10 research outputs found
Mitochondrial chaotic dynamics: Redox-energetic behavior at the edge of stability
Mitochondria serve multiple key cellular functions, including energy generation, redox balance, and regulation of apoptotic cell death, thus making a major impact on healthy and diseased states. Increasingly recognized is that biological network stability/instability can play critical roles in determining health and disease. We report for the first-time mitochondrial chaotic dynamics, characterizing the conditions leading from stability to chaos in this organelle. Using an experimentally validated computational model of mitochondrial function, we show that complex oscillatory dynamics in key metabolic variables, arising at the “edge” between fully functional and pathological behavior, sets the stage for chaos. Under these conditions, a mild, regular sinusoidal redox forcing perturbation triggers chaotic dynamics with main signature traits such as sensitivity to initial conditions, positive Lyapunov exponents, and strange attractors. At the “edge” mitochondrial chaos is exquisitely sensitive to the antioxidant capacity of matrix Mn superoxide dismutase as well as to the amplitude and frequency of the redox perturbation. These results have potential implications both for mitochondrial signaling determining health maintenance, and pathological transformation, including abnormal cardiac rhythms.publishedVersionKembro, Jackelyn Melissa. Universidad Nacional de CĂłrdoba. Facultad de Ciencias Exactas, FĂsicas y Naturales; Argentina.Kembro, Jackelyn Melissa. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de Investigaciones BiolĂłgicas y TecnolĂłgicas; Argentina.Cortassa, Sonia. National Institutes of Health. NIH · NIA Intramural Research Program; Estados Unidos.Lloyd, David. Cardiff University. School of Biosciences 1; Inglaterra.Sollot, Steven. Johns Hopkins University. Laboratory of Cardiovascular Science; Estados Unidos.Sollot, Steven. Johns Hopkins University. Laboratory of Cardiovascular Science; Estados Unidos
Contribution of Elevated Intracellular Calcium to Pulmonary Arterial Myocyte Alkalinization during Chronic Hypoxia
Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle
Preparation of primary cultured mesenteric artery smooth muscle cells for fluorescent imaging and physiological studies
New Insights into the Contribution of Arterial NCX to the Regulation of Myogenic Tone and Blood Pressure
Mitochondrial Reactive Oxygen Species (ROS) and Arrhythmias.
In this chapter we analyze the onset of cardiac arrhythmias from the perspective of mitochondrial redox state and energetic metabolism. Significant perturbations in the mitochondrial redox environment trigger mitochondrial membrane potential (ΔΨm) depolarization that under critical conditions can scale up to the whole heart, thereby producing fatal arrhythmias. Utilizing a combined experimental–theoretical approach, we evaluate the processes dynamics at each level of organization involved (molecular, mitochondrial, cardiomyocyte, whole heart) while highlighting their mechanistic interrelationships to explain the appearance of novel emergent properties. Under metabolically stressful conditions, the mitochondrial network of cardiac cells accumulate high level of reactive oxygen species (ROS) attaining a critical state – referred to as mitochondrial criticality. Under criticality, the slightest perturbation triggers a cell-wide collapse of ΔΨm, visualized as a depolarization wave throughout the cell, which is followed by whole cell sustained mitochondrial oscillations in ΔΨm, NADH, ROS, and glutathione. This macroscopic dynamic behavior escalates from the mitochondrion to the organ level driving the heart into catastrophic arrhythmias.Fil: Kembro, Jackelyn Melissa. University Johns Hopkins; Estados Unidos. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - CĂłrdoba. Instituto de Investigaciones BiolĂłgicas y TecnolĂłgicas. Universidad Nacional de CĂłrdoba. Facultad de Ciencias Exactas, FĂsicas y Naturales. Instituto de Investigaciones BiolĂłgicas y TecnolĂłgicas; ArgentinaFil: Cortassa, Sonia del Carme. University Johns Hopkins; Estados Unidos. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - La Plata. Instituto de Investigaciones BiotecnolĂłgicas. Instituto de Investigaciones BiotecnolĂłgicas "Dr. RaĂşl AlfonsĂn" (sede ChascomĂşs). Universidad Nacional de San MartĂn. Instituto de Investigaciones BiotecnolĂłgicas. Instituto de Investigaciones BiotecnolĂłgicas "Dr. RaĂşl AlfonsĂn" (sede ChascomĂşs); ArgentinaFil: Aon, Miguel A.. University Johns Hopkins; Estados Unido
Functional Impact of Ryanodine Receptor Oxidation on Intracellular Calcium Regulation in the Heart
Expert consensus document: Mitochondrial function as a therapeutic target in heart failure
Heart failure is a pressing worldwide public-health problem with millions of patients
having worsening heart failure. Despite all the available therapies, the condition carries a very
poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully
address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly
important given that most patients with heart failure have viable dysfunctional myocardium,
in which an improvement or normalization of function might be possible. Although the
pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important
target for therapy to improve cardiac function directly. Mitochondrial abnormalities include
impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen
species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion
homeostasis. In this Consensus Statement, insights into the mechanisms of mitochondrial
dysfunction in heart failure are presented, along with an overview of emerging treatments
with the potential to improve the function of the failing heart by targeting mitochondria.peerReviewe