Altered mitochondrial function is tightly linked to lifespan regulation, but underlying mechanisms remain unclear. Here, we report the chronological and replicative lifespan variation across 168 yeast knock-out strains, each lacking a single nuclear-coded mitochondrial gene, including 144 genes with human homologs, many associated with diseases. We dissected the signatures of observed lifespan differences by analyzing profiles of each strain's proteome, lipidome, and metabolome under fermentative and respiratory culture conditions, which correspond to the metabolic states of replicative and chronologically aging cells, respectively. Examination of the relationships among extended longevity phenotypes, protein, and metabolite levels revealed that although many of these nuclear-encoded mitochondrial genes carry out different functions, their inhibition attenuates a common mechanism that controls cytosolic ribosomal protein abundance, actin dynamics, and proteasome function to regulate lifespan. The principles of lifespan control learned through this work may be applicable to the regulation of lifespan in more complex organisms, since many aspects of mitochondrial function are highly conserved among eukaryotes.
Cognitive decline has been reported as a common consequence of COVID-19, and studies have suggested a link between COVID-19 infection and Alzheimer's disease (AD). However, the molecular mechanisms underlying this association remain unclear. To shed light on this link, we conducted an integrated genomic analysis using a novel Robust Rank Aggregation method to identify common transcriptional signatures of the frontal cortex, a critical area for cognitive function, between individuals with AD and COVID-19. We then performed various analyses, including the KEGG pathway, GO ontology, protein-protein interaction, hub gene, gene-miRNA, and gene-transcription factor interaction analyses to identify molecular components of biological pathways that are associated with AD in the brain also show similar changes in severe COVID-19. Our findings revealed the molecular mechanisms underpinning the association between COVID-19 infection and AD development and identified several genes, miRNAs, and TFs that may be targeted for therapeutic purposes. However, further research is needed to investigate the diagnostic and therapeutic applications of these findings.
Altered mitochondrial function is tightly linked to lifespan regulation, but underlying mechanisms remain unclear. Here, we report the chronological and replicative lifespan variation across 167 yeast knock-out strains, each lacking a single nuclear-coded mitochondrial gene, including 144 genes with human homologs, many associated with diseases. We dissected the signatures of observed lifespan differences by analyzing profiles of each strain’s proteome, lipidome, and metabolome under fermentative and respiratory culture conditions, which correspond to the metabolic states of replicative and chronologically aging cells, respectively. Examination of the relationships among extended longevity phenotypes, protein, and metabolite levels revealed that although many of these nuclear-encoded mitochondrial genes carry out different functions, their inhibition attenuates a common mechanism that controls cytosolic ribosomal protein abundance, actin dynamics, and proteasome function to regulate lifespan. The principles of lifespan control learned through this work may be applicable to the regulation of lifespan in more complex organisms, since many aspects of mitochondrial function are highly conserved among eukaryotes.
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