Protecting mitochondrial bioenergetic function

Raúl J Gazmuri ,Iyad M Ayoub ,Jeejabai Radhakrishnan

doi:10.22514/sv51.092010.7

Abstract

Reversal of cardiac arrest requires reestablishment of aerobic metabolism by reperfusion with oxygenated blood of tissues that have been ischemic for variables periods of time. However, reperfusion concomitantly activates a myriad of pathogenic mechanisms causing what is known as “reperfusion injury.” At the center of reperfusion injury are mitochondria, playing a critical role as effectors and targets of injury. Mitochondrial injury compromises oxidative phosphorylation and the ability to regenerate Adenosine-5'-triphosphate (ATP); i.e., bioenergetic function. Thus targeting mitochondria to protect bioenergetic function may represent a novel concept in resuscitation with the potential for altering clinical practice. We have identified sodium-hydrogen exchanger isoform-1 (NHE)-1 inhibition and erythropoietin as attractive candidate drugs for this purpose and demonstrated corresponding functional and clinical benefits. Further work on the subject may pave the way for further scientific discover focused on greater understating of underlying cell mechanisms, identification of additional and perhaps more potent strategies, and develop means for effective drug delivery.

Highlights

The working heart is a highly metabolic organ that under normal resting conditions extracts nearly 70% of the oxygen supplied by the coronary circulation [1,2] representing close to 10% of the total body oxygen consumption
The severe energy imbalance continues during the ensuing resuscitation effort when current closed-chest resuscitation techniques are used because of the very limited capability for generating systemic and coronary blood flow
Main contributors to reperfusion injury are mitochondrial Ca2+ overload [5,6] and generation of reactive oxygen species (ROS). [7] Various functional myocardial abnormalities develop consequent to ischemia and reperfusion during cardiac arrest and resuscitation that exert effects detrimental to cardiac resuscitation. These abnormalities can be grouped into those that manifest during the resuscitation effort and those that manifest after the return of spontaneous circulation

Summary

Introduction

The working heart is a highly metabolic organ that under normal resting conditions extracts nearly 70% of the oxygen supplied by the coronary circulation [1,2] representing close to 10% of the total body oxygen consumption. Work from our laboratory supports the concept that interventions able to protect mitochondrial bioenergetic function can prevent reductions in left ventricular myocardial distensibility during cardiopulmonary resuscitation (CPR), facilitate return of spontaneous circulation, ameliorate post-resuscitation myocardial dysfunction and improve resuscitation and survival with intact neurological function.

Results

Conclusion