Persistent organic pollutants (POPs) are lipid-soluble toxins that are not easily degraded; therefore, they accumulate in the environment and the human body. Several studies have indicated a correlation between POPs and metabolic diseases; however, their effects on mitochondria as a central organelle in cellular metabolism and the usage of mitochondria as functional markers for metabolic disease are barely understood. In this study, a zebrafish model system was exposed to two subclasses of POPs, organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), under two different conditions (solitary OCPs or OCPs with PCBs (Aroclor 1254)), and changes in the oxidative stress marker levels and mitochondrial enzyme activities in the electron transport chain of the tail were measured to observe the correlation between POPs and representative biomarkers for metabolic disease. The results indicated different responses upon exposure to OCPs and OCPs with Aroclor 1254, and accelerated toxicity was observed following exposure to mixed POPs (OCPs with Aroclor 1254). Males were more sensitive to changes in the levels of oxidative stress markers induced by POP exposure, whereas females were more susceptible to the toxic effects of POPs on the levels of mitochondrial activity markers. These results demonstrate that the study reflects real environmental conditions, with low-dose and multiple-toxin exposure for a long period, and that POPs alter major mitochondrial enzymes’ functions with an imbalance of redox homeostasis in a sex-dependent manner.

Type 2 diabetes (T2D) is characterized by defects in insulin action to target tissues, resulting in hyperglycemia, insulin resistance, and mitochondrial dysfunction. The eye is one of the organs susceptible to T2D, but knowledge regarding mitochondrial dysfunction in the eyes after hyperglycemia and T2D is based mainly on epidemiological evidence, with little experimental data. POPs are known as endocrine-disrupting chemicals and are associated with uncontrolled glucose and lipid metabolism, leading to the onset of diabetes. To determine the relationship between POPs and T2D, two model systems were developed: glucose-immersed zebrafish to induce hyperglycemia, and zebrafish exposed to low-dose POPs in a water circulating system for three months. To examine the role of mitochondrial function, the activity of mitochondrial complexes I, II, III, and IV from the eyes of the two zebrafish models was measured spectrophotometrically. Enhanced enzymatic activities of mitochondrial complexes III and IV were observed in the eyes of both hyperglycemia and low-dose POPs exposed models, especially in male zebrafish. These results demonstrate that POPs alleviate mitochondrial oxidative phosphorylation (OXPHOS) in a sex-dependent manner through a compensatory mechanism, which is also observed in acute hyperglycemia.

Type 2 diabetes mellitus is characterized by insulin resistance and pancreatic beta (β)-cell dysfunction. Accumulating evidence suggests that mitochondrial dysfunction may cause insulin resistance in peripheral tissues. As commercial hypoglycemic drugs have side effects, it is necessary to develop safe and effective natural compound-based hypoglycemic treatments. This study aimed to investigate the hypoglycemic effects of Mori Ramulus ethanol extract (ME) in a high-fat diet (HFD)-induced diabetes mouse model to decipher the underlying mechanisms focusing on apoptosis and mitochondrial function. ME significantly decreased tunicamycin-induced apoptotic cell death and increased insulin secretion following glucose stimulation in NIT-1 pancreatic β-cells. Tunicamycin-exposed NIT-1 pancreatic β-cells showed elevated reactive oxygen species levels and reduced mitochondrial membrane potential, which were reversed by ME treatment. ME inhibited the tunicamycin-induced apoptosis cascade in tunicamycin-exposed NIT-1 pancreatic β-cells. In HFD diabetic mice, the serum-free fatty acid and insulin levels decreased following a 15-week ME administration. Glucose and insulin tolerance tests showed that ME improved insulin sensitivity. Moreover, ME ameliorated pancreatic β-cell mass loss in diabetic mice. Finally, ME-treated HFD-fed mice showed improved hepatic mitochondrial function resulting in insulin sensitivity in target tissues. Thus, ME provides protection against pancreatic β-cell apoptosis and prevents insulin resistance by improving mitochondrial function.

Eun Ko · Seul-I Ku · Dae-yoon Kim · Sooim Shin · Moonsung Choi. JABC 2018;61:367-70. https://doi.org/10.3839/jabc.2018.051