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Spinocerebellar ataxia 1 (SCA1) is a devastating neurodegenerative disease associated with cerebellar degeneration and motor deficits. However, many patients also exhibit neuropsychiatric impairments such as depression and apathy; nevertheless, the existence of a causal link between the psychiatric symptoms and SCA1 neuropathology remains controversial. This study aimed to explore behavioral deficits in a knock-in mouse SCA1 (SCA1 154Q/2Q ) model and to identify the underlying neuropathology. We found that the SCA1 mice exhibit previously undescribed behavioral impairments such as increased anxiety- and depressive-like behavior and reduced prepulse inhibition and cognitive flexibility. Surprisingly, non-motor deficits characterize the early SCA1 stage in mice better than does ataxia. Moreover, the SCA1 mice exhibit significant hippocampal atrophy with decreased plasticity-related markers and markedly impaired neurogenesis. Interestingly, the hippocampal atrophy commences earlier than the cerebellar degeneration and directly reflects the individual severity of some of the behavioral deficits. Finally, mitochondrial respirometry suggests profound mitochondrial dysfunction in the hippocampus, but not in the cerebellum of the young SCA1 mice. These findings imply the essential role of hippocampal impairments, associated with profound mitochondrial dysfunction, in SCA1 behavioral deficits. Moreover, they underline the view of SCA1 as a complex neurodegenerative disease and suggest new avenues in the search for novel SCA1 therapies.

To evaluate a novel anticoagulation strategy in an extracorporeal circuit, we introduce a device that induces local hypothermia as blood flows through the circuit. Using a pig model, we assessed its technical feasibility, biocompatibility, and safety. Sixteen pigs were randomly assigned to either the cooled group or the control group and underwent midline laparotomy to establish extracorporeal circulation (blood flow 500 ml/min) via the caudal vena cava for up to four hours. Blood samples were collected at baseline and at 15, 60, and 240 min during the experiment. In the cooled group, blood was cooled to 20 °C and then rewarmed to 37 °C, while in the control group, blood was maintained at 37 °C. A total of 6 cooled and 4 control pigs completed 4 h of the experiment. Our findings confirm the technical feasibility of the proposed device, which effectively maintained the required temperature differentials while keeping the pressure differentials in the circuit within 150 mmHg. No issues with circuit patency were observed. Additionally, no adverse effects were detected on erythrocyte stability. Within the limitation of the short observation period, no adverse effects were observed on renal, liver, or cardiac function. Our data suggest that local hypothermia in the extracorporeal circuit may mitigate surgery-induced inflammation.

Treatment with mesenchymal stem cells (MSCs) has elicited considerable interest as an adjunctive therapy in sepsis. However, the encouraging effects of experiments with MSC in rodents have not been adequately studied in large-animal models with better relevance to human sepsis. Here, we aimed to assess safety and efficacy of bone marrow-derived MSCs in a clinically relevant porcine model of progressive peritonitis-induced sepsis. Thirty-two anesthetized, mechanically ventilated, and instrumented pigs were randomly assigned into four groups ( = 8 per group): (1) sham-operated group (CONTROL); (2) sham-operated group treated with MSCs (MSC-CONTROL); (3) sepsis group with standard supportive care (SEPSIS); and (4) sepsis group treated with MSCs (MSC-SEPSIS). Peritoneal sepsis was induced by inoculating cultivated autologous feces. MSCs (1 × 10 /kg) were administered intravenously at 6 h after sepsis induction. Before, 12, 18, and 24 h after the induction of peritonitis, we measured systemic, regional, and microvascular hemodynamics, multiple-organ functions, mitochondrial energy metabolism, systemic immune-inflammatory response, and oxidative stress. Administration of MSCs in the MSC-CONTROL group did not elicit any measurable acute effects. Treatment of septic animals with MSCs failed to mitigate sepsis-induced hemodynamic alterations or the gradual rise in Sepsis-related organ failure assessment scores. MSCs did not confer any protection against sepsis-mediated cellular myocardial depression and mitochondrial dysfunction. MSCs also failed to modulate the deregulated immune-inflammatory response. Intravenous administration of bone marrow-derived MSCs to healthy animals was well-tolerated. However, in this large-animal, clinically relevant peritonitis-induced sepsis model, MSCs were not capable of reversing any of the sepsis-induced disturbances in multiple biological, organ, and cellular systems.

