Rheumatoid arthritis (RA) is an inflammatory joint disease characterized by persistent synovitis and inflammation. The exact mechanism of mitochondrial function in the presence of inflammation and dysregulation of autophagic processes in the pathogenesis of RA is still unclear. The aim of our study is to determine mitochondrial function, gene and protein levels of biomolecules related to inflammation (YKL-40) and autophagy (LAMPs) and to search a connection between them in the RA context. Twenty newly diagnosed RA patients and ten healthy individuals were included in the study. Disease severity was assessed by ultrasonography. Conventional clinico-laboratory parameters, immunological markers and protein levels of LAMPs and YKL-40 were examined in plasma. Gene expression analysis for the quantitative measurement of LAMPs and YKL-40 were conducted in white blood cells (WBC). A real-time metabolic analysis was performed to assess mitochondrial function and cell metabolism in peripheral blood mononuclear cells (PBMCs). Increase in spare respiratory capacity in PBMCs of RA patients was detected. Decreased LAMPs plasma protein levels and increased protein levels of YKL-40 in RA patients compared to healthy individuals were measured. No significant differences were found in gene expressions. Correlations between mitochondrial, ultrasonographic and protein levels of the biomarkers related with inflammation and autophagy were established. New data on mitochondrial dysfunction in RA patients and links to inflammation and mitophagy are reported. The relationship between dysregulation of mitophagy and joint diseases deserves to be thoroughly investigated as it would be a promising therapeutic approach.

BACKGROUND: The interaction between physical activity, skeletal muscle health, and adiposity has been explored in normal weight and overweight/obesity grouped together; however, the overall risks associated with being overweight are less than those observed with obesity and can be confounded by disparities in both sex and race. Thus, the present study sought to investigate the intricate interplay of daily physical activity and skeletal muscle oxidative capacity (SMOC) in overweight and obesity, while exploring how sex and race impact this dynamic relationship.
METHODS: One hundred and forty participants were grouped by body mass index (BMI) as overweight (n = 73; BMI >25-<30 kg/m2) or obese (n = 67; BMI ≥30 kg/m2). SMOC was assessed using near-infrared spectroscopy and daily physical activity was assessed for 7 days using accelerometry.
RESULTS: Overweight individuals exhibited a higher (p = 0.004) SMOC and engaged in more (p = 0.007) vigorous physical activity compared to obese individuals. In addition, SMOC was lower (p = 0.005) in obese non-Hispanic Black (NHB) men compared to overweight NHB men. No relationships between physical activity and SMOC were observed.
CONCLUSIONS: Physical activity is not associated with differences in SMOC in overweight and obesity. Obese individuals engage in less vigorous physical activity and exhibit lower SMOC compared to overweight individuals and these differences are emphasised in NHB men.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant tumor known for its hypoxic environment, which contributes to resistance against the anticancer drug Sorafenib (SF). Addressing SF resistance in HCC requires innovative strategies to improve tumor oxygenation and effectively deliver therapeutics.
RESULTS: In our study, we explored the role of KPNA4 in mediating hypoxia-induced SF resistance in HCC. We developed hemoglobin nanoclusters (Hb-NCs) capable of carrying oxygen, loaded with indocyanine green (ICG) and SF, named HPRG@SF. In vitro, HPRG@SF targeted HCC cells, alleviated hypoxia, suppressed KPNA4 expression, and enhanced the cytotoxicity of PDT against hypoxic, SF-resistant HCC cells. In vivo experiments supported these findings, showing that HPRG@SF effectively improved the oxygenation within the tumor microenvironment and countered SF resistance through combined photodynamic therapy (PDT).
CONCLUSIONS: The combination of Hb-NCs with ICG and SF, forming HPRG@SF, presents a potent strategy to overcome drug resistance in hepatocellular carcinoma by improving hypoxia and employing PDT. This approach not only targets the hypoxic conditions that underlie resistance but also provides a synergistic anticancer effect, highlighting its potential for clinical applications in treating resistant HCC.

