Metabolic regulation of intestinal stem cell function in Drosophila melanogaster

Aging is a degenerative process characterized by the accumulation of cellular damage that results in altered tissue homeostasis, organ function, and, ultimately, death. Tissues with the potential for regeneration (muscle) or that undergo cellular turnover (intestine, blood, skin) rely on populations of adult stem or progenitor cells to divide and replace damaged cells to maintain tissue homeostasis. One hallmark of aging is reduced stem cell function, which can lead to decreased tissue homeostasis. The exact mechanisms for aging are still unclear, but recent evidence suggests an important role for adult stem cells in organismal aging. Current reports indicate that alterations in adult stem cell function via changes in stem cell metabolism can have widespread effects on tissue homeostasis and aging. Thanks to its relatively short lifespan and amenability to genetic manipulations, the model organism Drosophila melanogaster provides a convenient system to study the interaction between somatic stem cell metabolism and aging. A recently discovered population of intestinal stem cells in Drosophila bears many similarities to the stem cells of the mammalian small intestine. Genetic tractability, a simple cell lineage, and conserved pathways that regulate stem cell behavior combine to make the Drosophila midgut epithelium a powerful model system for the study of stem cell regulation and tissue homeostasis. Here, we show that increased mitochondrial biogenesis or enhanced electron transport chain function in the intestinal stem cells results in increased tissue homeostasis, a delay in age-related midgut phenotypes, and increased lifespan. This prompted us to study the roles of mitochondrial dynamics (fission, fusion, movement, and turnover) on intestinal stem cell function. We demonstrate that loss of either of two, mitophagy-related genes, pink1 or parkin, in Drosophila ISCs leads to: severe alterations in mitochondrial structure, nearly complete inhibition of stem cell proliferation during aging or stress, and the appearance of senescence-associated markers within the ISCs.