GEN Exclusives

More »

Feature Articles

More »
Apr 1, 2009 (Vol. 29, No. 7)

Unveiling Cellular Bioenergetics’ Secrets

Increasingly Dynamic Field Hones In on the Many Facets of Mitochondrial Biology

  • Atomic Detail

    Click Image To Enlarge +
    The movement of GFP-mitochondria in an intact segmental nerve of a live Drosophila larva (Peter J. Hollenbeck, Ph.D., Purdue University)

    “I think the challenge for the next decade will be to link atomic detail with physiological function and disease. At this time, this is possible only in a few cases, if at all,” says Ulrich Brandt, Ph.D., professor of molecular bioenergetics at the center of biological chemistry of the Goethe-University Frankfurt. Complex I represents the point of entry for the majority of electrons into the respiratory chain, and a hydrophobic segment embedded in the membrane together with a hydrophilic arm lying orthogonal to it, toward the mitochondrial matrix, give it an L-shaped appearance.

    “Most people make the obvious assumption that electrons have to be transferred close to the membrane because the substrate, ubiquinone, is extremely hydrophobic,” explains Dr. Brandt. At the “Molecular and Cellular Bioenergetics” meeting he will present recent findings that suggest that ubiquinone reduction takes place not in the membrane, but approximately 60Å away, in the peripheral arm, and this can be explained by envisioning ubiquinone motion occurring along a channel within the protein complex.

    While the recently solved partial x-ray structure of the peripheral, hydrophilic arm provides clues about the electron transfer process, it does not reveal details about proton pumping, thought to occur in the membrane segment. Electron microscopy single particle analysis using complex I mutants with selective proton pumping defects, performed in collaboration with Michael Radermacher, Ph.D., associate professor of molecular physiology and biophysics at the University of Vermont, revealed the existence of two proton pumping sites.

    Experimental approaches in the Brandt lab recently answered another long-standing question in mitochondrial biology. During recovery from ischemic episodes, reperfusion itself may cause organ damage. But in what has become known as ischemic or pharmacological preconditioning, brief episodes of ischemia and reperfusion, or certain compounds such as diazoxide, exert a protective effect if administered prior to a longer ischemic event.

    The molecular basis of the diazoxide activity has been debated for a long time, and the Brandt group recently revealed that two opposing effects of this compound, an increase in complex III reactive oxygen species (ROS) and a reduction in complex I ROS, can both be explained by an inhibitory action on mitochondrial complex II.

    While in vitro systems provide great contributions to neuronal biology, they do not accurately revisit the complexity of interactions in which live organisms participate. Peter J. Hollenbeck, Ph.D., professor of neurobiology at Purdue University, will present at the meeting in vivo work that his group performed using a Drosophila strain with GFP-tagged mitochondria generated by William Saxton, Ph.D., at the University of California Santa Cruz.

    “With this construct, under the confocal microscope, we can look at mitochondrial movement up and down the axon, and the axons are part of an intact neuron; it is kind of like a dream, after years of looking at neurons that divide in a culture dish,” says Dr. Hollenbeck.

    Research in the Hollenbeck group used this system to examine cellular changes in Friedrich’s ataxia, and the results were surprising. While excessive oxidative damage is reported for most mitochondrial disorders, no evidence of ROS was found up to the moment of neuronal death in this disease model. Instead, large numbers of depolarized mitochondria, with a low membrane potential and inability to generate ATP, accumulated at the synapse. “This is quite counterintuitive,” says Dr. Hollenbeck. “Instead of oxidative damage, relatively inactive mitochondria are piling up at the end of the axon, and that seems to underlie neuronal death.”


Add a comment

  • You must be signed in to perform this action.
    Click here to Login or Register for free.
    You will be taken back to your selected item after Login/Registration.

Related content

Jobs

GEN Jobs powered by HireLifeScience.com connects you directly to employers in pharma, biotech, and the life sciences. View 40 to 50 fresh job postings daily or search for employment opportunities including those in R&D, clinical research, QA/QC, biomanufacturing, and regulatory affairs.
 Searching...

Unable to get Jobs Listings.

More »

GEN Poll

More » Poll Results »

Biosimilars

Compared to the original biologics, do you think biosimilars run the risks of being less effective and causing more side effects?