Background and Relevance: Mitochondria form an essential component of all human cells. Of the more than 50 inherited diseases of metabolism, the most debilitating ones disrupt the mitochondrial electron transport chain (ETC), and as a consequence the ability of cells to make energy efficiently. Conditions such as MELAS, LHON, MNGIE, NARP and MERRF all have their origin in mitochondrial defects. Each year in the US alone, 1 in 4,000 children are born who will develop a mitochondrial disease before age 10. On top of these tragic disease, it has become increasingly clear that defects in mitochondrial ETC function are also linked with diseases more commonly associated with old age. These include heart disease, Type II diabetes, Parkinson's Disease, Alzheimer's dementia, and cancer. 15% of the US population currently suffer from these chronic degenerative disorders. While it cannot yet be said that mitochondria cause these problems it is clear that changes in mitochondria are involved, because their function is measurably altered. Unquestionably, there is a need to understand processes that maintain mitochondrial functionality throughout all ages. Study Objectives: One approach to countering age-related decline in mitochondrial function is to take advantage of conserved cellular mechanisms that oppose mitochondrial electron transport chain dysfunction dysfunction. Such mechanisms have been termed retrograde responses, because dysfunctional mitochondria are capable of sending a signal to the cell's nucleus to orchestrate adaptive responses. It follows that retrograde responses might be selectively activated in an effort to rejuvenate the mitochondrial network. We have discovered a novel mitochondrial retrograde response that can extend lifespan in the nematode C. elegans. Our primary study objectives are to mechanistically define how mitochondrial dysfunction triggers this novel retrograde response pathway, how it functions to extend life, and how this information can be translated to humans. To accomplish these studies quickly and rigorously we will employ state-of the art techniques including LC-ESI-MS/MS, CRISPR/Cas9 DNA editing, RNA-Seq, confocal microscopy, among other techniques. Expected Results and Impact: By the completion of this study we expect to have defined how a key pathway that is activated in C. elegans in response to mitochondrial electron transport chain dysfunction, works not only to counteract mitochondrial dysfunction, but to compensate to the point of increasing life span. We also expect to have determined the extent to which this pathway might be translatable to mammals. By learning how to harness mechanisms that delay mitochondrial dysfunction, our studies stand to have a major impact on aging. This is because mitochondrial dysfunction, whether causative or consequential, is a feature of every major age-related disease of western society.

Public Health Relevance

(Public Health Relevance) The vast majority of people who reside in Western society will typically die of a disease related to old age. In America, the leading causes of death for people over 65 are heart disease, cancer, chronic low-grade pulmonary disease, stroke, Alzheimer's Disease, diabetes, upper respiratory tract infection, nephritis and septicemia. In many of these disease, changes in mitochondrial function are measurably involved; in some, overt mitochondrial dysfunction is an underpinning factor leading to disease onset. In this proposal we will define molecular mechanisms that can be used to hopefully counter mitochondrial dysfunction into old age.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Fridell, Yih-Woei
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University of Washington
United States
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