mitochondrial fission and apoptosis in triple-negative breast cancer cells by isorhamnetin and chloroquine. J Exp Clin Cancer Res. 2019;38(1):225.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hu Y, Chen H, Zhang L, Lin X, Li X, et al. The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses. Autophagy. 2021;17(5):1142–56.

    Article  CAS  PubMed  Google Scholar 

  • Hu Y, Wang B, Wang L, Wang Z, Jian Z, Seng L. Mammalian STE20-like kinase 1 regulates pancreatic cancer cell survival and migration through Mfn2-mediated mitophagy. Mol Med Rep. 2020;22:398–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang C-Y, Chiang S-F, Chen WT-L, Ke T-W, Chen T-W, et al. HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer. Cell Death Dis. 2018;9:1004.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Huang Q, Zhan L, Cao H, Li J, Lyu Y, et al. Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy. 2016;12:999–1014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Humphries BA, Cutter AC, Buschhaus JM, et al. Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer. Breast Cancer Res. 2020;22:60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishihara N, Nomura M, Jofuku A, Kato H, et al. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat. Cell Biol. 2009;11:958–66.

    Article  CAS  PubMed  Google Scholar 

  • Iwata R, Casimir P, Vanderhaeghen P. Mitochondrial dynamics in postmitotic cells regulate neurogenesis. Science. 2020;369(6505):858–62.

    Article  CAS  PubMed  Google Scholar 

  • Izzo V, Bravo-San Pedro JM, Sica V, Kroemer G, Galluzzi L. Mitochondrial permeability transition: new findings and persisting uncertainties. Trends Cell Biol. 2016;26:655–67.

    Article  CAS  PubMed  Google Scholar 

  • Jang S, Javadov S. OPA1 regulates respiratory super-complexes assembly: the role of mitochondrial swelling. Mitochondrion. 2020;51:30–9.

    Article  CAS  PubMed  Google Scholar 

  • Jendrach M, Mai S, Pohl S, Vöth M, Bereiter-Hahn J. Short- and long-term alterations of mitochondrial morphology, dynamics and mtDNA after transient oxidative stress. Mitochondrion. 2008;8:293–304.

    Article  CAS  PubMed  Google Scholar 

  • Ježek J, Cooper KF, Strich R. Reactive oxygen species and mitochondrial dynamics: the Yin and Yang of mitochondrial dysfunction and cancer progression. Antioxidants (Basel). 2018; 7: 13.

  • Karimi D, Pedram N, Kakaei F, Asadi M, Poursaei E, Krmani TA. FIS1 Overexpression is correlated with tumor metastasis in gastric adenocarcinoma. J Gastrointest Cancer. 2021. https://doi.org/10.1007/s12029-021-00639-5.

  • Khacho M, Clark A, Harper M-E, Park DS, Slack RS. Mitochondrial dynamics impacts stem cell identity and fate decisions by regulating a nuclear transcriptional program. Cell Stem Cell. 2016;19:232–47.

    Article  CAS  PubMed  Google Scholar 

  • Khacho M, Clark A, Svoboda DS, MacLaurin JG, Lagace DC, et al. Mitochondrial dysfunction underlies cognitive defects as a result of neural stem cell depletion and impaired neurogenesis. Hum Mol Genet. 2017;26:3327–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim B, Song YS. Mitochondrial dynamics altered by oxidative stress in cancer. Free Radic Res. 2016;50:1065–70.

    Article  CAS  PubMed  Google Scholar 

  • Kim DY, Jung SY, Kim YJ, Kang Spark JH, et al. Hypoxia-dependent mitochondrial fission regulates endothelial progenitor cell migration, invasion, and tube formation. Korean J Physiol Pharmacol. 2018;22(2):203–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim S-Y. Cancer energy metabolism: shutting power off cancer factory. Biomolecules & Therapeutics. 2018;26(1):39–44.

    Article  CAS  Google Scholar 

  • Kingnate C, Charoenkwan K, Kumfu S, Chattipakorn N, Chattipakorn SC. Possible roles of mitochondrial dynamics and the effects of pharmacological interventions in chemo-resistant ovarian cancer. EBioMedicine. 2018;34:256–66.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kitamura S, Yanagi T, Imafuku K, Hiroo H, Abe R, Shimizu H. Drp1 regulates mitochondrial morphology and cell proliferation in cutaneous squamous cell carcinoma. J Dermatol Sci. 2017;88(3):298–307.

    Article  CAS  PubMed  Google Scholar 

  • Kong B, Tsuyoshi H, Orisaka M, Shieh D-B, Yoshida Y, Tsang BK. Mitochondrial dynamics regulating chemoresistance in gynecological cancers. Ann N Y Acad Sci. 2015;1350:1–16.

