The effect of low-density lipoprotein cholesterol on T-cell mitochondrial respiration

Aging is associated with an increase in chronic, sterile, low-grade inflammation, known as “inflammaging” that is implicated in the development of multiple diseases, including cardiovascular disease. Immune cells are the primary source of inflammaging, of which T-cells play a major contributing role. Mitochondria are essential for maintaining proper T-cell function and reduced mitochondrial respiration (MitoRESP) induces T-cell dysfunction and shifts T-cells towards a pro-inflammatory phenotype. Elevated low-density lipoprotein cholesterol (LDL-C) is cross-sectionally associated with lower MitoRESP in circulating immune cells and may contribute to the inflammaging phenotype, but whether LDL-C is causally related to impaired MitoRESP in T-cells is not known. We hypothesized that treating T-cells in vitro with a high concentration of exogenous LDL-C would mimic accelerated aging by impairing T-cell MitoRESP from young adults. Seven young adults were recruited for this study (6 female / 1 male, age: 23 ± 2 years, BMI: 23.29 ± 6.4 kg/m2, total cholesterol: 154 ± 16 mg/dl, high-density lipoprotein cholesterol: 59 ± 17 mg/dL, & LDL-C: 78 ± 14 mg/dL). CD4+ and CD8+ T-cells were separated from peripheral blood mononuclear cells isolated using magnetic bead separation (Miltenyi). CD4+ and CD8+ T-cells were treated exogenously with a physiologically normal (1.8 mMol/L) and high (4.9 mMol/L) concentration of LDL-C for 24 hours. MitoRESP was assessed using extracellular flux analysis (Agilent). Compared with the low LDL condition, the high LDL-C condition lowered basal (0.47 ± 0.06 vs. 0.35 ± 0.10 pMol/min/105 cells, p=0.031) and ATP-linked oxygen consumption rate (OCR) (0.51 ± 0.13 vs. 0.35 ± 0.12 pMol/min/105 cells, p=0.016) in CD8+ T-cells. High LDL-C also lowered non-mitochondrial OCR (0.71 ± 0.22 vs. 0.57 ± 0.20 pMol/min/105 cells, p=0.016) and augmented basal glycolysis (0.097 ± 0.049 vs. 0.14 ± 0.036 pMol/min/105 cells, p=0.031) in CD8+ T-cells. High LDL-C lowered ATP-linked OCR (0.69 ± 0.23 vs. 0.54 ± 0.22 pMol/min/105 cells, p=0.031) and non-mitochondrial OCR (0.80 ± 0.17 vs. 0.68 ± 0.21 pMol/min/105 cells, p=0.016), but did not statistically alter basal OCR (0.47 ± 0.056 vs. 0.35 ± 0.10 pMol/min/105 cells, p=0.063) or basal glycolysis (0.14 ± 0.031 vs. 0.18 ± 0.028 pMol/min/105 cells, p=0.063) in CD4+ T-cells. Treatment with a high LDL-C accelerated aging in T-cells from young adults by impairing MitoRESP and shifting T-cells towards glycolytic metabolism. Future studies should explore the relation between age-related impairments in T-cell MitoRESP and cardiovascular function in humans. Funding Sources: P20GM113125 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.