ABSTRACT
Throughout Earth's history, evolution's numerous natural 'experiments' have resulted in a diverse range of phenotypes. Though de novo phenotypes receive widespread attention, degeneration of traits inherited from an ancestor is a very common, yet frequently neglected, evolutionary path. The latter phenomenon, known as regressive evolution, often results in vertebrates with phenotypes that mimic inherited disease states in humans. Regressive evolution of anatomical and/or physiological traits is typically accompanied by inactivating mutations underlying these traits, which frequently occur at loci identical to those implicated in human diseases. Here we discuss the potential utility of examining the genomes of vertebrates that have experienced regressive evolution to inform human medical genetics. This approach is low cost and high throughput, giving it the potential to rapidly improve knowledge of disease genetics. We discuss two well-described examples, rod monochromacy (congenital achromatopsia) and amelogenesis imperfecta, to demonstrate the utility of this approach, and then suggest methods to equip non-experts with the ability to corroborate candidate genes and uncover new disease loci.
Subject(s)
Evolution, Molecular , Genetic Loci , Genetic Predisposition to Disease , Genome , Genomics , Models, Genetic , Vertebrates/genetics , Amelogenesis Imperfecta/diagnosis , Amelogenesis Imperfecta/genetics , Animals , Color Vision Defects/diagnosis , Color Vision Defects/genetics , Genetic Association Studies , Genomics/methods , Humans , Mutation , Phenotype , PseudogenesABSTRACT
Stem cell aging contributes to aging-associated tissue degeneration and dysfunction. Recent studies reveal a mitochondrial metabolic checkpoint that regulates stem cell quiescence and maintenance, and dysregulation of the checkpoint leads to functional deterioration of aged stem cells. Here, we present the evidence supporting the mitochondrial metabolic checkpoint regulating stem cell aging and demonstrating the feasibility to target this checkpoint to reverse stem cell aging. We discuss the mechanisms by which mitochondrial stress leads to stem cell deterioration. We speculate the therapeutic potential of targeting the mitochondrial metabolic checkpoint for rejuvenating aged stem cells and improving aging tissue functions.
Subject(s)
Cellular Senescence , Mitochondria/metabolism , Rejuvenation , Stem Cells/cytology , Animals , Cell Proliferation , Humans , Mice , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Oxidative Stress , Phenotype , Protein Folding , Sirtuin 2/metabolism , Sirtuin 3/metabolism , Sirtuins/metabolismABSTRACT
The mitochondrial unfolded protein response (UPRmt ), a cellular protective program that ensures proteostasis in the mitochondria, has recently emerged as a regulatory mechanism for adult stem cell maintenance that is conserved across tissues. Despite the emerging genetic evidence implicating the UPRmt in stem cell maintenance, the underlying molecular mechanism is unknown. While it has been speculated that the UPRmt is activated upon stem cell transition from quiescence to proliferation, the direct evidence is lacking. In this study, we devised three experimental approaches that enable us to monitor quiescent and proliferating hematopoietic stem cells (HSCs) and provided the direct evidence that the UPRmt is activated upon HSC transition from quiescence to proliferation, and more broadly, mitochondrial integrity is actively monitored at the restriction point to ensure metabolic fitness before stem cells are committed to proliferation.