    Article  CAS  PubMed  Google Scholar 

  • Kong B, Wang Q, Fung E, Xue Kai, Tsang BK. p53 is required for cisplatin-induced processing of the mitochondrial fusion protein L-Opa1 that is mediated by the mitochondrial metallopeptidase Oma1 in gynecologic Cancers. J Biol Chem. 2014; 289: 27134 –27145.

  • Koshiba T, Detner SA, Kaiser JT, Chen H, McCaffery JM, Chan DC. Structural basis of mitochondrial tethering by mitofusin complexes. Science. 2004;305(5685):858–62.

    Article  CAS  PubMed  Google Scholar 

  • Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell. 2014;14:275–91.

    Article  CAS  PubMed  Google Scholar 

  • Kumar S, Pan CC, Shah N, Wheeler SE, Hoyt KR, et al. Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion. Molecular Cell. 2016;62:520–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuruva CS, Manczak M, Yin X, Ogunmokun G, Redyy AP, Reddy PH. Aqua-soluble DDQ reduces the levels of Drp1 and Aβ and inhibits abnormal interactions between Aβ and Drp1 and protects Alzheimer’s disease neurons from Aβ- and Drp1-induced mitochondrial and synaptic toxicities. Hum Mol Genet. 2017;26:3375–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kushnareva YE, Gerencser AA, Bossy B, Ju WK, et al. Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity. Cell Death Differ. 2013;20:353–65.

    Article  CAS  PubMed  Google Scholar 

  • Kuznetsov AV, Javadov S, Margreiter R, Grimm M, Hagenbuchner J, et al. Structural and functional remodeling of mitochondria as an adaptive response to energy deprivation. Biochim Biophys Acta Bioenerg. 1862;2021(6):148393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwada I, Hasina R, Lennon FE, Bindokas VP, Ustauk P, et al. Paxillin mutations affect focal adhesions and lead to altered mitochondrial dynamics. Cancer Biol Ther. 2013;14(7):679–91.

    Article  Google Scholar 

  • Lapidot T, Sirard C, Vormoor J, Murdoch B, Hong T, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8.

    Article  CAS  PubMed  Google Scholar 

  • Lee H, Smith SB, Sheu SS, Yoon Y. The short variant of optic atrophy 1 (OPA1) improves cell survival under oxidative stress. J Biol Chem. 2020a;295:6543–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee H, Yoon Y. Mitochondrial membrane dynamics—functional positioning of OPA1. Antioxidants. 2018;7:186.

    Article  CAS  PubMed Central  Google Scholar 

  • Lee YG, Nam Y, Shin KJ, Yoon S, Park WS, et al. Androgen-induced expression of DRP1 regulates mitochondrial metabolic reprogramming in prostate cancer. Cancer Lett. 2020b;471:72–87.

    Article  CAS  PubMed  Google Scholar 

  • Leipnitz G, Mohsen AW, Karunanidhi A, Seminotti B, Roginskaya VY, et al. Evaluation of mitochondrial bioenergetics, dynamics, endoplasmic reticulum-mitochondria crosstalk, and reactive oxygen species in fibroblasts from patients with complex I deficiency. Sci Rep. 2018;8:1165.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Lennon FE, Salgia R. Mitochondrial dynamics: biology and therapy in lung cancer. Expt Opinion on Investigat Drugs. 2014;23:675–92.

    Article  CAS  Google Scholar 

  • Lenzi P, Ferese R, Biagioni F, Fulceri F, Busceti CL, et al. Rapamycin ameliorates defects in mitochondrial fission and mitophagy in glioblastoma cells. Int J Mol Sci. 2021;22(10):5379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li C, Zhang J, Lyu Z, Chen Y, Ji X, et al. Positive feedback loop between mitochondrial fission and Notch signaling promotes survivin-mediated survival of TNBC cells. Cell Death Dis. 2018; 9(11):1050.

  • Li M, Wang L, Wang Y, Zhang S, Zhou G, et al. Mitochondrial fusion via OPA1 and MFN1 supports liver tumor cell metabolism and growth. Cells. 2020;9(1):121.

    Article  CAS  PubMed Central  Google Scholar 

  • Li T, Han J, Jia L, Hu X, Chen L, Wang Y. PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation. Protein Cell. 2019;10(8):583–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liang J, Yang Y, Bai L, Li F, Li E. DRP1 upregulation promotes pancreatic cancer growth and metastasis through increased aerobic glycolysis. J Gastroenterology Hepatology. 2020a;35:885–95.

    Article  CAS  Google Scholar 

  • Liang W, Wang X, Yu X, Zuo Y, Cheng K, Yang M. Dynamin-related protein-1 promotes lung cancer A549 cells apoptosis through the F-actin/bax signaling pathway. J Recept Signal Transduct Res. 2020b;40(5):419–25.

    Article  CAS  PubMed  Google Scholar 

  • Liesa M, Borda-d’Augua B, Medina-Gomez G, Lelliott CJ, Paz JC, et al. Mitochondrial fusion is increased by the nuclear coactivator PGC-1β. PLoS ONE. 2008; 3(10): e3613.

  • Lin X-H, Qiu B-Q, Ma M, Zhang R, Hsu S-J, et al. Suppressing DRP1-mediated mitochondrial fission and mitophagy increases mitochondrial apoptosis of hepatocellular carcinoma cells in the setting of hypoxia. Oncogenesis. 2020;9(7):67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin Z, Lin X, Chen J, Huang G, Chen T, Zheng L. Mitofusin-2 is a novel anti-angiogenic factor in pancreatic cancer. J Gastrointest Oncol. 2021;12:484–95.

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu B, Fan Y, Song Z, Han B, Meng Y, et al. Identification of DRP1 as a prognostic factor correlated with immune infiltration in breast cancer. Int Immunopharmacol. 2020a; 89(Pt B):107078.

  • Liu D, Sun Z, Ye T, Li J, Zeng B, et al. The mitochondrial fission factor FIS1 promotes stemness of human lung cancer stem cells via mitophagy. FEBS Open Bio. 2021;11:1997–2007.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Liu R, Chan DC. The mitochondrial fission receptor Mff selectively recruits oligomerized Drp1. Mol Biol Cell. 2015;26:4466–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu X, Sun J, Yuan P, Shou K, Zhou Y, et al. Mfn2 inhibit proliferation and cell cycle in Hela cells via Ras-NF- kB signal pathway. Cancer Cell Int. 2019;19:197.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Liu Y, Shi Y. Mitochondria as a target in cancer treatment. Med Comm. 2020;1(2):129–39.

    Google Scholar 

  • Liu YJ, McIntyre RL, Janssens GE, Houtkooper RH. Mitochondrial fission and fusion: a dynamic role in aging and potential target for age-related disease. Mech Ageing Dev. 2020b;186:111212.

    Article  CAS  PubMed  Google Scholar 

  • Loberas L, Muñoz JP, Hernández-Álvarez MI, Cardona P-J, Zorzano A, Celada A. Macrophage mitochondrial MFN2 (mitofusin 2) links immune stress and immune response through reactive oxygen species (ROS) production. Autophagy. 2020;16:2307–9.

    Article  CAS  Google Scholar 

  • Long NP, Min JE, Anh NH, Kim SJ, Park S, et al. Isolation and metabolic assessment of cancer cell mitochondria. ACS Omega. 2020;5:27304–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Losón OC, Song Z, Chen H, Chan DC. Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell. 2013;24(5):659–67.

    Article  PubMed  PubMed Central  Google Scholar 

  • Loubiere C, Clavel S, Gilleron J, et al. The energy disruptor metformin targets mitochondrial integrity via modification of calcium flux in cancer cells. Sci Rep. 2017;7:5040.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Luan G, Li G, Ma X, Jin Y, Hu N, et al. Dexamethasone-induced mitochondrial dysfunction and insulin resistance-study in 3T3-L1 adipocytes and mitochondria isolated from mouse liver. Molecules. 2019;24(10):1982.

    Article  CAS  PubMed Central  Google Scholar 

  • Ma M, Lin X-H, Liu H-H, Zhang R, Chen RX. Suppression of DRP1-mediated mitophagy increases the apoptosis of hepatocellular carcinoma cells in the setting of chemotherapy. Oncol Rep. 2020a;43(3):1010–8.

    CAS  PubMed  Google Scholar 

  • Ma Y, Wang L, Jia R. The role of mitochondrial dynamics in human cancers Am J Cancer Res. 2020b;10:1278–93.

    CAS  PubMed  Google Scholar 

  • MacVicar T, Langer T. OPA1 processing in cell death and disease – the long and short of it. J Cell Sci. 2016;129(12):2297–306.

    CAS  PubMed  Google Scholar 

  • Marcia E, Ehrlich M, Massol R, Boucrot E, Brunner C, Kirchhausen T. Dynasore, a cell-permeable inhibitor of Dynamin. Dev Cell. 2006;10:839–50.

    Article  CAS  Google Scholar 

  • Marcu R, Zheng Y, Hawkins BJ. Mitochondria and Angiogenesis. Adv Exp Med Biol. 2017;982:371–406.

    Article  CAS  PubMed  Google Scholar 

  • Martínez J, Tarallo D, Martínez-Palma L, et al. Mitofusins modulate the increase in mitochondrial length, bioenergetics and secretory phenotype in therapy-induced senescent melanoma cells. Biochem J. 2019;476:2463–86.

