Interplay Between Mitochondrial Proteins and Age-Associated Risk of Cardiovascular Diseases

Normal functioning of mitochondria is crucial for cardiac performance. Mitochondria undergo mitophagy (mitochondrial autophagy) and biogenesis, and mitochondrial proteins are subject to extensive post-translational modifications (PTMs). The state of mitochondrial homeostasis reflects overall cellular fitness and longevity. Perturbed mitochondria produce less adenosine triphosphate (ATP), release greater amounts of reactive molecules, and are more prone to apoptosis. Therefore mitochondrial turnover is an integral aspect of quality control in which dysfunctional mitochondria are selectively eliminated through mitophagy. Currently, the progressive deterioration of physiological functions is seen as accumulation of modified/damaged proteins with limiting regenerative ability throughout aging in myocardial cells. Mitochondrial stress response to reactive species was evaluated as electron transport chain (ETC) complexes, redox-active molecules, and their possible communication. Protein-protein interactions revealed a strong linkage between age and ETC protein subunits. Redox state was strongly affected in senescent mitochondria with shift in favor of more pro-oxidizing condition within cardiomyocytes. Assume all together, dysfunctional proteostasis can play a causative role in aging and restoration of protein homeostasis machinery is protective against aging and possibly age-related disorders

Dietary Mg2+ Intake and the Na+/Mg2+ Exchanger SLC41A1 Influence Components of Mitochondrial Energetics in Murine Cardiomyocytes

Cardiomyocytes are among the most energy-intensive cell types. Interplay between the components of cellular magnesium (Mg) homeostasis and energy metabolism in cardiomyocytes is poorly understood. We have investigated the effects of dietary Mg content and presence/functionality of the Na+/Mg2+ exchanger SLC41A1 on enzymatic functions of selected constituents of the Krebs cycle and complexes of the electron transport chain (ETC). The activities of aconitate hydratase (ACON), isocitrate dehydrogenase (ICDH), α-ketoglutarate dehydrogenase (KGDH), and ETC complexes CI–CV have been determined in vitro in mitochondria isolated from hearts of wild-type (WT) and Slc41a1−/− mice fed a diet with either normal or low Mg content. Our data demonstrate that both, the type of Mg diet and the Slc41a1 genotype largely impact on the activities of enzymes of the Krebs cycle and ETC. Moreover, a compensatory effect of Slc41a1−/− genotype on the effect of low Mg diet on activities of the tested Krebs cycle enzymes has been identified. A machine-learning analysis identified activities of ICDH, CI, CIV, and CV as common predictors of the type of Mg diet and of CII as suitable predictor of Slc41a1 genotype. Thus, our data delineate the effect of dietary Mg content and of SLC41A1 functionality on the energy-production in cardiac mitochondria

ZrB2-SiC Composites with Rare-Earth Oxide Additives

The effect of different content (2, 5, and 10 wt.%) of two different types of rare earth (RE) oxides (Eu2O3 and Lu2O3) on the sintering, microstructure, room temperature mechanical properties, and ablation resistance of ZrB2-25vol.% SiC ceramics were investigated. The materials were prepared using non-reactive Field Assisted Sintering Technology (FAST) in the temperature range of 1950°C – 2050°C, with a pressure of 70 MPa and a dwell of 7 min. No significant effect of the addition of 2 and 5 wt.% RE2O3 on the microstructure and the room temperature mechanical properties (hardness, indentation fracture toughness, and flexural strength) were observed. On the other hand, the coarser microstructures led to the deterioration of flexural strength and the hardness of the composites sintered with 10 wt.% RE2O3. The ablation resistance of the materials (tested up to ~ 2670°C) gradually increased with the increasing amount of RE oxides. The material with 10 wt.% Lu2O3 showed the best ablation resistance among all of the investigated compositions, with more than two times a lower ablation rate than that of the reference ZrB2-25vol.%SiC

The Involvement of Mg 2+

Mg2+ is an essential mineral with pleotropic impacts on cellular physiology and functions. It acts as a cofactor of several important enzymes, as a regulator of ion channels such as voltage-dependent Ca2+ channels and K+ channels and on Ca2+-binding proteins. In general, Mg2+ is considered as the main intracellular antagonist of Ca2+, which is an essential secondary messenger initiating or regulating a great number of cellular functions. This review examines the effects of Mg2+ on mitochondrial functions with a particular focus on energy metabolism, mitochondrial Ca2+ handling, and apoptosis

Mitochondrial Dysfunction in Sporadic Amyotrophic Lateral Sclerosis Patients: Insights from High-Resolution Respirometry

