Mitochondrial Damage: A Target for New Therapeutic Horizons

Abstract

Summary: Traumatic brain injury (TBI) represents a leading cause of death and morbidity, as well as a considerable social and economical burden in western countries, and has thus emerged as a formidable therapeutic challenge. Yet despite tremendous efforts enlightening the mechanisms of neuronal death, hopes for the "magic bullet" have been repeatedly deceived, and TBI management has remained focused on the control of increased intracranial pressure. Indeed, impairment of cerebral metabolism is traditionally attributed to impaired oxygen delivery mediated by reduced cerebral perfusion in the swollen cerebral parenchyma. Although intuitively appealing, this hypothesis is not entirely supported by physiological facts and does not take into consideration mitochondrial dysfunction that has been repeatedly reported in both human and animal TBI. Although the nature and origin of the events leading to mitochondrial damage may be different, most share a permeabilization of mitochondrial membrane, which therefore may represent a logical target for new therapeutic strategies. Therefore, the proteins mediating these events may represent promising targets for new TBI therapies. Furthermore, mimicking anti-apoptotic proteins, such as Bcl-2 or XIAP, or inhibiting mitochondrial pro-apoptotic proteins, such as Smac/DIABLO, Omi/HTRA2, and ARTS (septin 4 isoform 2) may represent useful novel therapeutic strategies. This review focuses on mechanisms of the mitochondrial membrane permeabilization and its consequences and discusses the current and possible future therapeutic implications of this key event of neuronal death.

Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death

“…Mitochondrial proteins are considered to be potential therapeutic targets of many apoptosis-related diseases (Soustiel and Larisch 2010). Two main mitochondria proteins have been identified in mammalian cells, Smac/DIABLO and Omi/HtrA2 (Wilkinson et al 2004).…”

Improvement of Cerebral Metabolism Mediated by Ro5-4864 is Associated with Relief of Intracranial Pressure and Mitochondrial Protective Effect in Experimental Brain Injury

“…Accumulating evidence shows that mitochondrial damage represents a crucial step toward delayed neuronal death following TBI, both as a target for multiple pathophysiological subcellular events, such as free radicals and calcium load, and as the source of activation of the so-called intrinsic apoptotic pathway (9)(10)(11). Despite the different nature and the origin of these mechanisms, most are characterized by permeabilization of the mitochondrial membrane (MMP) with subsequent dissipation of Δψ M and disruption of ATP production and may, therefore, represent a logical target for new therapeutic strategies (9,(11)(12)(13)(14). The 18 kDa translocator protein (TSPO), also known as peripheral-type benzodiazepine receptor, is a binding protein complex (15) located at the outer mitochondrial membrane and associated with two core components of the mPTP: the 32-kDa voltagedependent anion channel and the 30-kDa adenine nucleotide translocator (16).…”

Can Soy Diet be Protective in Severe and Diffuse Traumatic Brain Injury?

“…It has also been suggested that soy isoflavones, have scavenging function [40]. The disruption of BBB is also due to development of inflammatory mechanisms [41]. Anti-inflammatory effect of soy isoflavone has been demonstrated [42].…”