The mitochondrial death pathway: a promising therapeutic target in diseases

Abstract

The mitochondrial pathway to apoptosis is a major pathway of physiological cell death in vertebrates. The mitochondrial cell death pathway commences when apoptogenic molecules present between the outer and inner mitochondrial membranes are released into the cytosol by mitochondrial outer membrane permeabilization (MOMP). BCL-2 family members are the sentinels of MOMP in the mitochondrial apoptotic pathway; the pro-apoptotic B cell lymphoma (BCL)-2 proteins, BCL-2 associated x protein and BCL-2 antagonist killer 1 induce MOMP whereas the anti-apoptotic BCL-2 proteins, BCL-2, BCL-xl and myeloid cell leukaemia 1 prevent MOMP from occurring. The release of pro-apoptotic factors such as cytochrome c from mitochondria leads to formation of a multimeric complex known as the apoptosome and initiates caspase activation cascades. These pathways are important for normal cellular homeostasis and play key roles in the pathogenesis of many diseases. In this review, we will provide a brief overview of the mitochondrial death pathway and focus on a selection of diseases whose pathogenesis involves the mitochondrial death pathway and we will examine the various pharmacological approaches that target this pathway.

Essential role of mitochondria in apoptosis of cancer cells induced by the marine alkaloid Lamellarin D

“…We observed a reduced expression of the Bcl-2 protein associated with a conformational activation of Bax. These Bcl-2 family proteins normally function to control the mitochondrial release of cytochrome c (25). However, our results show a reduction in Bcl-2 level long after the onset of cytochrome c release (2).…”

Mechanisms of Mitochondrial Damage in Keratinocytes by Pemphigus Vulgaris Antibodies

“…In addition, mitochondria often play an essential role in physiological cell death mechanisms (reviewed in Ref. 41). The results of the present study indicate that binding of PVIgG to mitochondrial targets can disrupt the electron transfer chain, resulting in a decline in ATP production, loss of electrochemical gradient across the inner membrane, and reduction in O 2 with increased generation of the ROS superoxide, hydrogen peroxide, and hydroxyl radical.…”

Cryptotanshinone protects against adriamycin-induced mitochondrial dysfunction in cardiomyocytes

“…Changes in MMP-controlled matrix remodeling lead to increased superoxide anion free radical (Herlein et al, 2011). Matrix remodeling to the condensed state results in crystal unfolding and exposes cytochrome c to the intermembrane space facilitating superoxide anion free radical increased during the injury on mitochondria (Gupta et al, 2009;Näpänkangas et al, 2012). Excessive generation of superoxide anion free radical amounts can break the balance in cellular reductionoxidation (redox) and disrupt normal cellular functions.…”