Abstract

This study investigated whether changes in metabolism occur during granulosa cells (GCs) senescence and the mechanisms that regulate these changes. Experimental laboratory study. We used excessive oxidative stress to induce cell senescence and examined the phenotype of aging. Protein and gene expression of different enzymes related to metabolism in senescent granulosa cells were analyzed by qPCR, protein array or immunofluorescence. Further, we applied bioinformatics methods and integrated publicly available resources to study the role of CREB1 gene expression in reproduction. Here, we show that mitochondrial regulator CREB1 is induced by excessive oxidative stress (OS) in human HGL5 granulosa cells, and at the cellular level, OS-like activation of CREB1 impacts a network that integrates mitochondrial status with metabolism and growth parameters. Proteomics profiling reveals that diverse functions, including biogenesis pathways, growth, structure, and macromolecule homeostasis, are responsive to CREB1. Delayed cellular proliferation, altered cytoskeleton, and attenuated growth signaling through post-transcriptional and post-translational mechanisms were also identified as outcomes of CREB1-directed mitochondrial activation. Furthermore, endogenous CREB1 expression was correlated with this same metabolism and growth network. These data show that small changes in metabolism have broad consequences that arguably would profoundly alter cell function. We suggest that this CREB1 sensitive network may be the basis for the association between mitochondrial function and aging where small deficiencies precipitate loss of function across a spectrum of cellular activities.

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