Plastics are widely used worldwide due to their convenience. However, microplastics (MPs) accumulation poses a serious threat to ecosystem health. Therefore, understanding the effects of MPs on living organisms within their native ecosystem is crucial. Previous studies have primarily focused on the impacts of MPs in aquatic environments, whereas the effects of MPs on terrestrial ecosystems have remained largely understudied. Therefore, our study assessed the impacts of MPs on soil ecosystems by characterizing their toxic effects on earthworms (Eisenia fetida). Here, we exposed earthworms to two representative plastics within soil environments: polyvinyl chloride (PVC) and low-density polyethylene (LDPE). Given the known link between MPs and oxidative stress, we next quantified oxidative stress markers and mitochondrial function to assess the effects of MPs on the redox metabolism of earthworms. Mitochondria are crucial metabolic organelles that generate reactive oxygen species via uncontrolled ATP production. Our findings demonstrated that MPs exert different effects depending on their type. Neither the PVC-exposed groups nor the LDPE-exposed groups exhibited changes in oxidative stress, as worked by the action of superoxide dismutase (SOD) and glutathione (GSH). While treatment of the two types of MP did not significantly affect the amount of reactive oxygen species/reactive nitrogen species (ROS/RNS) generated, PVC exhibited a more pronounced effect on antioxidant system compared to LDPE. However, mitochondrial function was markedly decreased in the group exposed to high LDPE concentrations, suggesting that the examined LDPE concentrations were too low to activate compensatory mechanisms. Collectively, our findings demonstrated that exposure of MPs not only influences the antioxidant defense mechanisms of earthworms but also alters their mitochondrial function depending on their types.

Mitochondrial function can be regulated by ion channels. Mitochondrial RNA splicing 2 (Mrs2) is a magnesium ion (Mg2+) channel located in the inner mitochondrial membrane, thereby mediating the Mg2+ influx into the mitochondrial matrix. However, its potential role in regulating the Mg homeostasis and mitochondrial function in aquatic species is still unclear. This study molecularly characterizes the gene encoding Mrs2 in fish M. amblycephala with its functions in maintaining the Mg homeostasis and mitochondrial function verified. The mrs2 gene is 2133 bp long incorporating a 1269 bp open reading frame, which encodes 422 amino acids. The Mrs2 protein includes two transmembrane domains and a conserved tripeptide Gly-Met-Asn, and has a high homology (65.92-97.64%) with those of most vertebrates. The transcript of mrs2 was relatively high in the white muscle, liver and kidney. The inhibition of mrs2 reduces the expressions of Mg2+ influx/efflux-related proteins, mitochondrial Mg content, and the activities of mitochondrial complex I and V in hepatocytes. However, the over-expression of mrs2 increases the expressions of Mg2+ influx/efflux-related proteins, mitochondrial Mg content, and the complex V activity, but decreases the activities of mitochondrial complex III and IV and citrate synthase in hepatocytes. Collectively, Mrs2 is highly conserved among different species, and is prerequisite for maintaining Mg homeostasis and mitochondrial function in fish.

Obesity and its complications have become a global health problem that needs to be addressed urgently. White adipose tissue (WAT) browning contributes to consuming excess energy in WAT, which is important for improving obesity and maintaining a healthy energy homeostasis. Mitochondria, as the energy metabolism center of cells, are extensively involved in many metabolic processes, including the browning of WAT. NADH: Ubiquinone oxidoreductase subunit A8 (NDUFA8) is a constituent subunit of respiratory chain complex I (CI), which has been found to participate in a wide range of physiological processes by affecting the activity of respiratory CI. However, the regulatory effect of Ndufa8 on the browning of WAT has not been reported. Here, we used β3-adrenergic agonis CL316, 243 to construct WAT browning models in vivo and in vitro to investigate the role and mechanism of Ndufa8 in the regulation of WAT browning. Briefly, Ndufa8 significantly increased CI activity and suppressed mitochondrial ROS levels in vitro, thereby improving mitochondrial function. Ndufa8 also increased the transcriptional levels and protein levels of UCP1 in vitro and in vivo, which promoted WAT browning. Our findings provide a new molecular approach for the research of browning of WAT in animals, as well as a new target for animal metabolism improvement and obesity treatments.

