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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

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    A GFP fusion in the outer mitochondrial membrane (Michael Ryan, Ph.D., and Catherine Palmer/ La Trobe University)

    As Immo Scheffler so insightfully remarks in his book Mitochondria, “where there is DNA, there must be mutations.” Few topics are so profoundly rooted in the history of science yet remain as actively expanding and full of surprises as mitochondrial biology. Recent advances position this organelle as a key participant in a plethora of cellular-signaling networks and increasingly reveal its involvement in disease pathogenesis.

    While historically mitochondria were depicted as individual organelles, this view is challenged by recent findings, which point toward an active interchange of mitochondrial contents as a result of dynamic fusion and fission events. “We found that mitochondrial fusion is necessary to protect the function of the mitochondrial population,” says David C. Chan, M.D., Ph.D., associate professor of biology at Caltech and Howard Hughes Medical Institute investigator.

    The Chan group recently generated a conditional mouse knockout for Mfn2, the gene encoding mitofusin 2, a mitochondrial GTPase involved in fusion. “There is something about the long neurons that makes them prone to defects in mitochondrial fusion,” says Dr. Chan. Mitochondria in Mfn2 knockout mice exhibited inner membrane ultrastructural defects, impaired respiratory complex activity, reduced fusion, and increased fragmentation, all of which lead to morphological changes and selective neurodegeneration of cerebellar Purkinje cells.

    Impaired localization of mitochondria, which were present in cell bodies, but rarely found in the dendritic branches, emerged as an additional defect. Another transgenic mouse model generated by the Chan group expresses a pathogenic Mfn2 allele and recapitulates several features observed in Charcot-Marie-Tooth 2A, thus becoming a promising model to dissect mitochondrial defects underlying this neurodegenerative condition that selectively affects motor and sensory functions in long peripheral neurons.

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