RESUMO
Autophagy is a fundamental multi-tasking adaptive cellular degradation and recycling strategy. Following its causal implication in age-related decline, autophagy is currently among the most broadly studied and challenged mechanisms within aging research. Thanks to these efforts, new cellular nodes interconnected with this phylogenetically ancestral pathway and unexpected roles of autophagy-associated genetic products are unveiled daily, yet the history of functional adaptations of autophagy along its evolutive trail is poorly understood and documented. Autophagy is traditionally studied in canonical and research-wise convenient model organisms such as yeast and mice. However, unconventional animal models endowed with extended longevity and exemption from age-related diseases offer a privileged perspective to inquire into the role of autophagy in the evolution of longevity. In this mini review we retrace the appearance and functions evolved by autophagy in eukaryotic cells and its protective contribution in the pathophysiology of aging.
Assuntos
Envelhecimento , Longevidade , Animais , Camundongos , Longevidade/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Autofagia/fisiologia , Saccharomyces cerevisiae , MamíferosRESUMO
Autophagy maintains cellular homeostasis and its dysfunction has been implicated in aging. Bats are the longest-lived mammals for their size, but the molecular mechanisms underlying their extended healthspan are not well understood. Here, drawing on >8 years of mark-recapture field studies, we report the first longitudinal analysis of autophagy regulation in bats. Mining of published population level aging blood transcriptomes (M. myotis, mouse and human) highlighted a unique increase of autophagy related transcripts with age in bats, but not in other mammals. This bat-specific increase in autophagy transcripts was recapitulated by the western blot determination of the autophagy marker, LC3II/I ratio, in skin primary fibroblasts (Myotis myotis,Pipistrellus kuhlii, mouse), that also showed an increase with age in both bat species. Further phylogenomic selection pressure analyses across eutherian mammals (n=70 taxa; 274 genes) uncovered 10 autophagy-associated genes under selective pressure in bat lineages. These molecular adaptations potentially mediate the exceptional age-related increase of autophagy signalling in bats, which may contribute to their longer healthspans.
Assuntos
Envelhecimento/genética , Autofagia/genética , Evolução Biológica , Quirópteros/genética , Longevidade/genética , Animais , Fibroblastos/metabolismo , Camundongos , TranscriptomaRESUMO
Bats possess extraordinary adaptations, including flight, echolocation, extreme longevity and unique immunity. High-quality genomes are crucial for understanding the molecular basis and evolution of these traits. Here we incorporated long-read sequencing and state-of-the-art scaffolding protocols1 to generate, to our knowledge, the first reference-quality genomes of six bat species (Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pipistrellus kuhlii and Molossus molossus). We integrated gene projections from our 'Tool to infer Orthologs from Genome Alignments' (TOGA) software with de novo and homology gene predictions as well as short- and long-read transcriptomics to generate highly complete gene annotations. To resolve the phylogenetic position of bats within Laurasiatheria, we applied several phylogenetic methods to comprehensive sets of orthologous protein-coding and noncoding regions of the genome, and identified a basal origin for bats within Scrotifera. Our genome-wide screens revealed positive selection on hearing-related genes in the ancestral branch of bats, which is indicative of laryngeal echolocation being an ancestral trait in this clade. We found selection and loss of immunity-related genes (including pro-inflammatory NF-κB regulators) and expansions of anti-viral APOBEC3 genes, which highlights molecular mechanisms that may contribute to the exceptional immunity of bats. Genomic integrations of diverse viruses provide a genomic record of historical tolerance to viral infection in bats. Finally, we found and experimentally validated bat-specific variation in microRNAs, which may regulate bat-specific gene-expression programs. Our reference-quality bat genomes provide the resources required to uncover and validate the genomic basis of adaptations of bats, and stimulate new avenues of research that are directly relevant to human health and disease1.
Assuntos
Adaptação Fisiológica/genética , Quirópteros/genética , Evolução Molecular , Genoma/genética , Genômica/normas , Adaptação Fisiológica/imunologia , Animais , Quirópteros/classificação , Quirópteros/imunologia , Elementos de DNA Transponíveis/genética , Imunidade/genética , Anotação de Sequência Molecular/normas , Filogenia , RNA não Traduzido/genética , Padrões de Referência , Reprodutibilidade dos Testes , Integração Viral/genética , Vírus/genéticaRESUMO
The Kuhl's pipistrelle (Pipistrellus kuhlii) is a small, vespertilionid bat species, with a large range extending from the Iberian Peninsula into the Near East and the Arabian Peninsula. In this study, we determine for the first time the complete mitogenome of this species. The P. kuhlii mitogenome is 16,991 base pairs long with 37 genes and 1 control region, showing conserved gene content and order with other vertebrate mitogenomes. The length of the 22 tRNA genes ranges between 60 bp (tRNA-Ser) and 75 bp (tRNA-Leu). The D-loop region is 1553 bp long with low CG content (39.8%).
