Impairment of Mitochondrial–Nuclear Cross Talk in Neutrophils of Patients with Type 2 Diabetes Mellitus

Abstract

Increased leukocyte apoptosis is intrinsically linked to disease patho-physiology, susceptibility to and severity of infections in type 2 diabetes mellitus (T2DM) patients. A consistent defect in neutrophil function is considered central to this increased risk for infections. Although redox imbalance is considered a potential mediator of these associated complications, detailed molecular evidence in clinical samples remains largely undetected. The study consisted of three groups (n = 50 each) of Asian Indians: early diagnosed diabetic patients, cases with late-onset diabetic complications and age and gender-matched healthy controls. We evaluated mitochondrial oxidative stress, levels of nuclear DNA damage and apoptosis in peripheral blood neutrophils isolated from T2DM patients. We observed that in both early and late diabetic subjects, the HbA1c levels in neutrophils were altered considerably with respect to healthy controls. Increased oxidative stress observed in both early and late diabetics imply the disentanglement of fine equilibrium of mitochondria-nuclear cross talk which eventually effected the augmentation of downstream nuclear cH2AX activation and caspase-3 expression. It would be overly naïve to refute the fact that mitochondrial deregulation in neutrophils perturbs immunological balance in type 2 diabetic conditions. By virtue of our data, we posit that maneuvering mitochondrial function might offer a prospective and viable method to modulate neutrophil function in T2DM. Nevertheless, similar investigations from other ethnic groups in conjunction with experimental evidences would be a preeminent need. Obviously, our study might aid to comprehend this complex interplay between mitochondrial dysfunction and neutrophil homeostasis in T2DM.

Successive exposure to moderate hypoxia does not affect glucose metabolism and substrate oxidation in young healthy men

“…Although the previous study by Mackenzie et al ( 2011) recruited patients with type 2 diabetes, the subjects in the present study were healthy adults with normal glycemic regulation. Patients with type 2 diabetes have lower glucose uptake ability by insulin (Gierach et al 2014) and insulin-independent signaling pathways (Barnes et al 2002; Sriwijitkamol et al 2006) due to increased fat mass (Saltiel and Olefsky 1996) or impaired mitochondrial function (Khan et al 2014). Nonetheless, sustained elevation of blood glucose concentration is thought to enable enhanced glucose uptake by hypoxic stimuli.…”

Mitochondrial anomalies driver to age associated degenerative human ailments

“…There should be a balance between oxidative stress and antioxidants as they are the major controller of the different cell proliferation processes. Despite a well established endogenous antioxidant system comprising of dismutase, catalase,and reduced glutathione, excessive levels of ROS are detrimental and may results in mitochondrial dysfunction (47)(48)(49). Oxidative damage to cells that results from an imbalance of ROS over production, particularly from O 2 _ and H 2 O 2 , is associated with a variety of cardiovascular diseases (CVD).…”

“…Oxidative damage to cells that results from an imbalance of ROS over production, particularly from O 2 _ and H 2 O 2 , is associated with a variety of cardiovascular diseases (CVD). Studies have also shown that increased ROS causes impaired mitochondria-nuclear crosstalk in endothelial cells (47) and neutrophils (48). Besides, age-related mitochondrial changes possibly affect different cellular physiological functions concurrently and contribute to progression of extensive range of age-related diseases.…”

“…However, it is a matter of debate that whether the insulin resistance seen in T2DM patients is related with altered mitochondrial function (67). An inverse correlation between mtDNA content in lymphocytes and glycolated hemoglobin levels have been recently reported in early and late diagnosed patients (48). Patti and co-workers showed that NRF-1 and PGC-1 expression decreases in insulin-resistant and diabetic subjects.…”

Molecular bio-dosimetry for carcinogenic risk assessment in survivors of Bhopal gas tragedy

“…Under normal physiological circumstances, the deleterious effects caused by the highly reactive nature of ROS are balanced by the presence of antioxidants, including glutathione, carotenoids, and antioxidant enzymes such as superoxide dismutase, glutathione reductase, catalase and glutathione peroxidase [32]. However, hyper-generated levels of ROS overwhelm the endogenous antioxidant defenses of the host cell, which in turn favors the production of excessive free radicals and thus emanation of oxidative stress [33]. Free radicals thus generated impact biochemical component of the cell, with lipids, proteins and nucleic acids being the most important targets.…”