    Article  PubMed  Google Scholar 

  • Mazumdar S, De R, Debsharma S, et al. Indomethacin impairs mitochondrial dynamics by activating the PKCζ–p38–DRP1pathway and inducing apoptosis in gastric cancer and normal mucosal cells. J Biol Chem. 2019;294:8238–58.

    Article  Google Scholar 

  • Meng H, Yan W-Y, Lei Y-H, Wan Z, et al. SIRT3 regulation of mitochondrial quality control in neurodegenerative diseases. 2019; 11:13.

  • Merkwirth C, Dargazanli S, Tatsuta T, Geimer S, et al. Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria. Genes Dev. 2008;22:476–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mishra N, Kar R, Singha PK, et al. Inhibition of mitochondrial division through covalent modification of Drp1 protein by 15 deoxy-Delta (12,14)-prostaglandin J2. Biochem Biophys Res Commun. 2010;395:17–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mishra P, Carelli V, Manfredi G, Chan DC. Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. Cell Metab. 2014;19(4):630–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mishra P, Chan DC. Metabolic regulation of mitochondrial dynamics. J Cell Biol. 2016;212:379–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagdas S, Kashatus JA, Nascimento A, Hussain SS, Trainor RE, et al. Drp1 promotes KRas-driven metabolic changes to drive pancreatic tumor growth. Cell Reports. 2019;28(7):1845–59.

    Article  CAS  PubMed  Google Scholar 

  • Olichon A, Emorine LJ, Descoins E, Pelloquin L, et al. The human dynamin-related protein OPA1 is anchored to the mitochondrial inner membrane facing the inter-membrane space. FEBS Lett. 2002;523:171–6.

    Article  CAS  PubMed  Google Scholar 

  • Osellame LD, Singh AP, Stroud DA, Palmer CS, Stojanovski D, et al. Cooperative and independent roles of the Drp1 adaptors Mff, MiD49 andMiD51 in mitochondrial fission. J. Cell Sci. 2016;129:2170–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pang G, Xie Q, Yao J. Mitofusin 2 inhibits bladder cancer cell proliferation and invasion via the Wnt/β-catenin pathway. Oncol Lett. 2019;18(3):2434–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Parte SC, Batra SK, Kakar SS. Characterization of stem cell and cancer stem cell populations in ovary and ovarian tumors. J Ovarian Res. 2018;11:69.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Patten DA, Wong J, Khacho M, Soubannier V, et al. OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand. EMBO J. 2014;33:2676–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pei S, Minhajuddin M, Adane B, Khan N, Stevans BM, et al. AMPK/FIS1-mediated mitophagy is required for self-Renewal of Human AML Stem Cells. Cell Stem Cell. 2018; 23:86-100.e6

  • Peiris-Pagès M, Bonuccelli G, Sotgia F, Lisanti MP. Mitochondrial fission as a driver of stemness in tumor cells: mDIVI1 inhibits mitochondrial function, cell migration and cancer stem cell (CSC) signalling. Oncotarget. 2018;9(17):13254–75.

    Article  PubMed  PubMed Central  Google Scholar 

  • Qi X, Qvit N, Su YC, Mochly-Rosen D. A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci. 2013;126(Pt 3):789–802.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Quintana-Cabrera R, Quirin C, Glytsou C, Corrado M, Urbani A, et al. The cristae modulator Optic atrophy 1 requires mitochondrial ATP synthase oligomers to safeguard mitochondrial function. Nature Communications. 2018;9:3399.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ramos ES, Motori E, Bru¨ser C, Ku¨hl I, Yeroslaviz A, Ruzzenente B, et al. Mitochondrial fusion is required for regulation of mitochondrial DNA replication. PLoS Genet. 2019;15(6):e1008085.

    Article  CAS  Google Scholar 

  • Rana A, Oliveira MP, Khamoui AV, et al. Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster. Nat Commun. 2017;8:448.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Rao S, Mondragón L, Pranjic B, et al. AIF-regulated oxidative phosphorylation supports lung cancer development. Cell Res. 2019;29:579–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raut GK, Chakrabarti M, Pamarthy D, Bhadra MP. Glucose starvation-induced oxidative stress causes mitochondrial dysfunction and apoptosis via Prohibitin 1 upregulation in human breast cancer cells. Free Radical Biology and Medicine. 2019;145:428–41.

    Article  CAS  PubMed  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.

    Article  CAS  PubMed  Google Scholar 

  • Rocha AG, Franco A, Krezel AM, Rumsey JM, et al. Mfn2 agonists reverse mitochondrial defects in preclinical models of Charcot Marie Tooth disease type 2A. Science. 2018;360(6386):336–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rovini A, Heslop K, Hunt EG, Morris ME, Fang D, et al. Quantitative analysis of mitochondrial membrane potential heterogeneity in unsynchronized and synchronized cancer cells. FASEB Journal. 2021;35(1):e21148.

