Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance.

Abstract

PURPOSE:

Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance.

METHODS AND RESULTS:

DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨm) depolarization, exhibited attenuated insulin signaling and 2-deoxy-d-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H2O2), they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨm depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H2O2-induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨm depolarization and impaired 2-DG uptake, however they improved insulin signaling.

CONCLUSIONS:

A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance.

• Authors: Tomoyuki Watanabe, Masao Saotome, Mamoru Nobuhara, Atsushi Sakamoto, Tsuyoshi Urushida, Hideki Katoh, Hiroshi Satoh, Makoto Funaki, Hideharu Hayashi
• Journal: Experimental cell research (Exp Cell Res) Vol. 323 Issue 2 Pg. 314-25 (May 01 2014) ISSN: 1090-2422 [Electronic] United States
• PMID: 24631294 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Insulin
• Palmitates
• Porphyrins
• Reactive Oxygen Species
• tetra(4-N-methylpyridyl)porphine
• Hydrogen Peroxide
• Dnm1l protein, rat
• Dynamins

Topics

• Animals
• Cell Line
• Dynamins (genetics, metabolism)
• Hydrogen Peroxide (toxicity)
• Insulin (pharmacology)
• Insulin Resistance
• Membrane Potential, Mitochondrial
• Mitochondria, Heart (drug effects, metabolism)
• Myocytes, Cardiac (drug effects, metabolism)
• Palmitates (pharmacology)
• Porphyrins (pharmacology)
• Rats
• Reactive Oxygen Species (metabolism)