Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury.

Abstract

Acute kidney injury (AKI) is a complication of sepsis and leads to a high mortality rate. Human and animal studies suggest that mitochondrial dysfunction plays an important role in sepsis-induced multi-organ failure; however, the specific mitochondrial targets damaged during sepsis remain elusive. We used a clinically relevant cecal ligation and puncture (CLP) murine model of sepsis and assessed renal mitochondrial function using high-resolution respirometry, renal microcirculation using intravital microscopy, and renal function. CLP caused a time-dependent decrease in mitochondrial complex I and II/III respiration and reduced ATP. By 4 h after CLP, activity of manganese superoxide dismutase (MnSOD) was decreased by 50% and inhibition was sustained through 36 h. These events were associated with increased mitochondrial superoxide generation. We then evaluated whether the mitochondria-targeted antioxidant Mito-TEMPO could reverse renal mitochondrial dysfunction and attenuate sepsis-induced AKI. Mito-TEMPO (10 mg/kg) given at 6 h post-CLP decreased mitochondrial superoxide levels, protected complex I and II/III respiration, and restored MnSOD activity by 18 h. Mito-TEMPO also improved renal microcirculation and glomerular filtration rate. Importantly, even delayed therapy with a single dose of Mito-TEMPO significantly increased 96-h survival rate from 40% in untreated septic mice to 80%. Thus, sepsis causes sustained inactivation of three mitochondrial targets that can lead to increased mitochondrial superoxide. Importantly, even delayed therapy with Mito-TEMPO alleviated kidney injury, suggesting that it may be a promising approach to treat septic AKI.

• Authors: Naeem K Patil, Nirmala Parajuli, Lee Ann MacMillan-Crow, Philip R Mayeux
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 306 Issue 7 Pg. F734-43 (Apr 01 2014) ISSN: 1522-1466 [Electronic] United States
• PMID: 24500690 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Electron Transport Chain Complex Proteins
• MitoTEMPO
• Organophosphorus Compounds
• Piperidines
• Adenosine Triphosphate
• Superoxide Dismutase
• superoxide dismutase 2
• Electron Transport Complex II
• Electron Transport Complex IV
• Electron Transport Complex I
• Electron Transport Complex III

Topics

• Acute Kidney Injury (enzymology, pathology, physiopathology, prevention & control)
• Adenosine Triphosphate (metabolism)
• Animals
• Antioxidants (pharmacology)
• Body Temperature Regulation (drug effects)
• Cell Respiration (drug effects)
• Disease Models, Animal
• Electron Transport Chain Complex Proteins (metabolism)
• Electron Transport Complex I (metabolism)
• Electron Transport Complex II (metabolism)
• Electron Transport Complex III (metabolism)
• Electron Transport Complex IV (metabolism)
• Kidney (blood supply, drug effects, enzymology, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Microcirculation (drug effects)
• Mitochondria (drug effects, enzymology, pathology)
• Organophosphorus Compounds (pharmacology)
• Oxidative Stress (drug effects)
• Piperidines (pharmacology)
• Renal Circulation (drug effects)
• Sepsis (drug therapy, enzymology, pathology, physiopathology)
• Superoxide Dismutase (metabolism)
• Time Factors