    Article  CAS  PubMed  Google Scholar 

  • Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel? Nat Rev Cancer. 2014;14:709–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sabouny R, Shutt TE. Reciprocal regulation of mitochondrial fission and fusion. Trends in Biochemical Sciences. 2020;45:564–77.

    Article  CAS  PubMed  Google Scholar 

  • Sánchez-Alvarez R, De Francesco EM, Fiorillo M, Sotgia F, Lisanti MP. Mitochondrial fission factor (MFF) Inhibits Mitochondrial metabolism and reduces breast cancer stem cell (CSC) activity. Front Oncol. 2020;10:1776.

    Article  PubMed  PubMed Central  Google Scholar 

  • Scarpulla RC. Nuclear control of respiratory chain expression by nuclear respiratory factors and PGC-1-related coactivator. Ann. N. Y. Acad. Sci. 2008a;1147:321–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scarpulla RC. Nuclear control of respiratory gene expression in mammalian cells. J. Cell. Biochem. 2006;97:673–83.

    Article  CAS  PubMed  Google Scholar 

  • Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol. Rev. 2008b;88:611–38.

    Article  CAS  PubMed  Google Scholar 

  • Senft D, Ronai ZA. Regulators of mitochondrial dynamics in cancer. Curr Opin Cell Biol. 2016;39:43–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seo JH, Agarwal E, Chae YC, Lee YG, Garlick DS, et al. Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer. EBioMedicine. 2019;48:353–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Serasinghe MN, Chipuk J. Mitochondrial Fission in Human Diseases. Hand Exp Pharmacol. 2017;240:159–88.

    Article  CAS  Google Scholar 

  • Serasinghe MN, Wieder SY, Renault TT, Elkholi R, Asciolla JJ, et al. Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Molecular Cell. 2015;57:521–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen F, Gai J, Xing J, Guan J, Fu L, Li Q. Dynasore suppresses proliferation and induces apoptosis of the non-small-cell lung cancer cell line A549. Biochem Biophys Res Commun. 2018;495(1):1158–66.

    Article  CAS  PubMed  Google Scholar 

  • Shin S-W, Seo C-Y, Han H, Han J-Y, Jeong J-S, et al. 15d-PGJ2 induces apoptosis by reactive oxygen species–mediated inactivation of Akt in leukaemia and colorectal cancer cells and shows in vivo antitumor activity. Clin Cancer Res. 2009;15(17):5414–25.

    Article  CAS  PubMed  Google Scholar 

  • Shiratori R, Furuichi K, Yamaguchi M, et al. Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner. Sci Rep. 2019;9:18699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simula L, Pacella I, Colamatteo A, et al. Drp1 controls effective T cell immune-surveillance by regulating T cell migration, proliferation, and cMyc-dependent metabolic reprogramming. Cell Reports. 2018; 25: 3059-3073.e10

  • Singh A, Faccenda D, Campanella M. Pharmacological advances in mitochondrial therapy. EBioMedicine. 2021;65:103244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smeitink J, LVD H, Mauro SD. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet. 2001;2(5):342–52.

    Article  CAS  PubMed  Google Scholar 

  • Smith G, Gallo G. To mdivi-1 or not to mdivi-1: is that the question? Dev. Neurobiol. 2017;77:1260–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soares CD, Morais TML, Carlos R, de Almeaida OP, Mariano FV, et al. Prognostic importance of mitochondrial markers in mucosal and cutaneous head and neck melanomas. Hum Pathol. 2019;85:279–89.

    Article  CAS  PubMed  Google Scholar 

  • Srinivasan S, Guha M, Kashina A, Avadhani NG. Mitochondrial dysfunction and mitochondrial dynamics-The cancer connection. Biochim Biophys Acta Bioenerg. 2017;1858(8):602–14.

    Article  CAS  PubMed  Google Scholar 

  • Su YC, Chiu HW, Hung JC, Hong JR. Beta-nodavirus B2 protein induces hydrogen peroxide production, leading to Drp1-recruited mitochondrial fragmentation and cell death via mitochondrial targeting. Apoptosis. 2014;19:1457–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sullivan LB, Chandel NS. Mitochondrial reactive oxygen species and cancer. Cancer & Metabolism. 2014;2:17.

    Article  Google Scholar 

  • Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: overview of molecular mechanisms. Essays Biochem. 2018;62:341–60.

    Article  PubMed  PubMed Central  Google Scholar 

  • Tran Q, Jung J-H, Park J, Lee H, Hong Y, et al. S6 kinase 1 plays a key role in mitochondrial morphology and cellular energy flow. Cell Signal. 2018;48:13–24.

