dictyNews
Electronic Edition
Volume 35, number 12
October 29, 2010

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Abstracts
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The Ras related GTPase Miro is not required for mitochondrial transport 
in Dictyostelium discoideum

Georgia Vlahou, Marek Elias, Jürgen-Christoph von Kleist-Retzow, 
Rudolf J. Wiesner and Francisco Rivero


European Journal of Cell Biology, in press

Ras-related GTPases of the Miro family have been implicated in mitochondrial 
homeostasis and microtubule-dependent transport. They consist of two 
GTP-binding domains separated by calcium-binding motifs and of a C-terminal 
transmembrane domain that targets the protein to the outer mitochondrial 
membrane. We disrupted the single Miro-encoding gene in Dictyostelium 
discoideum and observed a substantial growth defect that we attribute to a 
decreased mitochondrial mass and cellular ATP content. However, mutant 
cells even showed an increased rate of oxygen consumption, while glucose 
consumption, mitochondrial transmembrane potential and production of reactive
oxygen species were unaltered. Processes characteristic of the multicellular 
stage of D. discoideum life cycle were also unaltered. Although mitochondria 
occasionally use microtubules for transport in D. discoideum, their size and 
distribution were not visibly affected. We found Miro in all branches of the 
eukaryotic tree with the exception of a few protist lineages (mainly those lacking 
typical mitochondria). Trypanosomatids and ciliates possess structurally unique 
homologs lacking the N-terminal or the C-terminal GTPase domain, respectively. 
We propose that in D. discoideum, as in yeasts and plants, Miro plays roles in 
mitochondrial homeostasis, but the ability to build a complex that regulates its 
association to kinesin for microtubule-dependent transport probably arose in 
metazoans.


Submitted by Francisco Rivero [[log in to unmask]]
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Lead genetic studies in Dictyostelium discoideum and translational studies 
in human cells demonstrate that sphingolipids are key regulators of 
sensitivity to cisplatin and other anticancer drugs

Stephen Alexander and Hannah Alexander
Division of Biological Sciences, University of Missouri, Columbia, MO 65211 USA


Seminars in Cell and Developmental Biology, in press.

A Dictyostelium discoideum mutant with a disruption in the sphingosine-1-phosphate 
(S-1-P) lyase gene was obtained in an unbiased genetic analysis, using random 
insertional mutagenesis, for mutants with increased resistance to the widely used 
cancer chemotherapeutic drug cisplatin.   This finding opened the way to extensive 
studies in both D. discoideum and human cells on the role and mechanism of action 
of the bioactive sphingolipids S-1-P and ceramide in regulating the response to 
chemotherapeutic drugs.  These studies showed that the levels of activities of the 
sphingolipid metabolizing enzymes S-1-P lyase, sphingosine kinase and ceramide 
synthase, affect whether a cell dies or lives in the presence of specific drugs.  The 
demonstration that multiple enzymes of this biochemical pathway were involved in 
regulating drug sensitivity provided new opportunities to test whether 
pharmacological intervention might increase sensitivity.  Thus it is of considerable 
clinical significance that pharmacological inhibition of sphingosine kinase 
synergistically sensitizes cells to cisplatin, both in D. discoideum and human cells.  
Linkage to the p38 MAP kinase and protein kinase C (PKC) signaling pathways 
has been demonstrated.  This work demonstrates the utility of D. discoideum as a 
lead genetic system to interrogate molecular mechanisms controlling the sensitivity 
of tumor cells to chemotherapeutic agents and for determining novel ways of 
increasing efficacy.  The D. discoideum system could be easily adapted to a high 
throughput screen for novel chemotherapeutic agents.


Submitted by Steve Alexander [[log in to unmask]]
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[End dictyNews, volume 35, number 12]