Graduation Semester and Year

Spring 2025

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Quantitative Biology

Department

Biology

First Advisor

Mark Pellegrino

Second Advisor

Piya Ghose

Third Advisor

Clay Clark

Fourth Advisor

Subhrangsu S. Mandal

Fifth Advisor

Cara Boutte

Abstract

The lifespan of an organism is dictated by various genetic and environmental factors. One such determinant is the health of mitochondria which are organelles that mediate various critical cell functions including a significant role in generating the vast supply of cellular energy. Indeed, the gradual decline of mitochondrial function is believed to be a hallmark and possible cause of aging. Paradoxically, mild mitochondrial dysfunction early in life extends lifespan in various model organisms. Cells use diverse approaches to promote mitochondrial homeostasis, including the transcriptional reprogramming of cells by mitochondrial unfolded protein response (UPRmt) to mitigate mitochondrial stress. Consistently, UPRmt activation is correlated with mitochondrial stress conditions that prolong animal longevity including mild defects in mitochondrial respiration and mitochondrial translation. We have previously shown that changes in nutrient availability can activate the UPRmt and extend lifespan, specially through the restriction of the amino acid methionine. However, a detailed mechanistic insight into this relationship is lacking. Here, we leveraged the powerful genetics of the model organism Caenorhabditis elegans to dissect the regulation of the UPRmt and lifespan resulting from methionine restriction. Using this approach, we have identified novel regulators of methionine restriction associated UPRmt activity and lifespan extension including neuropeptide signaling and the canonical TGF-beta signaling pathway.

Keywords

Metabolism, stress, mitochondria

Disciplines

Bioinformatics | Cell Biology | Developmental Biology | Genetics | Genomics | Immunity | Organismal Biological Physiology | Other Animal Sciences | Pathogenic Microbiology

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