Coordinating mitochondrial network expansion and longevity via the Integrated Stress Response (ISR)

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Project Summary Mitochondrial function declines during normal aging and is accelerated in age-associated diseases such as Parkinson’s and Alzheimer’s. Thus, understanding how cells and organisms regulate mitochondrial network expansion during growth to meet cell-specific requirements, and maintain that mitochondrial network during aging, are essential steps to limiting pathologies associated with mitochondrial dysfunction and prolonging lifespan. Our published findings indicate that the mitochondrial network expansion that occurs during development is an emergent property of the synthesis of highly expressed mitochondrial proteins and ATFS-1- dependent mitochondrial UPR activation. Increased import flux of highly expressed mitochondrial proteins excludes the transcription factor ATFS-1 from mitochondria resulting in nuclear trafficking and UPRmt activation, which includes a mitochondrial biogenesis program. These findings suggest an interplay between protein synthesis, mitochondrial protein import capacity, and mitochondrial network expansion. Here, we examine the role of a translation control pathway known as the Integrated Stress Response (ISR) on the regulation of mitochondrial network expansion during development and aging. Surprisingly, our preliminary findings indicate that worms with an impaired ISR have substantially more mitochondrial biomass and increased longevity, suggesting potential approaches to recover mitochondrial function in aged cells. We hypothesize that the ISR provides two functions during cell growth; 1) it regulates protein synthesis rates via eIF2α phosphorylation so as not to overwhelm network assembly and expansion, and 2) increases ATFS-1/ATF5 expression to activate a transcriptional program to facilitate mitochondrial network expansion. While considerable work has demonstrated that the ISR is active during mitochondrial dysfunction, the functional outputs of the ISR as related to the mitochondrial network remain unclear. We will test this hypothesis in both C. elegans and mammalian cell culture via the following aims: 1. The role of the ISR in regulating mitochondrial network expansion in C. elegans. 2. Determine the impact of ISR-mediated translation regulation on C. elegans longevity. 3. Elucidate the role of the ISR in establishing a functional mitochondrial network in mammalian cells.