Amyotrophic lateral sclerosis is a severe neurodegenerative disease whose exact cause is still unclear. Currently, research attention is turning to the mitochondrion as a critical organelle of energy metabolism. Current knowledge is sufficient to confirm the involvement of the mitochondria in the pathophysiology of the disease, since the mitochondria are involved in many processes in the cell; however, the exact mechanism of involvement is still unclear. We used peripheral blood mononuclear cells isolated from whole fresh blood from patients with amyotrophic lateral sclerosis for measurement and matched an age- and sex-matched set of healthy subjects. The group of patients consisted of patients examined and diagnosed at the neurological clinic of the University Hospital Martin. The set of controls consisted of healthy individuals who were actively searched, and controls were selected on the basis of age and sex. The group consisted of 26 patients with sporadic forms of ALS (13 women, 13 men), diagnosed based on the definitive criteria of El Escorial. The average age of patients was 54 years, and the average age of healthy controls was 56 years. We used a high-resolution O2K respirometry method, Oxygraph-2k, to measure mitochondrial respiration. Basal respiration was lower in patients by 29.48%, pyruvate-stimulated respiration (respiratory chain complex I) was lower by 29.26%, and maximal respiratory capacity was lower by 28.15%. The decrease in succinate-stimulated respiration (respiratory chain complex II) was 26.91%. Our data confirm changes in mitochondrial respiration in ALS patients, manifested by the reduced function of complex I and complex II of the respiratory chain. These defects are severe enough to confirm this disease’s hypothesized mitochondrial damage. Therefore, research interest in the future should be directed towards a deeper understanding of the involvement of mitochondria and respiratory complexes in the pathophysiology of the disease. This understanding could develop new biomarkers in diagnostics and subsequent therapeutic interventions

Age-Dependent Changes in Calcium Regulation after Myocardial Ischemia–Reperfusion Injury

During aging, heart structure and function gradually deteriorate, which subsequently increases susceptibility to ischemia–reperfusion (IR). Maintenance of Ca2+ homeostasis is critical for cardiac contractility. We used Langendorff’s model to monitor the susceptibility of aging (6-, 15-, and 24-month-old) hearts to IR, with a specific focus on Ca2+-handling proteins. IR, but not aging itself, triggered left ventricular changes when the maximum rate of pressure development decreased in 24-month-olds, and the maximum rate of relaxation was most affected in 6-month-old hearts. Aging caused a deprivation of Ca2+-ATPase (SERCA2a), Na+/Ca2+ exchanger, mitochondrial Ca2+ uniporter, and ryanodine receptor contents. IR-induced damage to ryanodine receptor stimulates Ca2+ leakage in 6-month-old hearts and elevated phospholamban (PLN)-to-SERCA2a ratio can slow down Ca2+ reuptake seen at 2–5 μM Ca2+. Total and monomeric PLN mirrored the response of overexpressed SERCA2a after IR in 24-month-old hearts, resulting in stable Ca2+-ATPase activity. Upregulated PLN accelerated inhibition of Ca2+-ATPase activity at low free Ca2+ in 15-month-old after IR, and reduced SERCA2a content subsequently impairs the Ca2+-sequestering capacity. In conclusion, our study suggests that aging is associated with a significant decrease in the abundance and function of Ca2+-handling proteins. However, the IR-induced damage was not increased during aging

Dynamics in Redox-Active Molecules Following Ischemic Preconditioning in the Brain

It is well known that the brain is quite vulnerable to oxidative stress, initiating neuronal loss after ischemia-reperfusion (IR) injury. A potent protective mechanism is ischemic preconditioning (IPC), where proteins are among the primary targets. This study explores redox-active proteins’ role in preserving energy supply. Adult rats were divided into the control, IR, and IPC groups. Protein profiling was conducted to identify modified proteins and then verified through activity assays, immunoblot, and immunohistochemical analyses. IPC protected cortex mitochondria, as evidenced by a 2.26-fold increase in superoxide dismutase (SOD) activity. Additionally, stable core subunits of respiratory chain complexes ensured sufficient energy production, supported by a 16.6% increase in ATP synthase activity. In hippocampal cells, IPC led to the downregulation of energy-related dehydrogenases, while a significantly higher level of peroxiredoxin 6 (PRX6) was observed. Notably, IPC significantly enhanced glutathione reductase activity to provide sufficient glutathione to maintain PRX6 function. Astrocytes may mobilize PRX6 to protect neurons during initial ischemic events, by decreased PRX6 positivity in astrocytes, accompanied by an increase in neurons following both IR injury and IPC. Maintained redox signaling via astrocyte-neuron communication triggers IPC’s protective state. The partnership among PRX6, SOD, and glutathione reductase appears essential in safeguarding and stabilizing the hippocampus