A number of mitochondrial electron transport chain (ETC) mutants in invertebrates and recently in mice have been shown to exhibit increased longevity, a paradoxical result. My laboratory is studying one of these models, Surf1-/- mice, that lack Surf1, an ETC Complex IV assembly protein and as a result have reduced complex IV activity and a surprising increase in median lifespan (20-25%). A recent study in C elegans also reported that reduced complex IV achieved by RNAi to cco1 increases lifespan, and furthermore that lifespan extension can be achieved even when complex IV reduction is restricted to neurons or intestine (Durieux et al., 2011). This is consistent with a previous study showing that reduction of Surf1 targeted to neuronal tissue in Drosophila leads to increased lifespan (Zordan et al., 2006). The extended lifespan in the cco1 C elegans mutants was shown to require the induction of the mitochondrial unfolded protein response (mtUPR), a mitochondrial stress response pathway. More importantly, neuron specific reduction in complex IV was shown to induce the mtUPR in a distal tissue (intestine) in association with increased lifespan. Taken together, these findings suggest a novel pathway by which alterations in mitochondrial function in one tissue can signal changes in a distal tissue and impact aging in the whole organism. The goal of the current study is to determine whether similar mechanisms occur in mammals, i.e., can a tissue-specific alteration in mitochondrial function regulate aging in distal tissues through a signaling pathway? We propose to test the hypothesis that tissue-specific reduction of complex IV will generate a systemically released signal sensed by distal tissues, up-regulation of mitochondrial stress response pathways (mtUPR and mitochondrial biogenesis) and alterations in metabolism that could contribute to increased lifespan. We have generated conditional Surf1 mice that will allow us to delete Surf1 in specific tissues to determine whether tissue-specific inhibition of complex IV confers an increase mitochondrial stress response pathways in distal tissues. We have shown that tissues from the long-lived Surf1-/- mice have up-regulation of the mtUPR in several tissues including brain and adipose tissue, along with significant alterations in metabolism and increased insulin sensitivity. Here we will determine whether a tissue-specific (brain and adipose tissue) reduction in complex IV in mice can induce mitochondrial stress response pathways in other tissues and whether these changes initiate the same beneficial metabolic changes we measured in Surf1-/- mice. We will also initiate experiments to define the potential signaling factor (or mitokine) responsible for signaling between tissues using mass spectrometry and proteomic techniques. The potential for mitochondria in one tissue to communicate and modulate function in distal tissues through a secreted factor is an exciting and novel concept that could represent a paradigm shift in our understanding of the role of mitochondrial function in aging.

Public Health Relevance

Studies in invertebrates suggest that aging can be modulated by mitochondrial alterations in a single tissue (brain/intestine) and that mitochondrial induced signaling between tissues may also play a key role. In this proposal, we seek to determine if similar mechanisms occur in mammals. In particular, we ask for the first time whether a tissue specific alteration in mitochondrial function can regulate mitochondrial function in distal tissues through a novel signaling pathway.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Aging Systems and Geriatrics Study Section (ASG)
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Finkelstein, David B
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Oklahoma Medical Research Foundation
Oklahoma City
United States
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