Vascular dementia (VD) is one of the most common forms of dementia worldwide, characterized by problems with reasoning, planning, judgment, and memory. This study investigated the effect of a histone methyltransferase inhibitor on cognition and mitochondrial function in a rat model of VD, as well as its impact on H2O2-induced neurotoxicity in hippocampal neuronal cultures. In the in vivo experiments, VD was induced by bilateral occlusion of the common carotid artery (CCA) for one month. The histone methyltransferase inhibitor, BIX01294, was administered intracerebroventricularly for one month (22.5 µg.kg-1 three times/week). On day 30, behavioral tests, including the novel object recognition test and elevated plus maze test, were conducted. Mitochondrial enzyme activities, including aconitase, α-ketoglutarate dehydrogenase (α-KG), complex I, and complex IV, were evaluated in the hippocampus of rats following CCA ligation. In the in vitro experiments, the effect of BIX01294 (50-600 μM) on H2O2 (400 µM)-induced cytotoxicity in hippocampal neuronal cells was assessed using the MTT assay. Flow cytometry was performed to evaluate apoptosis. Our findings revealed that BIX01294 effectively improved memory function, Krebs cycle enzyme activity, and mitochondrial function in the rat model of VD. Moreover, in vitro results showed that BIX01294 at a concentration of 100 µM significantly reversed the cytotoxicity and apoptosis induced by H2O2 in neuronal cells. These findings suggest that BIX01294 may have the potential to improve VD complications by reducing oxidative stress and inhibiting histone methylation.

Ponicidin is a diterpenoid with demonstrated antitumor activity in clinical trials. However, the specific function and mechanism of action against hepatocellular carcinoma (HCC) remain unknown. In this study, it is found that ponicidin significantly inhibited the proliferation and migration of HCC cells. It is shown that ponicidin targets Keap1 and promotes the formation of the Keap1-PGAM5 complex, leading to the ubiquitination of PGAM5, using biotin-labeled ponicidin for target fishing and the HuProtTM Human Proteome Microarray V4.0. Ponicidin is found to activate the cysteine-dependent mitochondrial pathway via PGAM5, resulting in mitochondrial damage and ROS production, thereby promoting mitochondrial apoptosis in HepG2 cells. The first in vitro cocrystal structure of the PGAM5 IE 12-mer peptide and the Keap1 Kelch domain is obtained. Using molecular dynamics simulations to confirm the binding of ponicidin to the Keap1-PGAM5 complex. Based on the depth-based dynamic simulation, it is found that ponicidin can induce the tightening of the Keap1-PGAM5 interaction pocket, thereby stabilizing the formation of the protein complex. Finally, it is observed that ponicidin effectively inhibited tumor growth and promoted tumor cell apoptosis in a BALB/c nude mouse xenograft tumor model. The results provide insight into the anti-HCC properties of ponicidin based on a mechanism involving the Keap1-PGAM5 complex.

OBJECTIVE: The aim of this study was to investigate whether ASA VI controls osteoarthritis (OA) by regulating mitochondrial function.
METHODS: Primary chondrocytes were isolated and cultured from rat knee joints. The chondrocytes were treated with ASA VI and interleukin-1β (IL-1β) to simulate the inflammatory environment of OA. Cell viability, apoptosis, inflammatory cytokine levels, and extracellular matrix (ECM) component levels were assessed. Mitochondrial function, including ATP levels, mitochondrial membrane potential, reactive oxygen species (ROS) levels, and mitochondrial DNA content, was evaluated. The expression of Sirtuin 3 (Sirt3), a key regulator of mitochondrial homeostasis, was examined. Additionally, a rat OA model was established by destabilizing the medial meniscus, and the effects of ASA VI on cartilage degeneration were assessed.
RESULTS: ASA VI treatment improved cell viability, reduced apoptosis, and decreased IL-6 and TNF-α levels in IL-1β-induced chondrocytes. ASA VI also upregulated Collagen II and Aggrecan expression, while downregulating ADAMTS5 and MMP-13 expression. Furthermore, ASA VI mitigated IL-1β-induced mitochondrial dysfunction by increasing ATP levels, restoring mitochondrial membrane potential, reducing ROS production, and preserving mitochondrial DNA content. These effects were accompanied by the activation of Sirt3. In the rat OA model, ASA VI treatment increased Sirt3 expression and alleviated cartilage degeneration.
CONCLUSIONS: ASA VI exerts chondroprotective and anti-inflammatory effects on IL-1β-induced chondrocytes by improving mitochondrial function through Sirt3 activation. ASA VI also attenuates cartilage degeneration in a rat OA model. These findings suggest that ASA VI may be a potential therapeutic agent for the treatment of osteoarthritis by targeting mitochondrial dysfunction.