Abstract

Diabetes and aging involve multiorgan damage to vital organs such as the liver, kidneys, and brain. Both diabetes and aging are characterized by elevated levels of reactive oxygen species (ROS) that induce mitochondrial damage, cellular damage, inflammation, and insulin resistance. As a protective strategy against ROS, cells activate the expression of genes that play a crucial mitochondrial protective role. Here, we propose to uncover a novel retrograde nuclear transcriptional program that protects against diabetes/ROS-induced mitochondrial stress. Our initial results show that ROS/stress-induced regulatory transcription programs are initiated by the movement of mitochondrial protein GPS2 into the nucleus. GPS2, known to suppress the transcription of key pro-inflammatory genes by inhibiting the NF-κB signaling, hence regulates the insulin sensitization in macrophages. Which epigenetically alter the expression of nuclear Mito-protectant genes by changing the binding of a transcription factor CTCF, a well-known chromatin binding protein. CTCF binds to the low-affinity promoter binding sites of around 300 Mito-protectant gene promoters upon ROS stress. This includes a key gene, SIRT1, which is crucial for maintaining mitochondrial health and inflammation, and enhances insulin secretion and sensitivity. The knockdown of CTCF diminishes the expression of protectant genes upon stress. Here, we aim to pinpoint the genomic and epigenetic alterations and underlying retrograde molecular mechanisms that protect the cell from ROS-induced cellular and mitochondrial damage.