Custom Designed Nanoceria Augments Mitochondrial Redox Ability and Bioenergetics in Rat Muscle
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Respirometry
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Bioenergetics
Oxidation reduction
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Apoptosis (programmed cell death) is a cellular self-destruction mechanism that is essential for a variety of biological events, such as developmental sculpturing, tissue homeostasis, and the removal of unwanted cells. Mitochondria play a crucial role in regulating cell death. $Ca^{2+}$ has long been recognized as a participant in apoptotic pathways. Mitochondria are known to modulate and synchronize $Ca^{2+}$ signaling. Massive accumulation of $Ca^{2+}$ in the mitochondria leads to apoptosis. The $Ca^{2+}$ dynamics of ER and mitochondria appear to be modulated by the Bcl-2 family proteins, key factors involved in apoptosis. The number and morphology of mitochondria are precisely controlled through mitochondrial fusion and fission process by numerous mitochondria-shaping proteins. Mitochondrial fission accompanies apoptotic cell death and appears to be important for progression of the apoptotic pathway. Here, we highlight and discuss the role of mitochondrial calcium handling and mitochondrial fusion and fission machinery in apoptosis.
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Mitochondria play a central role in the survival and death of neurons. The detailed bioenergetic mechanisms by which isolated mitochondria generate ATP, sequester Ca 2+ , generate reactive oxygen species, and undergo Ca 2+ -dependent permeabilization of their inner membrane are currently being applied to the function of mitochondria in situ within neurons under physiological and pathophysiological conditions. Here we review the functional bioenergetics of isolated mitochondria, with emphasis on the chemiosmotic proton circuit and the application (and occasional misapplication) of these principles to intact neurons. Mitochondria play an integral role in both necrotic and apoptotic neuronal cell death, and the bioenergetic principles underlying current studies are reviewed.
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SUMMARY Mitochondria are the powerhouse of the cell and owing to their unique energetic demands, heart muscles contain a high density of mitochondria. In conditions such as heart failure and diabetes-induced heart disease, changes in the organization of cardiac mitochondria are common. While recent studies have also shown that cardiac mitochondria split and fuse throughout the cell, a mechanistic understanding of how mitochondrial dynamics may affect energy output is lacking. Using a mathematical model that has been fitted to experimental data, we test if briefly altering fission or fusion rates improves ATP production and supply in cardiomyocytes. Unexpectedly, we found that cardiac bioenergetics, e.g., the ADP/ATP ratio, were robust to changes in fusion and fission rates and consequently mitochondria organization. Our study highlights complex nonlinear feedback loops that are at play in the cross-talk between mitochondrial dynamics and bioenergetics. The study motivate further in-silico and experimental investigations to determine the mechanistic basis for new therapies that target mitochondrial dynamics.
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Physical function decreases with age, and though bioenergetic alterations contribute to this decline, the mechanisms by which mitochondrial function changes with age remains unclear. This is partially because human mitochondrial studies require highly invasive procedures, such as muscle biopsies, to obtain live tissue with functional mitochondria. However, recent studies demonstrate that circulating blood cells are potentially informative in identifying systemic bioenergetic changes. Here, we hypothesize that human platelet bioenergetics reflect bioenergetics measured in muscle biopsies.We demonstrate that maximal and ATP-linked respiratory rate measured in isolated platelets from older adults (86-93 years) correlates significantly with maximal respiration (r = 0.595; P = 0.003) measured by muscle biopsy respirometry and maximal ATP production (r = 0.643; P = 0.004) measured by 31P-MRS respectively, in the same individuals. Comparison of platelet bioenergetics in this aged cohort to platelets from younger adults (18-35 years) shows aged adults demonstrate lower basal and ATP-linked respiration. Platelets from older adults also show enhanced proton leak, which is likely due to increased protein levels of uncoupling protein 2, and correlates with increased gate speed in this cohort (r = 0.58; P = 0.0019). While no significant difference in glycolysis was observed in older adults compared to younger adults, platelet glycolytic rate correlated with fatigability (r = 0.44; P = 0.016).These data advance the mechanistic understanding of age-related changes in mitochondrial function. Further, they suggest that measuring platelet bioenergetics provides a potential supplement or surrogate for muscle biopsy measurement and may be a valuable tool to study mitochondrial involvement in age-related decline of physical function.
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Previous studies indicate that mitochondria-localized lactate dehydrogenase (mLDH) might be a significant contributor to metabolism. In the heart, the presence of mLDH could provide cardiac mitochondria with a higher capacity to generate reducing equivalents directly available for respiration, especially during exercise when circulating lactate levels are high. The purpose of this study was to test the hypothesis that mLDH contributes to striated muscle bioenergetic function. Mitochondria isolated from murine cardiac and skeletal muscle lacked an appreciable ability to respire on lactate in the absence or presence of exogenous NAD+. Although three weeks of treadmill running promoted physiologic cardiac growth, mitochondria isolated from the hearts of acutely exercised or exercise-adapted mice showed no further increase in lactate oxidation capacity. In all conditions tested, cardiac mitochondria respired at >20-fold higher levels with provision of pyruvate compared with lactate. Similarly, skeletal muscle mitochondria showed little capacity to respire on lactate. Protease protection assays of isolated cardiac mitochondria confirmed that LDH is not localized within the mitochondrion. We conclude that mLDH does not contribute to cardiac bioenergetics in mice.
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Cardiac muscle
Cellular respiration
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[Irreversible changes in energy processes in the mitochondria after chronic exposure to detergents].
Chronic inhalational exposure of white rats to a synthetic detergent 'LOTOS' in concentrations 25 and 100 mg/m3 caused liver mitochondria bioenergetics changes from a reversible low energetic shift up to an irreversible mitochondria damage of an organ-structural character. The degree of the damaging effect depended on the duration of exposure and the concentration of the detergent.
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The changes in mitochondria bioenergetics play a critical role in neuronal function with age. Mitochondria from synaptosomes in the cerebral cortex of young (6 months), middle‐age (13 months) and old (26months) mice were isolated and transferred to mitochondria DNA‐less LL/2‐m21 cell line (rho‐zero) to generate cybrids. Mitochondria bioenergetics studies of the cybrids show that there was significant reduction with age in mitochondria membrane potential (MMP), P<0.05, in the young, middle‐aged and old synaptosomal mitochondria bearing cybrids respectively. Adenosine triphosphate (ATP) levels were also significantly lower in the old mitochondria bearing cybrids compared with middle age and young cybrids (P<0.05). Melatonin pre‐treatment at a concentration of 1mM in glucose replaced with galactose medium containing 1mM melatonin after 6 hours significantly improved cell viability and restored MMP in the old mitochondria bearing cybrids , S‐O‐48 (P<0.05). Furthermore, melatonin treatment in young mitochondria bearing cybrids, S‐Y‐24 lowered MMP (P<0.05) and increased MMP in middle aged mitochondrial bearing cybrid S‐M‐29 (P<0.05) in galactose medium. In the young cybrids, there was no significant difference in ATP levels between the melatonin treated cybrids and cybrids without treatment (P>0.05). The young mitochondria bearing cybrids were able to produce ATP optimally in the galactose medium which shows they have functional mitochondria. ATP was significantly increased in the middle‐aged mitochondria cybrid, S‐M‐29, and old mitochondria bearing cybrids, S‐O‐48, with melatonin treatment. These results establish a strong relationship between melatonin and mitochondria bioenergetics. It also gives support to other evidences that melatonin may be a potential therapeutic mitochondria target in aging.
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Adenosine triphosphate
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