Inhibition of the Mitochondrial Permeability Transition for Cytoprotection: Direct versus Indirect Mechanisms.

Cécile Martel,Le Ha Huynh,Catherine Brenner,Anne Garnier,Renée Ventura-Clapier

doi:10.1155/2012/213403

Abstract

Mitochondria are fascinating organelles, which fulfill multiple cellular functions, as diverse as energy production, fatty acid β oxidation, reactive oxygen species (ROS) production and detoxification, and cell death regulation. The coordination of these functions relies on autonomous mitochondrial processes as well as on sustained cross-talk with other organelles and/or the cytosol. Therefore, this implies a tight regulation of mitochondrial functions to ensure cell homeostasis. In many diseases (e.g., cancer, cardiopathies, nonalcoholic fatty liver diseases, and neurodegenerative diseases), mitochondria can receive harmful signals, dysfunction and then, participate to pathogenesis. They can undergo either a decrease of their bioenergetic function or a process called mitochondrial permeability transition (MPT) that can coordinate cell death execution. Many studies present evidence that protection of mitochondria limits disease progression and severity. Here, we will review recent strategies to preserve mitochondrial functions via direct or indirect mechanisms of MPT inhibition. Thus, several mitochondrial proteins may be considered for cytoprotective-targeted therapies.

Highlights

Mitochondria are intracellular organelles, whose first discovered function is energy production by oxidative phosphorylation [1]
Since the emergence of the concept of mitochondrial control of cell death in the 95’s, it became evident that mitochondria participate to various types of cell death, that are, apoptosis, necrosis, oncosis and mitotic catastrophy via mitochondrial membrane permeabilization (MMP), release of proapoptotic factors contained in the intermembrane space to the cytosol and possibly fission, even if mitochondrial fragmentation is not sufficient per se to induce cell death [4, 5]
Silencing of cyclophilin D (CypD) by siRNA to prevent the induction of mitochondrial permeability transition (MPT) is becoming mandatory in cellulo, since the genetic demonstration that CypD is critical for MPT and cell death [35]

Summary

Introduction

Mitochondria are intracellular organelles, whose first discovered function is energy production by oxidative phosphorylation [1]. In chronic pathologies, such as cardiac volume overloadinduced hypertrophy [8], mitochondrial dysfunction precedes cell loss by apoptosis and necrosis, meaning that both dysfunctions can be separated chronologically during the progression of the disease. This is observed in the pathogenesis of nonalcoholic steatohepatitis, whatever its initial cause, as extensively reviewed [9]. Biochemistry Research International by a decrease in energy production and energy transfer capacity [10] This leads to a decrease in energy charge of the myocardium that has been described as a prognostic factor in dilated cardiomyopathies [11]. The discussion of MPT regulatory mechanisms will be based on selected articles focusing on heart diseases and cancer

Mitochondrial Membrane Permeability and PTPC

Direct Mechanisms of MPT Inhibition

Findings

Conclusion and Open Questions