Transient complex I inhibition at the onset of reperfusion by extracellular acidification decreases cardiac injury

Abstract

A reversible inhibition of mitochondrial respiration by complex I inhibition at the onset of reperfusion decreases injury in buffer-perfused hearts. Administration of acidic reperfusate for a brief period at reperfusion decreases cardiac injury. We asked if acidification treatment decreased cardiac injury during reperfusion by inhibiting complex I. Exposure of isolated mouse heart mitochondria to acidic buffer decreased the complex I substrate-stimulated respiration, whereas respiration with complex II substrates was unaltered. Evidence of the rapid and reversible inhibition of complex I by an acidic environment was obtained at the level of isolated complex, intact mitochondria and in situ mitochondria in digitonin-permeabilized cardiac myocytes. Moreover, ischemia-damaged complex I was also reversibly inhibited by an acidic environment. In the buffer-perfused mouse heart, reperfusion with pH 6.6 buffer for the initial 5 min decreased infarction. Compared with untreated hearts, acidification treatment markedly decreased the mitochondrial generation of reactive oxygen species and improved mitochondrial calcium retention capacity and inner mitochondrial membrane integrity. The decrease in infarct size achieved by acidic reperfusion approximates the reduction obtained by a reversible, partial blockade of complex I at reperfusion. Extracellular acidification decreases cardiac injury during reperfusion in part via the transient and reversible inhibition of complex I, leading to a reduction of oxyradical generation accompanied by a decreased susceptibility to mitochondrial permeability transition during early reperfusion.

Inhibition of mitochondrial complex I improves glucose metabolism independently of AMPK activation

“…In this study, inhibition of complex I presented no toxicity in all experiments. In addition to the beneficial effects of complex I inhibition on glucose metabolism, a number of studies revealed that administration of complex I inhibitor, that is rotenone or amobarbital, before cardiac ischaemia onset significantly attenuated damage to mitochondria and decreased myocardial injury . The UK Prospective Diabetes Study (UKPDS) Group reported metformin significantly reduced cardiovascular mortality in overweight diabetic patients , the protective effect of metformin on cardiovascular system may be due to the complex I inhibition.…”

“…In this study, inhibition of complex I presented no toxicity in all experiments. In addition to the beneficial effects of complex I inhibition on glucose metabolism, a number of studies revealed that administration of complex I inhibitor, that is rotenone or amobarbital, before cardiac ischaemia onset significantly attenuated damage to mitochondria and decreased myocardial injury [24][25][26][27][28][29]. The UK Fig.…”

Activation of volume-sensitive Cl− channel mediates autophagy-related cell death in myocardial ischaemia/reperfusion injury

“…However reperfusion may contribute to newer myocardial injury called as myocardial ischemia/reperfusion (I/R) injury, in which oxidative damage plays a critical role to initiate excess reactive oxygen species (ROS) generation and eventually progresses to cell necrotic, apoptotic and autophagic cell death [3–5]. Current anti-apoptosis has been largely reported to protect the heart from I/R injury, however increasing evidence indicates that modulation of autophagy is a novel therapeutic strategy in myocardial I/R injury [6–8].…”

Electron flow into cytochrome c coupled with reactive oxygen species from the electron transport chain converts cytochrome c to a cardiolipin peroxidase: role during ischemia–reperfusion

“…H 2 O 2 release is an index of oxidants directed toward the intermembrane space, whereas aconitase provides and indication of oxidants directed toward the matrix [34]. Using succinate plus rotenone as substrates, inhibition of complex II with TTFA or inhibition of the Qi site of complex III with antimycin A each increased the release of H 2 O 2 from mitochondria (succinate+rotenone 51±4; plus TTFA 67±16; plus antimycin A 86±16; pmol/min/mg, ±SE, n=3).…”

“…The production and release of H 2 O 2 from mitochondria was measured using Amplex Red as previously described [33]. Oxidative stress in the mitochondrial matrix was assessed by measurement of the oxidatively sensitive enzyme aconitase [34, 35]. …”