Back to Search
Start Over
Inhibition of mitochondrial complex I improves glucose metabolism independently of AMPK activation.
- Source :
- Journal of Cellular & Molecular Medicine; Feb2018, Vol. 22 Issue 2, p1316-1328, 13p
- Publication Year :
- 2018
-
Abstract
- Abstract: Accumulating evidences showed metformin and berberine, well‐known glucose‐lowering agents, were able to inhibit mitochondrial electron transport chain at complex I. In this study, we aimed to explore the antihyperglycaemic effect of complex I inhibition. Rotenone, amobarbital and gene silence of NDUFA13 were used to inhibit complex I. Intraperitoneal glucose tolerance test and insulin tolerance test were performed in db/db mice. Lactate release and glucose consumption were measured to investigate glucose metabolism in HepG2 hepatocytes and C2C12 myotubes. Glucose output was measured in primary hepatocytes. Compound C and adenoviruses expressing dominant negative AMP‐activated protein kinase (AMPK) α1/2 were exploited to inactivate AMPK pathway. Cellular NAD<superscript>+</superscript>/NADH ratio was assayed to evaluate energy transforming and redox state. Rotenone ameliorated hyperglycaemia and insulin resistance in db/db mice. It induced glucose consumption and glycolysis and reduced hepatic glucose output. Rotenone also activated AMPK. Furthermore, it remained effective with AMPK inactivation. The enhanced glycolysis and repressed gluconeogenesis correlated with a reduction in cellular NAD<superscript>+</superscript>/NADH ratio, which resulted from complex I suppression. Amobarbital, another representative complex I inhibitor, stimulated glucose consumption and decreased hepatic glucose output <italic>in vitro</italic>, too. Similar changes were observed while expression of NDUFA13, a subunit of complex I, was knocked down with gene silencing. These findings reveal mitochondrial complex I emerges as a key drug target for diabetes treatment. Inhibition of complex I improves glucose homoeostasis <italic>via</italic> non‐AMPK pathway, which may relate to the suppression of the cellular NAD<superscript>+</superscript>/NADH ratio. [ABSTRACT FROM AUTHOR]
- Subjects :
- BERBERINE
LACTATES
ROTENONE
BENZOPYRANS
GENE silencing
Subjects
Details
- Language :
- English
- ISSN :
- 15821838
- Volume :
- 22
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- Journal of Cellular & Molecular Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 127562948
- Full Text :
- https://doi.org/10.1111/jcmm.13432