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Apr 1, 2009 (Vol. 29, No. 7)

Unveiling Cellular Bioenergetics’ Secrets

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

  • Signaling Pathways

    Increasingly, mitochondria have surfaced as essential players in many signaling pathways. “In recent years, the widely held view that mitochondria are simply stewards of energy metabolism and apoptosis is giving way to the realization that they have multiple, additional functions in cells. These include roles in oxygen sensing, signal transduction, and immune system function, to name just a few,” says Gerald S. Shadel, Ph.D., professor of pathology and genetics at Yale University.

    “It is, therefore, becoming quite clear,” explains Dr. Shadel, “that mitochondria contribute to human disease and age-related pathology to a much greater degree than previously thought and this involves mechanisms that not only include, but transcend their accepted roles in cellular metabolism and cell death.”

    The Shadel lab cloned h-mtTFB1, a mitochondrial transcription factor that concomitantly functions as an rRNA methyltransferase, and linked it to maternally inherited deafness, possibly via its methylation of a conserved 12S rRNA stem-and-loop structure.

    In collaboration with Akiko Iwasaki, Ph.D., the Shadel group recently established a connection between mitochondrial ROS and antiviral signaling, and revealed that in the absence of autophagy, cells accumulate dysfunctional mitochondria, which produce more reactive oxygen species and activate antiviral signaling pathways.

    In another exciting development, the Shadel lab revealed that inhibition of TOR signaling affects the mitochondrial proteome dynamics by increasing both mitochondrial- and nuclear- encoded protein subunits involved in oxidative phosphorylation, along with other proteins localized to the mitochondria.

    A few years ago, Vamsi Mootha, M.D., associate professor of systems biology at the Broad Institute, used a DNA microarray-based approach to reveal that mitochondrial gene expression is reduced in prediabetic and diabetic muscle, and subsequent work from other groups revealed increased ROS in certain prediabetic tissues. A recent chemical screen performed in the Mootha lab that relied on four types of cell-based assays, including multiplexed gene-expression analysis, tested almost 2,500 compounds—40% of them FDA-approved drugs—for their effects on mitochondrial physiology, and unveiled a set of compounds that increase mitochondrial gene expression and reduce ROS.

    “We are excited about this result because we are able to reverse, at least in cell culture, two of the signatures of the diabetic muscle,” says Dr. Mootha. One class of compounds is a group of 7–8 microtubule stabilizers and destabilizers that, although structurally diverse, share the ability to reduce mitochondrial ROS and stimulate the transcriptional regulators of mitochondrial gene expression. This freely available compendium provides a valuable discovery tool for exploring mitochondrial signaling, mitochondrial drug toxicity, and mitochondrial therapeutics.

    Mitochondrial biology illustrates how multiple disciplines converge to define new concepts, which sometimes challenge old views, making cellular bioenergetics an increasingly dynamic field. Insights into novel cellular pathways and promises of new therapeutic targets provide a testimony of the reputation that this organelle righteously enjoys, a reputation that Nick Lane, in his book Power, Sex, Suicide: Mitochondria and the Meaning of Life, so relevantly refers to as “a badly kept secret.”

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