Background The pathophysiology of sepsis-induced acute kidney injury remains elusive. Although mitochondrial dysfunction is often perceived as the main culprit, data from preclinical models yielded conflicting results so far. The aim of this study was to assess the immune-metabolic background of sepsis-associated renal dysfunction using sequential biopsy approach with mitochondria function evaluation in a large clinically relevant porcine models mimicking two different paces and severity of sepsis and couple this approach with traditional parameters of renal physiology. Methods In this randomized, open-label study, 15 anaesthetized, mechanically ventilated and instrumented (renal artery flow probe and renal vein catheter) pigs were randomized in two disease severity groups—low severity (LS) sepsis (0.5 g/kg of autologous faeces intraperitoneally) and high severity (HS) sepsis (1 g/kg of autologous faeces intraperitoneally). Sequential cortical biopsies of the left kidney were performed and a pyramid-shaped kidney specimen with cortex, medulla and renal papilla was resected and processed at the end of the experiment. Oxygraphic data and western blot analysis of proteins involved in mitochondrial biogenesis and degradation were obtained. Results In contrast to increased mitochondrial activity observed in LS sepsis, a significant decrease in the oxidative phosphorylation capacity together with an increase in the respiratory system uncoupling was observed during the first 24 h after sepsis induction in the HS group. Those changes preceded alterations of renal haemodynamics. Furthermore, serum creatinine rose significantly during the first 24 h, indicating that renal dysfunction is not primarily driven by haemodynamic changes. Compared to cortex, renal medulla had significantly lower oxidative phosphorylation capacity and electron-transport system activity. PGC-1-alfa, a marker of mitochondrial biogenesis, was significantly decreased in HS group. Conclusions In this experimental model, unique sequential tissue data show that the nature and dynamics of renal mitochondrial responses to sepsis are profoundly determined by the severity of infectious challenge and resulting magnitude of inflammatory insult. High disease severity is associated with early and stepwise progression of mitochondria dysfunction and acute kidney injury, both occurring independently from later renal macro-haemodynamic alterations. Our data may help explain the conflicting results of preclinical studies and suggest that sepsis encompasses a very broad spectrum of sepsis-induced acute kidney injury endotypes.

The contribution of environmental pollutants to the obesity pandemic is still not yet fully recognized. Elucidating possible cellular and molecular mechanisms of their effects is of high importance. Our study aimed to evaluate the effect of chronic, 21-day-long, 2,2-bis (4-chlorophenyl)-1,1-dichlorethylenedichlorodiphenyldichloroethylene (p,p′-DDE) exposure of human adipose-derived mesenchymal stem cells committed to adipogenesis on mitochondrial oxygen consumption on days 4, 10, and 21. In addition, the mitochondrial membrane potential (MMP), the quality of the mitochondrial network, and lipid accumulation in maturing cells were evaluated. Compared to control differentiating adipocytes, exposure to p,p′-DDE at 1 μM concentration significantly increased basal (routine) mitochondrial respiration, ATP-linked oxygen consumption and MMP of intact cells on day 21 of adipogenesis. In contrast, higher pollutant concentration seemed to slow down the gradual increase in ATP-linked oxygen consumption typical for normal adipogenesis. Organochlorine p,p′-DDE did not alter citrate synthase activity. In conclusion, in vitro 1 μM p,p′-DDE corresponding to human exposure is able to increase the mitochondrial respiration per individual mitochondrion at the end of adipocyte maturation. Our data reveal that long-lasting exposure to p,p′-DDE could interfere with the metabolic programming of mature adipocytes.

Mitochondria play a key role in energy metabolism in many tissues, including cardiac and skeletal muscle, brain, liver, and adipose tissue. Three types of adipose depots can be identified in mammals, commonly classified according to their colour appearance: the white (WAT), the brown (BAT), and the beige/brite/brown-like (bAT) adipose tissues. WAT is mainly involved in the storage and mobilization of energy and BAT is predominantly responsible for nonshivering thermogenesis. Recent data suggest that adipocyte mitochondria might play an important role in the development of obesity through defects in mitochondrial lipogenesis and lipolysis, regulation of adipocyte differentiation, apoptosis, production of oxygen radicals, efficiency of oxidative phosphorylation, and regulation of conversion of white adipocytes into brown-like adipocytes. This review summarizes the main characteristics of each adipose tissue subtype and describes morphological and functional modifications focusing on mitochondria and their activity in healthy and unhealthy adipocytes.

