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Senior Scholar Award in Aging
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Seymour
Benzer,
Ph.D.
California Institute of Technology
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Mitochondrial swirls, a link between oxidative stress and aging in Drosophila
One of the characteristics of aging is progressive deterioration of muscle function. We will study this phenomenon using the fruit fly, Drosophila, as a model organism. Drosophila flight muscle is among the most metabolically active tissues in any organism. Its mitochondria, the source of energy production, are packed in columns, filling the available space between the muscle fibrils. The folded membranes, or cristae, within each mitochondrion, are very densely packed, so that any changes in their configuration are easily seen. Under exposure to high oxygen levels, we observe a profound remodeling of the mitochondrial ultrastructure. In the earliest event visible by electron microscopy, the cristae in a restricted region of a mitochondrion expand from their tightly packed and orderly structure, to form what appears in the electron microscope as a local swirl, within an otherwise normal-looking mitochondrion. With continued exposure to high oxygen, there is a rapid increase in the number of swirls per mitochondrion. High oxygen induces an accelerated version of what normally happens with age, so that results can be obtained in days rather than weeks. The long-lived mutant methuselah, which displays a 35% increase in longevity, shows longer survival also under hyperoxic conditions, and also a markedly lower rate of appearance of mitochondrial swirls. This is consistent with the hypothesis that swirls are a biomarker of physiological age.
The proposal is to utilize the genetic, molecular and biochemical tools available with Drosophila to incisively dissect this phenomenon. We have also identified mutants that have unusually high sensitivity to hyperoxia. These are of great interest, as the disrupted genes are apparently necessary for coping with oxidative stress. One such mutant, named hyperswirl, displays an overabundance of mitochondrial swirls, even under normoxic conditions. From these studies, we can conclude that the normal version of the hyperswirl gene protects the mitochondria from age-related oxidative damage. We will characterize the role of this gene in the aging process, and screen for drugs that protect the mitochondria against swirl formation.
Contact
Dr. Benzer.
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