Modulation of mitochondrial biogenesis by the Integrated Stress Response (ISR)

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Project Summary Mitochondrial function declines during aging. The dysfunction is accelerated in age-associated diseases such as Alzheimer’s Disease and Parkinson’s Disease. Thus, therapeutic approaches to maintain or recover mitochondrial function may promote healthy aging or slow age-associated disease progression. Recently, we have shown that the mitochondrial network expansion that occurs during development is an emergent property of the synthesis of highly expressed mitochondrial proteins. Increased mitochondrial import of the highly expressed mitochondrial proteins outcompete the transcription factor ATFS-1, preventing it from entering mitochondria. This allows ATFS-1 to traffic to the nucleus and activate a mitochondrial network expansion transcription program known as UPRmt. These findings suggest an interplay between protein synthesis, mitochondria protein import capacity, and mitochondrial network expansion. The Integrated Stress Response (ISR) is a translation control pathway that reduces overall protein synthesis while preferentially increases translation of ATF-4 in response to diverse stressors including amino acid depletion, ER dysfunction and mitochondrial perturbations. The ISR is mediated by 4 kinases (3 in C. elegans) that all phosphorylate the translation initiation factor eIF2α, which in turn modulates protein synthesis. While considerable work has demonstrated that the ISR is active in response to mitochondrial perturbation, the functional outputs of the ISR related to mitochondrial biology remain unknown. I have obtained or generated several C. elegans strains in which the ISR is impaired. Quite surprisingly, these worms have increased mitochondrial mass and mitochondrial genomes. Intriguingly, these animals also live significantly longer than wildtype worms, suggesting that increased mitochondrial mass is sufficient to extend organismal lifespan. I hypothesize that the ISR matches mitochondrial network expansion with the physiological and environmental inputs that activate the ISR by antagonizing ATFS-1 function. Here, I focus on the role of ISR-dependent translation attenuation or ATF-4 synthesis as direct or indirect regulators of ATFS-1-dependent transcription via the following aims. 1. Determine the mechanisms by which the ISR regulates ATFS-1-dependent mitochondrial biogenesis. 2. Elucidate the mechanisms by which the ISR modulates longevity and healthspan.