Uniformed Services University of the Health Sciences
Department of Biochemistry and Molecular Biology
4301 Jones Bridge Road, C1094
Bethesda, Maryland 20814-4799
Fax: (301) 295-3512
Lab: B3043 (301) 295-0324
Fly room: B3047 (301) 295-1427
Mitochondria are cellular organelles that produce the majority of ATP in eukaryotic cells. Historically, they have been intensively studied biochemically, and many of the metabolic pathways that take place in mitochondria, such as the TCA cycle and electron-transfer, are well characterized. Mitochondria are unique in that they contain their own DNA, mtDNA. While this DNA is small, approximately 16kb in metazoans, it is critical for normal mitochondrial function. Because mitochondria cannot be made de novo, all of your mitochondria and mtDNA were inherited from your mother's oocyte cytoplasm.
In the last twenty years, an increasing number of diseases have been linked to mutations in either mtDNA or nuclear genes encoding mitochondrial proteins. While the general observation that faulty mitochondria can lead to disease may not be surprising given the important role mitochondria play in cellular function, the specificity with which only certain cell types are affected by single mutations has been. In addition, there is mounting evidence for a role of mitochondrial dysfunction in common diseases, such as neurodegenerative disease and diabetes.
In the past decade or so, a previously under-appreciated aspect of mitochondrial biology has come to light. Mitochondria are not simply static ATP-producing machines (the so-called "power house of the cell"), but are instead very dynamic. They change shape and size due to growth and fission/fusion, and mitochondria can rapidly transit around the cell by moving along the actin and microtubule cytoskeleton.
The broad interests in my lab are studying how mitochondria change shape, location physiology and mtDNA content in response to developmental changes, and elucidating which genes and pathways are responsible. To address these general questions, we use the model system Drosophila melanogaster, or fruit fly. The advantages to using fruit flies are that they have a rich genetic history, allowing rapid and straightforward mutant acquisition, researchers understand much about organ and tissue development, and mitochondria can be imaged in fixed and live tissue at single organelle resolution. While fruit flies are interesting in and of themselves, it is important to note that an estimated 75% of human disease genes have a functional homolog in flies. The overwhelming similarity of genes and molecular pathways between humans and flies allows researchers to apply knowledge gained from Drosophila to elucidate the causes of human disease.
mtDNA has a higher mutation rate than nuclear DNA and mitochondria are maternally inherited. Despite this, females can reproducibly and reliably produce hardy offspring. We are interested in identifying the genes and mechanisms involved in ensuring the mother deposits only highly functional mitochondria into the oocyte in order to support embryonic development. We can clearly visualize mitochondria during all of oogenesis in both fixed and live tissue and we have characterized several genes involved in normal mitochondrial function in the ovary. Mitochondria exhibit stereotypical changes during oogenesis (for one example, see image below), thus mutations that perturb mitochondrial localization or function can be readily identified.
The gene we are currently studying, clueless, is involved in mitochondrial localization and function. Flies mutant for clu are sterile, uncoordinated and have reduced life-spans. In clu mutant ovaries, mitochondria are distinctly mislocalized to the plus-end of microtubules. Clu protein is highly conserved and present in particles in the germline.
We believe clu acts to maintain mitochondrial function. When absent, mitochondria accumulate damage and subsequently undergo directed movement to the plus-ends of microtubules.