Authors: Mehvish Batool, Dr. M. Rizwan Alam
Disruption of blood supply (Ischemia) to heart and brain due to arterial occlusion is the fundamental cause of heart attack and brain stroke. These are the top diseases responsible for most deaths worldwide according to the World Health Organization. High blood pressure, smoking, diabetes, obesity and unhealthy diet are the leading risk factors for development of these pathologies. Opening of blocked arteries by angioplasty or by injecting tissue plasminogen activator remains the gold standard for treating heart and brain ischemia respectively. Although re-supply of blood (reperfusion) to the ischemic organ is crucial for saving the patient’s life, entry of fresh blood in the starved tissue can instigate further damage known as Ischemia-Reperfusion Injury (IRI). Death of heart and brain cells by necrosis is the primary cellular event which participates in the pathogenesis of IRI. Unfortunately, despite decades of research in this area of medicine, not a single clinically approved drug is commercially available to ameliorate IRI.
The Pore Behind IRI
Mitochondria are little bioenergetic factories of the cells specialized for saving our lives by providing energy. Their importance can be realized by the fact that >30% volume of heart tissue is composed of mitochondria for an uninterrupted supply of energy throughout our lives.
Calcium concentration in the mitochondria is an important regulatory switch that fine-tunes ATP synthesis and other mitochondrial functions.
These metabolic engines supply approximately 90% of ATP required for functioning of the heart. Interestingly, calcium concentration in the mitochondria is an important regulatory switch that fine-tunes ATP synthesis and other mitochondrial functions. However, under stressful conditions like IRI, mitochondria accumulate overwhelmingly high calcium which in combination with oxidative stress can cause the formation of a tiny pore in the mitochondrial membrane known as Permeability Transition Pore (mPTP). Calcium-induced opening of mPTP is the major trigger for starting a complex series of molecular events that culminate in the death of cardiomyocytes and neurons during IRI.
What is mPTP?
mPTP is a non-specific, high-conductance mega-channel located in the inner mitochondrial membrane. In physiological conditions, it displays a transient and flickering opening that contributes to mitochondrial bioenergetics and ion homeostasis. However, a prolonged opening of mPTP may lead to mitochondrial depolarization, bioenergetic collapse and swelling that can stimulate pro-apoptotic or pro-necrotic pathways leading to cellular demise. Molecular identity of mPTP is one of the greatest enigmas of cell biology research. Despite work of many decades, a consensus does not exist on the proteins involved in the formation of mPTP which has seriously hindered the global efforts to develop therapeutic drugs for inhibiting IRI.
During recent years ATP synthase, a molecular motor that performs ATP synthesis, has received much attention as a promising target that may form mPTP. However, many questions still remain about the conversion of this life-saving protein into mPTP.
Although, low matrix pH during ischemia serves as an inhibitor of mPTP, normalization of pH during reperfusion is one of the contributing factors for mPTP opening.
How Reperfusion Causes mPTP opening?
During reperfusion, as the ischemic tissue starts getting enough oxygen, the mitochondria come under stress due to accumulation of matrix calcium. Dysfunction of electron transport chain causes the production of reactive oxygen species (ROS). Although, low matrix pH during ischemia serves as an inhibitor of mPTP, normalization of pH during reperfusion is one of the contributing factors for mPTP opening.
A dire need exists to identify the exact molecular nature of ‘the pore’ that will pave the way for development of authentic mPTP inhibitors in order to protect the patients from lethal outcomes of IRI.
The oxygen return causes the recommencement of respiration and ATP synthesis. Resulting increased mitochondrial membrane potential accelerates the uptake of calcium into matrix. Likewise, the availability of oxygen causes increased production of ROS. Thus, an amalgamation of calcium accumulation, ROS imbalance and matrix pH normalization leads to opening of MPTP that allows entry of molecules up to 1.5 KDa. Influx of water and solutes ultimately lead to rupture of mitochondrial membranes instigating cell death.
Can mPTP be a Therapeutic Target for Heart Attack and Brain Stroke?
Despite lack of agreement on the exact identity of mPTP, it is considered as one of the potential therapeutic targets for cardiovascular diseases including heart attack and brain stroke. A plethora of pre-clinical studies have demonstrated the attenuation of IRI upon inhibition of mPTP. However, failure of several clinical trials has impeded the translation of drugs from bench to bed-side. Therefore, a dire need exists to identify the exact molecular nature of ‘the pore’ that will pave the way for development of authentic mPTP inhibitors in order to protect the patients from lethal outcomes of IRI.