Mitochondria and Mitophagy: The Yin and Yang of Cell Death Control

University of California, San Diego, 9500 Gilman Dr MC 0758, La Jolla, CA 92093-0758. .
Circulation Research (Impact Factor: 11.09). 10/2012; 111(9):1208-21. DOI: 10.1161/CIRCRESAHA.112.265819
Source: PubMed

ABSTRACT Mitochondria are primarily responsible for providing the contracting cardiac myocyte with a continuous supply of ATP. However, mitochondria can rapidly change into death-promoting organelles. In response to changes in the intracellular environment, mitochondria become producers of excessive reactive oxygen species and release prodeath proteins, resulting in disrupted ATP synthesis and activation of cell death pathways. Interestingly, cells have developed a defense mechanism against aberrant mitochondria that can cause harm to the cell. This mechanism involves selective sequestration and subsequent degradation of the dysfunctional mitochondrion before it causes activation of cell death. Induction of mitochondrial autophagy, or mitophagy, results in selective clearance of damaged mitochondria in cells. In response to stress such as ischemia/reperfusion, prosurvival and prodeath pathways are concomitantly activated in cardiac myocytes. Thus, there is a delicate balance between life and death in the myocytes during stress, and the final outcome depends on the complex cross-talk between these pathways. Mitophagy functions as an early cardioprotective response, favoring adaptation to stress by removing damaged mitochondria. In contrast, increased oxidative stress and apoptotic proteases can inactivate mitophagy, allowing for the execution of cell death. Herein, we discuss the importance of mitochondria and mitophagy in cardiovascular health and disease and provide a review of our current understanding of how these processes are regulated.

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    • "Apoptosis, also called programmed cell death, plays a critical role in many biological processes including development, maintenance of homeostasis and immune defense [1] [2]. Apoptosis is a complex and highly regulated cellular process and the delicate balance between the pro-and anti-apoptotic mechanisms determines whether a cell will commit suicide or live when a cell is under stress and the cell death signal is activated [3] [4]. Apoptosis is usually divided into two pathways: the intrinsic or mitochondrial pathway and the extrinsic or death receptor pathway [2]. "
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    ABSTRACT: Apoptosis plays significant roles in maintenance of homeostasis, immune defense and development. The Bcl-2 family proteins are important regulators of the intrinsic apoptosis. In the study, we have characterized a Bcl-2-like gene (named CfBcl-2) and a Bax-like gene (named CfBax) from the Zhikong scallop Chlamys farreri. The full-length of the CfBcl-2 cDNA is 944 nucleotides (nt) encoding a putative protein of 225 amino acid residues (aa) that contains four Bcl-2 homology (BH) domains, and the CfBax cDNA is 505 nt encoding a putative protein of 115 aa that contains three Bcl-2 BH domains. Sequence and phylogenetic analysis demonstrate that CfBcl-2 and CfBax present typical domain organization of the corresponding Bcl-2 related proteins and are more similar and clustered with their homologues of other molluscs. The two genes are ubiquitously expressed in six tissues of C. farreri, with the highest expression level of CfBcl-2 in adductor muscle and highest expression level of CfBax in gill. The expressions of CfBcl-2 and CfBax in hemocytes were both significantly up-regulated after an in vivo exposure of scallops to air, injection with lipopolysaccharide and infection with acute viral necrobiotic disease virus, and the expression patterns of the two genes after the three treatments vary in different change magnitude and up-regulation timespan. Yeast two-hybrid assay reveals a direct interaction between the CfBcl-2 and CfBax proteins. These results indicate that the CfBcl-2 and CfBax may participate in the apoptosis-based stress and immune responses against noxious stimulation. Copyright © 2015. Published by Elsevier Ltd.
    Fish &amp Shellfish Immunology 02/2015; 44(1). DOI:10.1016/j.fsi.2015.02.011 · 3.03 Impact Factor
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    • "Selective autophagic degradation of mitochondria is termed mitophagy [53] [54] [55]. Although mitochondria may be degraded during nonselective autophagy, it is now clear that functional status of mitochondria degraded during generalized autophagy may be very different from the functional status of mitochondria targeted for selective degradation by mitophagy [25] [53]. The mitochondrial fission can facilitate removal of damaged mitochondrial components by partitioning them to a daughter mitochondrion that can then be targeted and removed by mitophagy [56]. "
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    ABSTRACT: Diabetic cardiomyopathy (DCM) is a common consequence of longstanding type 2 diabetes mellitus (T2DM) and encompasses structural, morphological, functional, and metabolic abnormalities in the heart. Myocardial energy metabolism depends on mitochondria, which must generate sufficient ATP to meet the high energy demands of the myocardium. Dysfunctional mitochondria are involved in the pathophysiology of diabetic heart disease. A large body of evidence implicates myocardial insulin resistance in the pathogenesis of DCM. Recent studies show that insulin signaling influences myocardial energy metabolism by impacting cardiomyocyte mitochondrial dynamics and function under physiological conditions. However, comprehensive understanding of molecular mechanisms linking insulin signaling and changes in the architecture of the mitochondrial network in diabetic cardiomyopathy is lacking. This review summarizes our current understanding of how defective insulin signaling impacts cardiac function in diabetic cardiomyopathy and discusses the potential role of mitochondrial dynamics. Copyright © 2015 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 02/2015; 1853(5). DOI:10.1016/j.bbamcr.2015.02.005 · 5.30 Impact Factor
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    • "In turn, ROS and ATP depletion activate cell death pathways, which induce the release of proapoptotic proteins from mitochondria. Macroautophagy may mitigate these effects by the selective sequestration and subsequent degradation of the dysfunctional mitochondria and other ROS-damaged subcellular structures before the activation of prodeath pathways [30] [35] [36]. Thus, macroautophagy, and, in particular, mitophagy, most likely represents a key prosurvival pathway in cells exposed to palladium. "
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