    Article  CAS  PubMed  Google Scholar 

  • Trotta AP, Chipuk JE. Mitochondrial dynamics as regulators of cancer biology. Cell Mol Life Sci. 2017;74(11):1999–2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsuyoshi H, Orisaka M, Fujita Y, Asare-Werehene M, et al. Prognostic impact of Dynamin related protein 1 (Drp1) in epithelial ovarian cancer. BMC Cancer. 2020;20(1):467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vijayan M, Bose C, Reddy PH. Anti-brain aging effects of small molecule inhibitor DDQ. Mol Neurobiol. 2021;58(7):3588–600.

    Article  CAS  PubMed  Google Scholar 

  • Vogel F, Bornhovd C, Neupert W, Reichert AS. Dynamic sub compartmentalization of the mitochondrial inner membrane. J. Cell Biol. 2006;175:237–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vyas S, Zagannjor E, Haigis MC. Mitochondria and cancer. Cell. 2016;166:555–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wakabayashi J, Zhang Z, Wakabayashi N, Tamura Y, et al. The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice. J. Cell Biol. 2009; 186: 805-816.

  • Wanet A, Arnould T, Najimi M, Renard P. Connecting mitochondria, metabolism, and stem cell fate. Stem cell Dev. 2015;24:1957–71.

    Article  CAS  Google Scholar 

  • Wang J, Huang Y, Cai J, Ke Q, Xiao J, et al. A nestin-cyclin-dependent kinase 5-dynamin-related protein 1 axis regulates neural stem/progenitor cell stemness via a metabolic shift. Stem Cells. 2018a;36(4):589–601.

    Article  CAS  PubMed  Google Scholar 

  • Wang R, Mishra P, Garbis SD, Moradian A, et al. Identification of new OPA1 cleavage site reveals that short isoforms regulate mitochondrial fusion. Mol Biol Cell. 2021a;32(2):157–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang W, Liu X, Guo X, Quan H. Mitofusin-2 triggers cervical carcinoma cell hela apoptosis via mitochondrial pathway in mouse model. Cell Physiol Biochem. 2018b;46(1):69–81.

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Liu Y, Sun J, Gong W, Sun P, et al. Mitofusin-2 acts as biomarker for predicting poor prognosis in hepatitis B virus related hepatocellular carcinoma. Infect Agent Cancer. 2018c; 26:13:36.

  • Wang X, Su B, Lee HG, Li X, Perry G, et al. Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J of Neuroscience. 2009;29(28):9090–103.

    Article  CAS  Google Scholar 

  • Wang Y, Agarwal E, Bertolini I, Ghosh JC, et al. IDH2 reprograms mitochondrial dynamics in cancer through a HIF-1α–regulated pseudohypoxic state. FASEB J. 2019;33(12):13398–411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Liu H-H, Cao Y-T, Zhang L-L, Huang F, Yi C. The role of mitochondrial dynamics and mitophagy in carcinogenesis, metastasis and therapy. Front. Cell Dev. Biol. 2020;8:413.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang LT, He P-C, Li A-Q, Cao K-X, et al. Caffeine promotes angiogenesis through modulating endothelial mitochondrial dynamics. Acta Pharmacol Sin. 2021b. https://doi.org/10.1038/s41401-021-00623-6.

  • Wee Y, Liu Y, Lu J, Li X, Zhao M. Identification of novel prognosis-related genes associated with cancer using integrative network analysis. Sci Rep. 2018;8(1):3233.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol. 2010;11(12):872–84.

    Article  CAS  PubMed  Google Scholar 

  • Woo SM, Min K-J, Kwon TK. Inhibition of Drp1 sensitizes cancer cells to cisplatin-induced apoptosis through transcriptional inhibition of c-FLIP expression. Molecules. 2020;25(24):5793.

    Article  CAS  PubMed Central  Google Scholar 

  • Wu D, Dasgupta A, Chen KH, Neuber-Hess M, Patel J, et al. Identification of novel dynamin-related protein 1 (Drp1) GTPase inhibitors:Therapeutic potential of Drpitor1 and Drpitor1a in cancer and cardiac ischemia-reperfusion injury. FASEB J. 2020;34:1447–64.

    Article  CAS  PubMed  Google Scholar 

  • Wu M-J, Chen Y-S, Ki MR, Chang C-C, Gampala S, et al. Epithelial-mesenchymal transition directs stem cell polarity via regulation of mitofusin. Cell Metab. 2019; 29(4):993-1002.e6.

  • Xie L, Shi F, Li Y, Li W, Yu X, et al. Drp1-dependent remodelling of mitochondrial morphology triggered by EBV-LMP1 increases cisplatin resistance. Sig Transduct Target Ther. 2020;5:56.

