Faculty mentor/PI email address
santhanam@rowan.edu
Keywords
Mitochondria, Transcriptomics, RNA-Sequencing, Lipid Deposition, Hepatocellular Stress, Gene Knockout
IRB or IACUC Protocol Number
2024-1383
Date of Presentation
5-6-2026 12:00 AM
Poster Abstract
Calcium overload during fatty diet consumption induces oxidative stress and mitochondrial apoptosis. Intramitochondrial magnesium inhibits calcium uptake into mitochondria; therefore, modulating the activity of the mitochondrial magnesium transporter Mrs2 may regulate calcium-induced hepatocellular stress. As previous work demonstrates that liver-specific Mrs2 inhibition increases hepatic lipid deposition, RNA-sequencing was performed to identify potential transcriptional mechanisms for hepatocellular stress.
Mrs2 knockout (Mrs2KO) mice were generated by crossing male Mrs2fl/fl mice with liver-specific-Cre transgenic mice. Eight-week-old wild-type (Mrs2WT) and Mrs2KO mice were placed on chow or high-fat diet (HFD) for 12 months (n=3/group). Whole liver was collected for RNA sequencing. Differential expression and pathway analyses were performed to compare the response to HFD in Mrs2WT and Mrs2KO mice. Statistical significance was evaluated as P-adj < 0.05.
In Mrs2KO mice, HFD induced differential expression of 216 genes associated with lipid metabolism, cytochrome P450 enzymes, cytokine signaling, nuclear receptor signaling, and positive regulation of the ERK1/ERK2 cascade. In Mrs2WT mice, HFD induced differential expression of 208 genes associated with retinol metabolism, steroid hormone biosynthesis, and negative regulation of the ERK1/ERK2 cascade. Key modulators of ERK phosphorylation were differentially expressed, suggesting increased activation in Mrs2KO mice and inactivation in Mrs2WT mice. Modulators of lipid accumulation in hepatocytes, including CD36 and Plin4, were upregulated in Mrs2KO mice, implicating an ERK-PPARγ cascade-mediated upregulation of fatty acid transport into hepatocytes.
Our results implicate mitochondrial magnesium availability as a significant regulator of nuclear transcription during dietary stress, via differential modulation of the ERK1/ERK2 cascade and transcription of lipid accumulation-enhancing genes.
Disciplines
Biochemical Phenomena, Metabolism, and Nutrition | Medical Neurobiology | Medicine and Health Sciences
Impaired Mitochondrial Magnesium Transport Induces Genome-Wide Transcriptional Changes in Hepatic Steatosis, Inflammatory Signaling, and Detoxification Pathways during High-Fat Diet Feeding
Calcium overload during fatty diet consumption induces oxidative stress and mitochondrial apoptosis. Intramitochondrial magnesium inhibits calcium uptake into mitochondria; therefore, modulating the activity of the mitochondrial magnesium transporter Mrs2 may regulate calcium-induced hepatocellular stress. As previous work demonstrates that liver-specific Mrs2 inhibition increases hepatic lipid deposition, RNA-sequencing was performed to identify potential transcriptional mechanisms for hepatocellular stress.
Mrs2 knockout (Mrs2KO) mice were generated by crossing male Mrs2fl/fl mice with liver-specific-Cre transgenic mice. Eight-week-old wild-type (Mrs2WT) and Mrs2KO mice were placed on chow or high-fat diet (HFD) for 12 months (n=3/group). Whole liver was collected for RNA sequencing. Differential expression and pathway analyses were performed to compare the response to HFD in Mrs2WT and Mrs2KO mice. Statistical significance was evaluated as P-adj < 0.05.
In Mrs2KO mice, HFD induced differential expression of 216 genes associated with lipid metabolism, cytochrome P450 enzymes, cytokine signaling, nuclear receptor signaling, and positive regulation of the ERK1/ERK2 cascade. In Mrs2WT mice, HFD induced differential expression of 208 genes associated with retinol metabolism, steroid hormone biosynthesis, and negative regulation of the ERK1/ERK2 cascade. Key modulators of ERK phosphorylation were differentially expressed, suggesting increased activation in Mrs2KO mice and inactivation in Mrs2WT mice. Modulators of lipid accumulation in hepatocytes, including CD36 and Plin4, were upregulated in Mrs2KO mice, implicating an ERK-PPARγ cascade-mediated upregulation of fatty acid transport into hepatocytes.
Our results implicate mitochondrial magnesium availability as a significant regulator of nuclear transcription during dietary stress, via differential modulation of the ERK1/ERK2 cascade and transcription of lipid accumulation-enhancing genes.