Background Emerging evidence has linked mitochondrial dysfunction to the pathogenesis of many renal disorders, including acute kidney injury, sepsis and even chronic kidney disease. Proteomics is a powerful tool in elucidating the role of mitochondria in renal pathologies. Since the pig is increasingly recognized as a major mammalian model for translational research, the lack of physiological proteome data of large mammals prompted us to examine renal mitochondrial proteome in porcine kidney cortex and medulla Methods Kidneys were obtained from six healthy pigs. Mitochondria from cortex and medulla were isolated using differential centrifugation and proteome maps of cortical and medullar mitochondria were constructed using two-dimensional gel electrophoresis (2DE). Protein spots with significant difference between mitochondrial fraction of renal cortex and medulla were identified by mass spectrometry. Results Proteomic analysis identified 81 protein spots. Of these spots, 41 mitochondrial proteins were statistically different between renal cortex and medulla ( p  < 0.05). Protein spots containing enzymes of beta oxidation, amino acid metabolism, and gluconeogenesis were predominant in kidney cortex mitochondria. Spots containing tricarboxylic acid cycle enzymes and electron transport system proteins, proteins maintaining metabolite transport and mitochondrial translation were more abundant in medullar mitochondria. Conclusion This study provides the first proteomic profile of porcine kidney cortex and medullar mitochondrial proteome. Different protein expression pattern reflects divergent functional metabolic role of mitochondria in various kidney compartments. Our study could serve as a useful reference for further porcine experiments investigating renal mitochondrial physiology under various pathological states.

The objective of the present study was to evaluate platelet mitochondrial oxygen consumption using high-resolution respirometry (HRR) and metabolic flux analysis (MFA) and to verify the effect of advanced age on these parameters. HRR was used to analyze permeabilized and intact platelets, MFA to measure oxygen consumption rates (OCR), extracellular acidification rates (ECAR) and ATP production rate in intact fixed platelets. Two groups of healthy volunteers were included in the study: YOUNG (20-42 years, n=44) and older adults (OLD; 70-89 years; n=15). Compared to YOUNG donors, platelets from group OLD participants displayed significantly lower values of oxygen consumption in the Complex II-linked phosphorylating and uncoupled states and the Complex IV activity in HRR protocols for permeabilized cells and significantly lower resting and uncoupled respirations in intact cells when analyzed by both methods. In addition, mitochondrial ATP production rate was also significantly lower in platelets isolated from older adults. Variables measured by both methods from the same bloods correlated significantly, nevertheless those acquired by MFA were higher than those measured using HRR. In conclusion, the study verifies compromised mitochondrial respiration and oxidative ATP production in the platelets of aged persons and documents good compatibility of the two most widely used methods for determining the global performance of the electron-transporting system, i.e. HRR and MFA.

Mitochondria represent pivotal cellular organelles endowed with multifaceted functionalities encompassing cellular respiration, metabolic processes, calcium turnover, and the regulation of apoptosis, primarily through the generation of reactive oxygen species (ROS). Perturbations in mitochondrial dynamics have been intricately linked to the etiology of numerous cardiovascular pathologies, such as heart failure, ischemic heart disease, and various cardiomyopathies. Notably, recent attention has been directed towards the detrimental impact of micro- and nanoplastic pollution on mitochondrial integrity, an area underscored by a paucity of comprehensive investigations. Given the escalating prevalence of plastic particle contamination and the concomitant burden of cardiovascular disease in aging populations, understanding the interplay between mitochondria within the cardiovascular system and micro- and nanoplastic pollution assumes paramount importance. This review endeavors to elucidate the current albeit limited comprehension surrounding this complex interplay.

Chronic wound is a serious medical issue due to its high prevalence and complications; hyperbaric oxygen therapy (HBOT) is also considered in comprehensive treatment. Clinical trials, including large meta-analyses bring inconsistent results about HBOT efficacy. This review is summarizing the possible effect of HBOT on the healing of chronic wound models at the cellular level. HBOT undoubtedly escalates the production of reactive oxygen and nitrogen radicals (ROS and RNS), which underlie both the therapeutic and toxic effects of HBOT on certain tissues. HBOT paradoxically elevates the concentration of Hypoxia inducible factor (HIF) 1 by diverting the HIF-1 degradation to pathways that are independent of the oxygen concentration. Elevated HIF-1 stimulates the production of different growth factors, boosting the healing process. HBOT supports synthesis of Heat shock proteins (HSP), which are serving as chaperones of HIF-1. HBOT has antimicrobial effect, increases the effectiveness of some antibiotics, stimulates fibroblasts growth, collagen synthesis and suppresses the activity of proteolytic enzymes like matrix metalloproteinases. All effects of HBOT were investigated on cell cultures and animal models, the limitation of their translation is discussed at the end of this revie