    Article  CAS  Google Scholar 

  • Xie Q, Wu Q, Horbinski CM, Flavahan WA, Yang K, et al. Mitochondrial control by DRP1 in brain tumor initiating cells. Nature Neuroscience. 2015;18:501–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu K, Chen G, Li X, Wu X, Chang Z, et al. MFN2 suppresses cancer progression through inhibition of mTORC2/Akt signaling. Sci. Rep. 2017;7:41718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xue R, Meng Q, Lu D, Liu X, Wang Y, Hao J. Mitofusin2 induces cell autophagy of pancreatic cancer through inhibiting the PI3K/Akt/mTOR signaling pathway. Oxid Med Cell Longev. 2018;2018:2798070.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamada S, Nomoto S, Fujii T, Kaneko T, et al. Correlation between copy number of mitochondrial DNA and clinico-pathologic parameters of hepatocellular carcinoma. Eur. J. Surg. Oncol. 2006;32:303–7.

    Article  CAS  PubMed  Google Scholar 

  • Yan C, Luo L, Guo C-Y, Goto S, Urata Y, et al. Doxorubicin-induced mitophagy contributes to drug resistance in cancer stem cells from HCT8 human colorectal cancer cells. Cancer Lett. 2017;388:34–42.

    Article  CAS  PubMed  Google Scholar 

  • Yan H, Qiu C, Sun W, Gu M, Xiao F, et al. Yap regulates gastric cancer survival and migration via SIRT1/Mfn2/mitophagy. Oncol Rep. 2018;39(4):1671–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yao N, Wang C, Hu N, Li Y, Liu M, et al. Inhibition of PINK1/Parkin-dependent mitophagy sensitizes multidrug-resistant cancer cells to B5G1, a new betulinic acid analog. Cell Death Dis. 2019;10:232.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Yapa NMB, Lisnyak V, Reljic B, Ryan MT. Mitochondrial dynamics in health and disease. FEBS Letters. 2002; 595: 1184–1204.

  • Yazdani HO, Roy E, Comerci AJ. Windt DJv, Zhang H, et al. Neutrophil extracellular traps drive mitochondrial homeostasis in tumors to augment growth. Cancer Res. 2019;79(21):5626–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin M, Lu Q, Liu X, Wang T, Liu Y, Chen L. Silencing Drp1 inhibits glioma cells proliferation and invasion by RHOA/ ROCK1 pathway. Biochem Biophys Res Commun. 2016;478(2):663–8.

    Article  CAS  PubMed  Google Scholar 

  • You MH, Jeon MJ, Kim Sr, Lee WK, Chen S-y, et al. Mitofusin-2 modulates the epithelial to mesenchymal transition in thyroid cancer progression. Sci Rep. 2021; 11: 2054.

  • Yu M, Nguyen ND, Huang Y, Lin D, Fujimoto TN, et al. Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer. JCI Insight. 2019;5(16):e126915.

    Article  Google Scholar 

  • Yu M, Wan Y, Zou Q. Decreased copy number of mitochondrial DNA in Ewing’s sarcoma. Clin. Chim. Acta. 2010;411:679–83.

    Article  CAS  PubMed  Google Scholar 

  • Yu M, Zhou Y, Shi Y, Ning L, et al. Reduced mitochondrial DNA copy number is correlated with tumor progression and prognosis in Chinese breast cancer patients. IUBMB. Life. 2007;59:450–7.

    Article  CAS  PubMed  Google Scholar 

  • Yu R, Liu T, Jin S-B, Ning C, Lendah U, et al. MIEF1/2 function as adaptors to recruit Drp1 to mitochondria and regulate the association of Drp1 with Mff. Scientific Reports. 2017a;7:880.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Yu Y, Xu L, Qi L, Wang C, et al. ABT737 induces mitochondrial pathway apoptosis and mitophagy by regulating DRP1-dependent mitochondrial fission in human ovarian cancer cells. Biomed Pharmacother. 2017b;96:22–9.

    Article  CAS  PubMed  Google Scholar 

  • Yu Y-R, Imrichova H, Wang H, Chao T, Xiao Z. Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. Nat Immunol. 2020;21(12):1540–51.

    Article  CAS  PubMed  Google Scholar 

  • Yue W, Chen Z, Liu H, Yan C, et al. A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30. Cell Res. 2014;24(4):482–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhan L, Cao H, Wang G, Lyu Y, Sun X, et al. Drp1-mediated mitochondrial fission promotes cell proliferation through crosstalk of p53 and NF-κB pathways in hepatocellular carcinoma. Oncotarget. 2016;7(40):65001–11.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Sun L, Li W, Wang Y, Li X, Liu Y. Overexpression of macrophage stimulating 1 enhances the anti-tumor effects of IL-24 in esophageal cancer via inhibiting ERK-Mfn2 signaling-dependent mitophagy. Biomed Pharmacother. 2019;114:108844.

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Trushin S, Christensen T, Bachmeire BV, et al. Altered brain energetics induces mitochondrial fission arrest in Alzheimer’s Disease. Sci Rep. 2016;6:18725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang L, Zhang Y, Chang X, et al. Imbalance in mitochondrial dynamics induced by low PGC-1α expression contributes to hepatocyte EMT and liver fibrosis. Cell Death Dis. 2020a;11:226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Chan DC. Structural basis for recruitment of mitochondrial fission complexes by Fis1. Proc Natl Acad Sci U S A. 2007;104(47):18526–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Z, Li T-E, Chen M, Xu D, Zhu Y, et al. MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming. British J Cancer. 2020b;122:209–20.

    Article  CAS  Google Scholar 

  • Zhao J, Zhang J, Yu M, Xie Y, Huang Y, et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene. 2013;32:4814–24.

    Article  CAS  PubMed  Google Scholar 

  • Zhao Q, Ye M, Yang W, Wang M, Li M, et al. Effect of Mst1 on endometriosis apoptosis and migration: role of Drp1-related mitochondrial fission and Parkin-required mitophagy. Cell Physiol Biochem. 2018;45(3):1172–90.

    Article  CAS  PubMed  Google Scholar 

  • Zheng X, Qian Y, Fu B, Jiao D, Jiang Y, et al. Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance. Nat Immunol. 2019;20(12):1656–67.

    Article  CAS  PubMed  Google Scholar 

  • Zhong B, Shi D, Wu F, Wang S, Hu H, et al. Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cisplatin via STAT3 pathway in osteosarcoma. Cell Death Dis. 2019a;10(10):687.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zhong X, Cui P, Cai Y, Wang L, He X, et al. Mitochondrial dynamics is critical for the full pluripotency and embryonic developmental potential of pluripotent stem cells. Cell Metab. 2019b; 29:979-992.e4.

  • Zhou J, Li G, Zheng Y, Shen H-M, Hu X, et al. A novel autophagy/mitophagy inhibitor liensinine sensitizes breast cancer cells to chemotherapy through DNM1L-mediated mitochondrial fission. Autophagy. 2015;11:1259–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Q, Sun Y. MLN4924: additional activities beyond neddylation inhibition. Molecular & Cellular Oncology. 2019; 6:5, e1618174.

  • Zhou T-J, Zhang S-L, He C-Y, Zhuang Q-Y, Han P-Y, et al. Downregulation of mitochondrial cyclooxygenase-2 inhibits the stemness of nasopharyngeal carcinoma by decreasing the activity of dynamin-related protein 1. Theranostics. 2017;7:1389–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou X, Li R, Chen R, Liu J. Altered mitochondrial dynamics, biogenesis, and functions in the paclitaxel-resistant lung adenocarcinoma cell line A549/Taxol. Med Sci Monit. 2020;26:e918216.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu PP, Patterson A, Stadler J, Seeburg DP, et al. Intra- and intermolecular domain interactions of the C-terminal GTPase effector domain of the multimeric dynamin-like GTPase Drp1. J Biol Chem. 2004;279(34):35967–74.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

SK is thankful to DST SERB for awarding core research grant, DBT for granting Ramalingaswami re-entry fellowship, and Indian Institute of Science Education & Research (IISER), Tirupati, for their support. We sincerely apologize to the authors whose principal findings are not cited in this article. We acknowledge Biorender.com, which used to create a graphical abstract.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Funding

This work was supported by IISER, Tirupati, DST-SERB (CRG/2019/002104), Ramalingaswami re-entry fellowship, DBT (BT/RLF/Re-entry/13/2016), funds to SK. RA is thankful to IISER Tirupati for fellowship. ACK is grateful to DST for granting the DST-INSPIRE fellowship.

Author information

Authors and Affiliations

  1. Division of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Karkambadi Road, Rami Reddy Nagar, Mangalam, Tirupati, Andhra Pradesh, 517507, India

    Sanjay Kumar, Rahail Ashraf & Aparna C.K.

Authors
  1. Sanjay Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rahail Ashraf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aparna C.K.
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SK performed the research, designed the concept, and wrote the manuscript. RA and ACK helped in literature mining and data collection. ACK made Figure 1. Modification and improvement of the manuscript were done by RA, ACK, and SK. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Sanjay Kumar.

Ethics declarations

Consent for publication

Not applicable.

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised: Due to error in the abstract section and figure legends.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumar, S., Ashraf, R. & C.K., A. Mitochondrial dynamics regulators: implications for therapeutic intervention in cancer. Cell Biol Toxicol 38, 377–406 (2022). https://doi.org/10.1007/s10565-021-09662-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-021-09662-5

Keywords

Search

Navigation