title: Role and clinical significance of lymphocyte mitochondrial dysfunction in type 2 diabetes mellitus.
abstract: Lymphocyte homeostasis in type 2 diabetes mellitus (T2DM) is associated with increased susceptibility to infections. Mitochondrial oxidative stress is implicated primarily in the immune pathophysiology of diabetes; however, the molecular underpinnings of lymphocyte mitochondrial dysfunction and ensuing downstream cellular effects are hitherto unreported. Both in early diagnosed patients and patients with late complications, we observed an inverse correlation between mitochondrial DNA content in lymphocytes and hemoglobin A1 (HbA1c) levels. This relation established for the first time might serve as a general, yet direct, predictor or indicator for mitochondrial dysfunction in T2DM. Compared with controls, nuclear DNA damage response was higher (P ≤ 0.001) in diabetic subjects with increased accumulation of phospho-ataxia-telangiectasia (ATM), γ-H2AX, along with active recruitment of repair proteins (Mre11, Rad50, and Nbs1). A higher frequency (>2%) of stable chromosomal anomalies with loss of telomere integrity was observed in cases with late complications. A significant decrease (P ≤ 0.001) in enzyme activity of complex II, III, and IV of mitochondrial respiratory chain was evident in both diabetic groups in comparison with healthy controls. Activation in the cascade of nuclear factor kappa-beta (NF-κβ)-mediated feed-forward proinflammatory cytokine response was noted among T2DM subjects. Increased oxidative stress, mitochondrial membrane depolarization, activation of caspase-3, and PARP observed in diabetic groups indicated bax triggered mitochondrial mediated cellular apoptosis. Our results provide the first insights of lymphocyte mitochondrial dysfunction that might be helpful in explaining the clinical significance of immunologic perturbation observed in type 2 diabetic conditions. Our data also indicate that maneuvering through the mitochondrial function might be a viable, indirect method to modulate lymphocyte homeostasis in T2DM.
authors: Research Wing, Bhopal Memorial Hospital & Research Centre, Bhopal, India.
authors: Saba
authors: S
authors: Khan
authors: Gorantla V
authors: GV
authors: Raghuram
authors: Arpit
authors: A
authors: Bhargava
authors: Neelam
authors: N
authors: Pathak
authors: Dolly H
authors: DH
authors: Chandra
authors: Subodh K
authors: SK
authors: Jain
authors: Pradyumna K
authors: PK
authors: Mishra
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000276:immunology; D064007:Ataxia Telangiectasia Mutated Proteins; D015415:Biomarkers / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002869:Chromosome Aberrations; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology; D004272:DNA, Mitochondrial / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006657:Histones / Q000378:metabolism; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007239:Infections / Q000276:immunology* / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000276:immunology* / Q000378:metabolism; D018384:Oxidative Stress / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016615:Telomere / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D018797:Cell Cycle Proteins; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases