Abstract
Mitochondrial dysfunction is a hallmark of multiple cardiovascular disorders, including ischemic heart disease. Although mitochondria are well recognized for their role in energy production and cell death, mechanisms by which they control excitation-contraction coupling, excitability, and arrhythmias are less clear. The translocator protein (TSPO) is an outer mitochondrial membrane protein that is expressed in multiple organ systems. The abundant expression of TSPO in macrophages has been leveraged to image the immune response of the heart to inflammatory processes. More recently, the recognition of TSPO as a regulator of energy-dissipating mitochondrial pathways has extended its utility from a diagnostic marker of inflammation to a therapeutic target influencing diverse pathophysiological processes. Here, we provide an overview of the emerging role of TSPO in ischemic heart disease. We highlight the importance of TSPO in the regenerative process of reactive oxygen species (ROS) induced ROS release through its effects on the inner membrane anion channel (IMAC) and the permeability transition pore (PTP). We discuss evidence implicating TSPO in arrhythmogenesis in the settings of acute ischemia-reperfusion injury and myocardial infarction.
Highlights
The translocator protein (TSPO), formerly known as the peripheral benzodiazepine receptor (PBR), is an 18 kDa mitochondrial protein consisting of 169 amino acids [1]
We highlight the link between TSPO and the pathological process of reactive oxygen species (ROS) induced ROS release (RIRR) which we propose to be a master regulator of electrical dysfunction on one hand and cell death on the other hand
We demonstrated the functional significance of ROS induced ROS release TSPO (RIRR) in terms of arrhythmia propensity [42,43,44,45]
Summary
The translocator protein (TSPO), formerly known as the peripheral benzodiazepine receptor (PBR), is an 18 kDa mitochondrial protein consisting of 169 amino acids [1]. Enriched in the outer mitochondrial membrane (OMM), TSPO is an integral component of a macromolecular complex of proteins that regulates cell survival and death pathways [1, 2]. The widespread distribution of TSPO is consistent with its diverse physiological functions. These include, but are not limited to, membrane biogenesis, heme biosynthesis, immunomodulation, bioenergetics, redox balance, apoptosis, and cholesterol binding and transport [1, 7,8,9,10,11]. We highlight the link between TSPO and the pathological process of reactive oxygen species (ROS) induced ROS release (RIRR) which we propose to be a master regulator of electrical dysfunction on one hand and cell death on the other hand. We implicate TSPO in the adverse remodeling associated with ischemia-reperfusion injury and myocardial infarction, both of which are major risk factors for arrhythmias (Figure 1)
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