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: 11.02). 10/2012; 111(9):1208-21. DOI: 10.1161/CIRCRESAHA.112.265819
Source: PubMed


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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    • "In response to various environmental stresses, cellular ATP synthesis can be disrupted. Mitochondria then become major producers of ROS, which causes cellular damage and can initiate the apoptotic pathway (Kubli & Gustafsson, 2012). "
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    ABSTRACT: Cardiac hypertrophy is often initiated as an adaptive response to hemodynamic stress or myocardial injury, and allows the heart to meet an increased demand for oxygen. Although initially beneficial, hypertrophy can ultimately contribute to the progression of cardiac disease, leading to an increase in interstitial fibrosis and a decrease in ventricular function. Metabolic changes have emerged as key mechanisms involved in the development and progression of pathological remodelling. As a highly oxidative tissue, mitochondria play a central role in maintaining optimal performance of the heart. "Mitochondrial dynamics", the processes of mitochondrial fusion, fission, biogenesis and mitophagy that determine mitochondrial morphology, quality, and abundance, have recently been implicated in cardiovascular disease. Studies link mitochondrial dynamics to the balance between energy demand and nutrient supply, suggesting that changes in mitochondrial morphology may act as a mechanism for bioenergetic adaptation during cardiac pathological remodelling. Another critical function of mitochondrial dynamics is the removal of damaged and dysfunctional mitochondria through mitophagy, which is dependent on the fission/fusion cycle. In this article, we discuss the latest findings regarding the impact of mitochondrial dynamics and mitophagy on the development and progression of cardiovascular pathologies, including diabetic cardiomyopathy, atherosclerosis, damage from ischemia-reperfusion, cardiac hypertrophy and decompensated heart failure. We will address the ability of mitochondrial fusion and fission to impact all cell types within the myocardium, including cardiac myocytes, cardiac fibroblasts and vascular smooth muscle cells. Finally, we will discuss how these findings can be applied to improve the treatment and prevention of cardiovascular diseases. This article is protected by copyright. All rights reserved.
    The Journal of Physiology 11/2015; DOI:10.1113/JP271301 · 5.04 Impact Factor
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    • "Induction of ROS levels stimulates autophagy and mitophagy as exemplified by lower mtDNA content in placental tissue (Kubli and Gustafsson 2012). In the current study, stratified analyses indicated a stronger inverse association between placental mtDNA content and prenatal NO 2 exposure in newborn boys than in girls. "
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    ABSTRACT: Mitochondria are sensitive to environmental toxicants due to their lack of repair capacity. Changes in mitochondrial DNA (mtDNA) content may represent a biologically relevant intermediate outcome in mechanisms linking air pollution and fetal growth restriction. We investigated whether placental mtDNA content is a possible mediator of the association between prenatal NO2 exposure and birth weight. We used data from two independent European cohorts: INMA (n=376; Spain) and ENVIRONAGE (n=550; Belgium). Relative placental mtDNA content was determined as the ratio of two mitochondrial genes (MT-ND1 and MTF3212/R3319) to two control genes (RPLP0 and ACTB). Effect estimates for individual cohorts and the pooled dataset were calculated using multiple linear regression and mixed models. We also performed a mediation analysis. Pooled estimates indicated that a 10µg/m(3) increment in average NO2 exposure during pregnancy was associated with a 4.9% decrease in placental mtDNA content (95% confidence interval (CI): -9.3, -0.3%). and a 48g decrease (95% CI: -87, -9g) in birth weight. However, the association with birth weight was significant for INMA (-66g; 95% CI: -111, -23g) but not for ENVIRONAGE (-20g; 95% CI: -101, 62g). Placental mtDNA content was associated with significantly higher mean birth weight (pooled analysis, IQR increase: 140g; 95% CI: 43, 237g). Mediation analysis estimates, which were derived for the INMA cohort only, suggested that 10% (95% CI: 6.6, 13.0g) of the association between prenatal NO2 and birth weight was mediated by changes in placental mtDNA content. Our results suggest that mtDNA content can be one of the potential mediators of the association between prenatal air pollution exposure and birth weight.
    Environmental Health Perspectives 08/2015; DOI:10.1289/ehp.1408981 · 7.98 Impact Factor
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    • "As a third model, we used HD patient-derived fibroblasts (Trettel et al, 2000; Wexler et al, 2004) and compared them to human fibroblasts derived from healthy controls. Mitophagy is regulated by a number of proteins in response to stress and/or various external insults such as nutrient starvation and oxidative stress (Youle & Narendra, 2011; Kubli & Gustafsson, 2012). Here, we determined whether the novel form of micromitophagy , whereby catalytically inactive GAPDH mediates direct uptake of damaged mitochondria into the lysosomal vacuoles (Yogalingam et al, 2013), is impaired in HD. "
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    ABSTRACT: Mitochondrial dysfunction is implicated in multiple neurodegenerative diseases. In order to maintain a healthy population of functional mitochondria in cells, defective mitochondria must be properly eliminated by lysosomal machinery in a process referred to as mitophagy. Here, we uncover a new molecular mechanism underlying mitophagy driven by glyceraldehyde-3-phosphate dehydrogenase (GAPDH) under the pathological condition of Huntington's disease (HD) caused by expansion of polyglutamine repeats. Expression of expanded polyglutamine tracts catalytically inactivates GAPDH (iGAPDH), which triggers its selective association with damaged mitochondria in several cell culture models of HD. Through this mechanism, iGAPDH serves as a signaling molecule to induce direct engulfment of damaged mitochondria into lysosomes (micro-mitophagy). However, abnormal interaction of mitochondrial GAPDH with long polyglutamine tracts stalled GAPDH-mediated mitophagy, leading to accumulation of damaged mitochondria, and increased cell death. We further demonstrated that overexpression of inactive GAPDH rescues this blunted process and enhances mitochondrial function and cell survival, indicating a role for GAPDH-driven mitophagy in the pathology of HD. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    EMBO Molecular Medicine 08/2015; 7(10). DOI:10.15252/emmm.201505256 · 8.67 Impact Factor
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