Proinflammatory cytokine MIF plays a role in the pathogenesis of type-2 diabetes mellitus, but does not affect hepatic mitochondrial function.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in the pathogenesis of type 2 diabetes mellitus (T2DM). Although the effect of high glucose on liver function has been described, the role of MIF in hepatic mitochondrial function during T2DM has not been studied. OBJECTIVE: We examine the influence of MIF to hepatic mitochondrial function in T2DM mouse model. METHODS: WT and Mif-/- BALB/c mice were treated with a single dose of streptozotocin (STZ). After an 8-week follow-up, serum glucose, proinflammatory cytokines, C-reactive protein (CRP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzyme quantification, and liver histological analyses were performed. Liver mitochondria were extracted, and mitochondrial function was evaluated by oximetry, swelling and peroxide production. RESULTS: Following treatment with STZ, WT mice (WT/STZ) developed significant hyperglycemia and high serum levels of MIF, tumor necrosis factor (TNF)-α, interleukin-ß (IL-ß), and CRP. Liver damage enzymes ALT and AST were found at high levels. In contrast, Mif-/-STZ lacked serum MIF levels and showed smaller increases in blood glucose, less TNF-α, IL-1ß, CPR, ALT and AST, and failure to develop clinical signs of disease compared to the WT/STZ group. Mitochondria extracted from the Mif-/-STZ liver showed similar respiratory control (RC) to WT/STZ or healthy mice with glutamate/malate or succinate as substrates. The four respiratory chain complexes also had comparable activities. WT/STZ-isolated mitochondria showed low swelling with calcium compared to mitochondria from Mif-/-STZ or healthy mice. Peroxide production was comparable in all groups. CONCLUSION: These results show although high systemic levels of MIF contribute to the development of T2DM pathology, the liver mitochondria remain unaltered. Importantly, the absence of MIF reduced the pathology of T2DM, also without altering liver mitochondrial function. These support MIF as a therapeutic target for the treatment of this disease in humans.

Cardiomiopatia mitocôndrica hipertrófica associada à síndrome de Wolff-Parkinson-White / Mitochondrial hypertrophic cardiomyopathy associated with Wolff-Parkinson-White syndrome

Atualmente, diversas doenças cardíacas são reconhecidas como de origem genética. As mutações em genes, que codificam várias proteínas do sarcômero com desarranjo miofibrilar e dos miócitos, e a mutação associada à síndrome de Wolff-Parkinson-White, identificada no cromossomo 7q3 como resultado de uma mutação pontual no gene, que codifica uma subunidade reguladora de AMP - proteína quinase ativada, expressa em hipertrofia ventricular, pré-excitação ventricular ou ambas, são dois exemplos de cardiomiopatia hipertrófica familiar 1-3. Outras doenças cardíacas congênitas, nas quais a cardiomiopatia hipertrófica ou dilatada e distúrbios elétricos, podem estar presentes em cerca de 20 a 30 por cento de pacientes, incluem algumas doenças mitocondriais4-6. Apresentamos um caso de uma recém nascida com taquicardia persistente secundaria à síndrome de Wolf-Parkinson-White, na qual hipertrofia importante e outras anormalidades sistêmicas foram atribuídas à doença mitocondrial.