Dynamin-Related Protein 1 at the Crossroads of Cancer

The FASEB Journal, 2012

Mitochondria exist in dynamic networks that undergo fusion and fission. Mitochondrial fusion and fission are mediated by several GTPases in the outer mitochondrial membrane, notably mitofusin-2 (Mfn-2), which promotes fusion, and dynamin-related protein (Drp-1), which promotes fission. We report that human lung cancer cell lines exhibit an imbalance of Drp-1/Mfn-2 expression, which promotes a state of mitochondrial fission. Lung tumor tissue samples from patients demonstrated a similar increase in Drp-1 and decrease in Mfn-2 when compared to adjacent healthy lung. Complementary approaches to restore mitochondrial network formation in lung cancer cells by overexpression of Mfn-2, Drp-1 inhibition, or Drp-1 knockdown resulted in a marked reduction of cancer cell proliferation and an increase in spontaneous apoptosis. The number of cancer cells in S phase decreased from 32.4 ؎ 0.6 to 6.4 ؎ 0.3% with Drp-1 inhibition (P<0.001). In a xenotransplantation model, Mfn-2 gene therapy or Drp-1 inhibition could regress tumor growth. The tumor volume decreased from 205.6 ؎ 59 to 70.6 ؎ 15 mm 3 (P<0.05) with Mfn-2 overexpression and from 186.0 ؎ 19 to 87.0 ؎ 6 mm 3 (P<0.01) with therapeutic Drp-1 inhibition. Impaired fusion and enhanced fission contribute fundamentally to the proliferation/apoptosis imbalance in cancer and constitute promising novel therapeutic targets.

Developmental Cell, 2001

chondrial membrane potential (⌬ m ) and perturbed outer 1 Biochemistry Section mitochondrial membrane integrity, followed by the sub-Surgical Neurology Branch sequent release of apoptogenic intermembrane space National Institute of Neurological Disorders proteins (such as certain procaspases, AIF, cytochrome and Stroke c, Smac/DIABLO) into the cytosol. This cascade of 2 Laboratory of Tumor Immunology and Biology events appears to culminate in the activation of cytosolic National Cancer Institute effector proteases (caspases) (Green and Reed,

2010

Mitochondria dynamically fuse and divide within cells, and the proper balance of fusion and fission is necessary for normal mitochondrial function, morphology, and distribution. Drp1 is a dynamin-related GTPase required for mitochondrial fission in mammalian cells. It harbors four distinct domains: GTP-binding, middle, insert B, and GTPase effector. A lethal mutation (A395D) within the Drp1 middle domain was reported in a neonate with microcephaly, abnormal brain development, optic atrophy, and lactic acidemia (

Journal of Biological Chemistry, 2007

Recruitment of a dynamin-like GTPase (Drp1/Dlp1/Dnm1) to membranes requires the mitochondrial dynamics protein Fis1. Mdv1 has been proposed to act as an adaptor between Fis1 and Dnm1 in Saccharomyces cerevisiae. We show that S. cerevisiae Fis1 binds directly to Dnm1 and to Mdv1. Two Fis1 regions have been previously implicated in Mdv1 recruitment: an Nterminal "arm" and a concave surface formed by evolutionarily conserved residues in the tetratricopeptide repeat domain. Perturbing either Fis1 region does not affect Mdv1 binding, but both regions influence Dnm1 binding. Fis1 lacking its N-terminal arm binds tightly to Dnm1, and binding is abolished by mutations to the Fis1 concave surface. The Fis1-Dnm1 interaction decreases more than 100-fold in the presence of the Fis1 arm, suggesting that the arm acts in an autoinhibitory manner to restrict access to the Dnm1 binding site on Fis1. Our data indicate that the concave surface of the Fis1 tetratricopeptide repeat-like domain is evolutionarily conserved to bind the dynamin-like GTPase Dnm1 and not Mdv1 as previously predicted.

Experimental Neurobiology, 2013

Human Molecular Genetics

The purpose of our study was to better understand the effects of mitochondrial-division inhibitor 1 (Mdivi-1) on mitochondrial fission, mitochondrial biogenesis, electron transport activities and cellular protection. In recent years, researchers have found excessive mitochondrial fragmentation and reduced fusion in a large number of diseases with mitochondrial dysfunction. Therefore, several groups have developed mitochondrial division inhibitors. Among these, Mdivi-1 was extensively studied and was found to reduce dynamin-related protein 1 (Drp1) levels and excessive mitochondrial fission, enhance mitochondrial fusion activity and protect cells. However, a recent study by Bordt et al. (1) questioned earlier findings of the beneficial, inhibiting effects of Mdivi-1. In the current study, we studied the protective effects of Mdivi-1 by studying the following: mRNA and protein levels of electron transport chain (ETC) genes; mitochondrial dynamics and biogenesis genes; enzymatic activities of ETC complexes I, II, III and IV; the mitochondrial network; mitochondrial size & number; Drp1 GTPase enzymatic activity and mitochondrial respiration (1) in N2a cells treated with Mdivi-1, (2) overexpressed with full-length Drp1 + Mdivi-1-treated N2a cells and (3) Drp1 RNA silenced+Mdivi-1-treated N2a cells. We found reduced levels of the fission genes Drp1 and Fis1 levels; increased levels of the fusion genes Mfn1, Mfn2 and Opa1; and the biogenesis genes PGC1α, nuclear respiration factor 1, nuclear respiratory factor 2 and transcription factor A,

eLife, 2021

Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. Also, mitochondrial fission and its opposing process of mitochondrial fusion are emerging as crucial regulators of stemness. Intriguingly, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Using our newly derived carcinogen transformed human cell model we demonstrate that fine-tuned Drp1 repression primes a slow cycling &#39;stem/progenitor-like state&#39;, which is characterized by small networks of fused mitochondria and a gene-expression profile with elevated functional stem/progenitor markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Fine tuning Drp1 protein by reducing its activating phosphorylation sustains the neoplastic stem cell markers. Whereas, fine-tuned reduction of Drp1 protein maintains the characteristic mitochondrial shape and gene-expression of the primed &#39;stem/progenitor-like state&#39...

Cell Death &amp; Differentiation, 2010

The Journal of Cell Biology, 2003

Abalance between fission and fusion events determines the morphology of mitochondria. In yeast, mitochondrial fission is regulated by the outer membrane–associated dynamin-related GTPase, Dnm1p. Mitochondrial fusion requires two integral outer membrane components, Fzo1p and Ugo1p. Interestingly, mutations in a second mitochondrial-associated dynamin-related GTPase, Mgm1p, produce similar phenotypes to fzo1 and ugo cells. Specifically, mutations in MGM1 cause mitochondrial fragmentation and a loss of mitochondrial DNA that are suppressed by abolishing DNM1-dependent fission. In contrast to fzo1ts mutants, blocking DNM1-dependent fission restores mitochondrial fusion in mgm1ts cells during mating. Here we show that blocking DNM1-dependent fission in Δmgm1 cells fails to restore mitochondrial fusion during mating. To examine the role of Mgm1p in mitochondrial fusion, we looked for molecular interactions with known fusion components. Immunoprecipitation experiments revealed that Mgm1p i...

The FASEB Journal, 2019

Mitochondrial fission is important in physiological processes, including coordination of mitochondrial and nuclear division during mitosis, and pathologic processes, such as the production of reactive oxygen species (ROS) during cardiac ischemiareperfusion injury (IR). Mitochondrial fission is mainly mediated by dynaminrelated protein 1 (Drp1), a large GTPase. The GTPase activity of Drp1 is essential for