TY - JOUR
T1 - Pancreatic mitochondrial complex I exhibits aberrant hyperactivity in diabetes
AU - Wu, Jinzi
AU - Luo, Xiaoting
AU - Thangthaeng, Nopporn
AU - Sumien, Nathalie
AU - Chen, Zhenglan
AU - Rutledge, Margaret A.
AU - Jing, Siqun
AU - Forster, Michael J.
AU - Yan, Liang Jun
N1 - Funding Information:
This work was supported in part by UNTHSC seed Grants RI10015 and RI10039 to LJY who was also supported in part by NIH (Grant#: R01NS079792). SJ was supported in part by the 2016 Innovation Talents of International Cooperation Projects of China Scholarship Council (Grant no. [2015]7642).
Publisher Copyright:
© 2017 The Authors
PY - 2017/9
Y1 - 2017/9
N2 - It is well established that NADH/NAD+ redox balance is heavily perturbed in diabetes, and the NADH/NAD+ redox imbalance is a major source of oxidative stress in diabetic tissues. In mitochondria, complex I is the only site for NADH oxidation and NAD+ regeneration and is also a major site for production of mitochondrial reactive oxygen species (ROS). Yet how complex I responds to the NADH/NAD+ redox imbalance and any potential consequences of such response in diabetic pancreas have not been investigated. We report here that pancreatic mitochondrial complex I showed aberrant hyperactivity in either type 1 or type 2 diabetes. Further studies focusing on streptozotocin (STZ)-induced diabetes indicate that complex I hyperactivity could be attenuated by metformin. Moreover, complex I hyperactivity was accompanied by increased activities of complexes II to IV, but not complex V, suggesting that overflow of NADH via complex I in diabetes could be diverted to ROS production. Indeed in diabetic pancreas, ROS production and oxidative stress increased and mitochondrial ATP production decreased, which can be attributed to impaired pancreatic mitochondrial membrane potential that is responsible for increased cell death. Additionally, cellular defense systems such as glucose 6-phosphate dehydrogenase, sirtuin 3, and NQO1 were found to be compromised in diabetic pancreas. Our findings point to the direction that complex I aberrant hyperactivity in pancreas could be a major source of oxidative stress and β cell failure in diabetes. Therefore, inhibiting pancreatic complex I hyperactivity and attenuating its ROS production by various means in diabetes might serve as a promising approach for anti-diabetic therapies.
AB - It is well established that NADH/NAD+ redox balance is heavily perturbed in diabetes, and the NADH/NAD+ redox imbalance is a major source of oxidative stress in diabetic tissues. In mitochondria, complex I is the only site for NADH oxidation and NAD+ regeneration and is also a major site for production of mitochondrial reactive oxygen species (ROS). Yet how complex I responds to the NADH/NAD+ redox imbalance and any potential consequences of such response in diabetic pancreas have not been investigated. We report here that pancreatic mitochondrial complex I showed aberrant hyperactivity in either type 1 or type 2 diabetes. Further studies focusing on streptozotocin (STZ)-induced diabetes indicate that complex I hyperactivity could be attenuated by metformin. Moreover, complex I hyperactivity was accompanied by increased activities of complexes II to IV, but not complex V, suggesting that overflow of NADH via complex I in diabetes could be diverted to ROS production. Indeed in diabetic pancreas, ROS production and oxidative stress increased and mitochondrial ATP production decreased, which can be attributed to impaired pancreatic mitochondrial membrane potential that is responsible for increased cell death. Additionally, cellular defense systems such as glucose 6-phosphate dehydrogenase, sirtuin 3, and NQO1 were found to be compromised in diabetic pancreas. Our findings point to the direction that complex I aberrant hyperactivity in pancreas could be a major source of oxidative stress and β cell failure in diabetes. Therefore, inhibiting pancreatic complex I hyperactivity and attenuating its ROS production by various means in diabetes might serve as a promising approach for anti-diabetic therapies.
KW - Complex I
KW - Diabetes
KW - Hyperactivity
KW - Mitochondria
KW - Pancreas
KW - Redox imbalance
KW - Streptozotocin
UR - http://www.scopus.com/inward/record.url?scp=85024836942&partnerID=8YFLogxK
U2 - 10.1016/j.bbrep.2017.07.007
DO - 10.1016/j.bbrep.2017.07.007
M3 - Article
AN - SCOPUS:85024836942
SN - 2405-5808
VL - 11
SP - 119
EP - 129
JO - Biochemistry and Biophysics Reports
JF - Biochemistry and Biophysics Reports
ER -