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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Dr. David Garcia-Dorado,
Mitochondrial have been recognized for a long time as the powerhouses of cells, and are particularly numerous in tissues with a high energetic demand like myocardium. Mitochondria represent approximately 40% of cardiomyocyte volume and are densely packaged in three main compartments: subsarcolemmal, interfibrillar and peri-nuclear. Mitochondria are tightly connected to other cell organelles, in particular, sarcoplasmic reticulum. Far form being quiescent bodies, mitochondria change continuously of shape and size. They merge with other mitochondria formed longer organelles (fusion) or divide themselves (fission) giving place to a lager number of smaller particles, and, in most cell types, continuously move within the cell. All these processes are generally known as mitochondrial dynamics. Mitochondrial dynamics is governed by tightly controlled processed involving specific proteins, and is intimately related to the generation and disappearance of mitochondria within a cell (mitophagy). These are particularly important in terminally differentiated cardiomyocytes lasting, without experiencing division for most of the life span in most mammalians including humans. A number of recent studies have demonstrated that different pathologic conditions, as ischemia-reperfusion, are associated to altered mitochondrial dynamics and have aroused interest in this process as a potential therapeutic target. These exciting advances were reviewed and discussed in the session “Mitochondrial Dynamics in Cardiovascular Health and Disease”.
The first speaker, Dr. Viola Kooij, from Johns Hopkins University, discussed the potential of advanced proteomics methods to investigate different aspects of mitochondrial function, with emphasis in post-translational modifications, using mass spectrometry. Discussed in detail was the application of these methods to the analysis of mitochondrial changes associated to cardiac resynchronization therapy in a canine model of heart failure. Particularly relevant were the changes observed in the phosphorylation status and disulfide bonds in ATP synthase, and their impact on the activity of this critical enzyme.
Dr. Derek Hausenloy, from the University College London, analyzed the role of altered mitochondrial dynamics in myocardial ischemia-reperfusion. By using different cell models, and modification of proteins involved in either mitochondrial fusion (Mfn1 and 2, OPA1) and fission (Drp1, hFis, Mff, Mid49/51) his group had been able to provide evidence for a detrimental effect of increased fission in ischemia-reperfusion injury. They suggest that fission may be increased in ischemia by calcineurin dependent phosphorylation of DrP1. Genetic or pharmacological inhibition of Drp1 inhibited fission and was cardioprotective in the adult mouse heart, as it was OPA1 deficiency, while Mf2 or DJ-1 deficiency induced mitochondrial fragmentation and were detrimental.
Dr. Luca Sorrano went beyond the involvement of mitochondrial dynamics in health and disease to demonstrate its role in cardiomyocyte differentiation. By using an array of molecular techniques his group found that Mfn2 and Opa1 are required for differentiation of embryonic stem cells into beating cardiomyocytes, and that Notch activity is involved in this role. Changes in Notch activity were not due to altered bionergetic function in the absence of Mnf2 and Opa1, but mitochondria were smaller and closer to the plasma membrane of embryonic stem cells, and calcineurin activity was higher, and this suggests that the resulting changes in intracellular Ca2+ activate Notch signaling. In fact, ¡pharmacological inhibition of calcineurin abolished the increase in Notch activity and rescued cardiomyocyte differenciation
In the last talk of this session, Dr. Christoph Maack, from the Saarlandes University Hospital in Homburg, focused on the pathophysilogical importance of mitofusins. His group has recently the influence of mitofusins on a sequence of events of critical importance for mitochondrial function. Mitochondrial Ca2+ uptake stimulates key enzymes of the Krebs cycle, which produces NADH for ATP production and NADPH that is required for elimination of H2O2. In heart failure, dysregulation of cytosolic Ca2+ and Na+ homeostasis accounts for reduced mitochondrial Ca2+ uptake which results in energetic mismatch and oxidative stress. The close association between the sarcoplasmic reticulum (SR) and mitochondria (through Ca2+ microdomains) appears to be essential for the efficient mitochondrial Ca2+ uptake despite a low Ca2+ affinity of the mitochondrial Ca2+ uniporter. In functional experiments, this group obtained evidence for the existence of these microdomains by observing that mitochondrial Ca2+ uptake was most efficient when Ca2+ was released rapidly from the SR, whereas slow and diffusional Ca2+ influx via the cell membrane was less efficient for mitochondrial Ca2+ uptake. Mitochondria are tethered to the SR via mitofusin 2 (Mfn2), and cardiomyocyte-specific deletion of Mfn2 hampered mitochondrial Ca2+ uptake and the bioenergetic feedback response, inducing energetic deficit and oxidative stress.
All talks were followed by intense discussion, and the session boosted the interest of the audience on the machinery of mitochondrial dynamics as a key player in cardiomyocyte differentiation, function, failure, and death.
Mitochondrial dynamics in cardiovascular health and disease
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