T cells display mitochondria hyperpolarization in human type 1 diabetes

Abstract

T lymphocytes constitute a major effector cell population in autoimmune type 1 diabetes. Despite essential functions of mitochondria in regulating activation, proliferation, and apoptosis of T cells, little is known regarding T cell metabolism in the progression of human type 1 diabetes. In this study, we report, using two independent cohorts, that T cells from patients with type 1 diabetes exhibited mitochondrial inner-membrane hyperpolarization (MHP). Increased MHP was a general phenotype observed in T cell subsets irrespective of prior antigen exposure, and was not correlated with HbA1C levels, subject age, or duration of diabetes. Elevated T cell MHP was not detected in subjects with type 2 diabetes. T cell MHP was associated with increased activation-induced IFNγ production, and activation-induced IFNγ was linked to mitochondria-specific ROS production. T cells from subjects with type 1 diabetes also exhibited lower intracellular ATP levels. In conclusion, intrinsic mitochondrial dysfunction observed in type 1 diabetes alters mitochondrial ATP and IFNγ production; the latter is correlated with ROS generation. These changes impact T cell bioenergetics and function.

Human CD8+T-cells Require Glycolysis to Elicit Effector Function

“…Studies in disease models of lupus have previously shown that 2DG treatment of mice reduced the biomarkers and disease-associated changes through normalization of T-cell metabolism 14 . In T1D, studies using murine models have indicated that T-cell mitochondrial dysfunction may participate in the pathogenesis 15 . We have also more recently discovered that T-cells from patients with T1D, exhibit mitochondrial inner membrane hyperpolarization (MHP) when compared to controls 15 .…”

“…In T1D, studies using murine models have indicated that T-cell mitochondrial dysfunction may participate in the pathogenesis 15 . We have also more recently discovered that T-cells from patients with T1D, exhibit mitochondrial inner membrane hyperpolarization (MHP) when compared to controls 15 . Further, mitochondrial respiration and glycolysis are dysregulated in T-cells from T1D patients.…”

Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways

“…This data is consistent with previous observations where overexpression of IRGM leads to mitochondrial fission and depolarization (Singh et al, 2010), and here we observed fused and hyperpolarized mitochondria in IRGM deficient cells. The hyperpolarized state of mitochondria is often associated with the production of mitochondrial reactive oxygen species (mtROS) leading to apoptosis or necrosis and also autoimmune diseases (Angajala et al, 2018;Chen et al, 2017;Galloway and Yoon, 2012;Gergely et al, 2002a;Gergely et al, 2002b;Perl et al, 2004). Indeed, the mitochondrial superoxide and cellular total ROS levels, as measured by MitoSOX™ and CellRox™ dyes, were elevated in IRGM-depleted THP-1 cells, mice BMDM's and human PBMC's ( Figure 5P, Supplementary figure 5G and 5H).…”

Multistable Thermal Actuators Via Multimaterial 4D Printing

“…[35] In fact, there have been several recent works on 3D-printed local bistabilities that could be used for deployment and energy absorption. [32,[36][37][38] However, these works were mainly limited to simpler translational motion. In our rotational structure design, special joints are introduced that allow 3D printing of the whole structure without postassembly.…”