The Decline of Mitochondrial Form and Function in Aging Cells
2013 new Scholar Award in aging
Mitochondria produce the energy needed for cellular growth and activity. Decline in mitochondrial form and function are widely recognized but poorly understood features of aged cells, and key features of aging-related diseases such as Parkinson’s and Alzheimer’s. My long-term goal is to identify therapeutic targets that promote youthfulness, health, and longevity by obtaining a deeper understanding of the mechanisms that regulate age-dependent mitochondrial decline. One prevailing explanation for age-dependent mitochondrial decline is that mitochondrial function itself generates damaging byproducts whose accumulation over time damages the mitochondria. A mitochondrial quality control mechanism has been advanced to explain how mitochondrial health might be maintained despite continual exposure to these byproducts, yet mitochondrial function declines over time nonetheless. This mechanism integrates mitochondrial fission and fusion dynamics with selective segregation and degradation of damaged mitochondria. Two different explanations for age-dependent decline are: 1) The function of the quality control mechanism is unchanged over time, but becomes overwhelmed by increasing byproduct resulting from mitochondrial or mitochondrial-independent, age-dependent cellular processes. 2) Byproduct accumulation remains constant, but the efficacy of the mitochondrial quality control mechanism is compromised in an age-dependent manner. It is also possible that mitochondrial decline is due to a combination of both factors. Either way, the efficacy of the quality control mechanism is a critical component of age-dependent mitochondrial decline.
Previous research in this area has been limited to qualitative description of declining mitochondrial health, or of the effects of severe alterations to mitochondrial networks. For example, deleting the key fission gene inhibits mitochondrial fragmentation, which, for unknown reasons, increases replicative lifespan. To identify potential therapeutic targets, it is vital to understand not only whether a perturbation can alter the aging process, but how much of a perturbation is required. Until now, it has been impossible to perform more realistic experiments because methods did not exist to simultaneously measure mitochondrial network structure (size, connectivity, distribution of tubules in the cell), fusion/fission dynamics, and mitochondrial function directly and accurately. This is the technical gap we will close.
We exploit the strengths of the widely used model organism Saccharomyces cerevisae (budding yeast) to explore the molecular mechanisms regulating mitochondrial metabolism, morphology, and aging. S. cerevisae life history allows investigation of both the replicative and chronological forms of aging in cells. The replicative aging process is akin to the maintenance of the regenerative “youthfulness” of stem cells through asymmetric cell division while the chronological aging process is similar to that seen in terminally differentiated cells in multi-cellular tissues that naturally stop dividing and continue to live for a period of time before death. We will use novel microscope-based techniques that allow simultaneous quantification of mitochondrial network structure, dynamics, and function in aging cells. We will quantify the subtle changes in mitochondrial structure, dynamics, and quality control that occur during age-dependent mitochondrial decline using replicative and chronological aging assays. We will alter the quality control mechanism to modify mitochondrial decline by manipulating fission and fusion dynamics. We will also test a set of known aging-related mutants to determine how integral mitochondrial decline is to known aging-related pathways. Our rigorous quantitative approach allows us to successfully breach barriers that have previously prevented sufficiently deep characterization of the processes that act to age cells.