Mitochondrion最新文献

Activation of the sympatho-β-adrenergic receptor (βAR) system is the hallmark of heart disease with adverse consequences that facilitate the onset and progression of heart failure (HF). Use of β-blocking drugs has become the front-line therapy for HF. Last decade has witnessed progress in research demonstrating a pivotal role of Hippo pathway in cardiomyopathy and HF. Clinical studies have revealed myocardial Hippo pathway activation/YAP-TEAD1 inactivation in several types of human cardiomyopathy. Experimental activation of cardiac Hippo signaling or inhibition of YAP-TEAD1 have been shown to leads dilated cardiomyopathy with severe mitochondrial dysfunction and metabolic reprogramming. Studies have also convincingly shown that stimulation of βAR activates cardiac Hippo pathway with inactivation of the down-stream effector molecules YAP/TAZ. There is strong evidence for the adverse consequences of the βAR-Hippo signaling leading to HF. In addition to promoting cardiomyocyte death and fibrosis, recent progress is the demonstration of mitochondrial dysfunction and metabolic reprogramming mediated by βAR-Hippo pathway signaling. Activation of cardiac βAR-Hippo signaling is potent in downregulating a range of mitochondrial and metabolic genes, whereas expression of pro-inflammatory and pro-fibrotic factors are upregulated. Coupling of βAR-Hippo pathway signaling is mediated by several kinases, mechanotransduction and/or Ca²⁺ signaling, and can be blocked by β-antagonists. Demonstration of the converge of βAR signaling and Hippo pathway bears implications for a better understanding on the role of enhanced sympathetic nervous activity, efficacy of β-antagonists, and metabolic therapy targeting this pathway in HF. In this review we summarize the progress and discuss future research directions in this field.

Mitochondrial dysfunction is linked to various systemic and localized diseases, including oral diseases like periodontitis, oral cancer, and temporomandibular joint disorders. This paper explores the intricate mechanisms underlying mitochondrial dysfunction in oral pathologies, encompassing oxidative stress, inflammation, and impaired energy metabolism. Furthermore, it elucidates the bidirectional relationship between mitochondrial dysfunction and oral diseases, wherein the compromised mitochondrial function exacerbates disease progression, while oral pathologies, in turn, exacerbate mitochondrial dysfunction. Understanding these intricate interactions offers insights into novel therapeutic strategies targeting mitochondrial function for managing oral diseases. This paper pertains to the mechanisms underlying mitochondrial dysfunction, its implications in various oral pathological and inflammatory conditions, and emerging versatile treatment approaches. It reviews current therapeutic strategies to mitigate mitochondrial dysfunction, including antioxidants, mitochondrial-targeted agents, and metabolic modulators.

Mitochondria are essential for energy supplementation and metabolic homeostasis of cancer cells. Using mitochondria transplantation to reduce the malignancy of gastric cancer (GC) cells is herein proposed. In our study normal human gastric mucous epithelium cell line (GES-1) showed a lower mitochondrial membrane potential (MMP) compared to immortalized human vascular endothelial cell line (EAhy 926) and human gastric adenocarcinoma cell line (AGS). The transplantation of GES-1 mitochondria to AGS were confirmed both by confocal microscopy and flow cytometry. After transplanting GES-1 mitochondria, the AGS showed a reduced cell migration, and invasion without affecting cell viability and apoptosis. Investigating the expression of proteins involved in epithelial-mesenchymal-transition (EMT), transplanted GES-1 mitochondria reduced the expression of mesenchymal markers α-SMA, MMP-9, snail, vimentin and N-cadherin, whereas the epithelial markers E-cadherin and clauding-1 were not changed. The proteins implicated in the cell cycle such as cyclin B1 and D1 were decreased. In mice, inoculation with AGS carrying the transplanted GES-1 mitochondria resulted in smaller sized tumors. Further investigating the mitochondrial balance, the transplanted GES-1 mitochondria were more stably preserved compared to endogenous AGS mitochondria. The MMP, ATP production and mitochondrial mass decreased in GES-1 mitochondria and the mitophagic proteins LC3 II and PINK1 were up-regulated. In conclusion the decreased malignancy of AGS was a result of exogenous GES-1 mitochondria transplantation. This suggests for a therapy with low efficiency mitochondria transplantation in the treatment of cancer cells.

Background

Evidence about early cardiac mechanics abnormalities in patients with mitochondrial diseases (MDs) before overt cardiomyopathy is limited.

Methods

In this prospective study, we performed a comparative analysis of conventional and speckle tracking echocardiographic parameters between patients with genetically identified MDs and no overt cardiomyopathy vs controls matched for age, sex and cardiovascular risk factors. The Newcastle mitochondrial disease adult scale (NMDAS) was calculated, using a threshold of > 21 as indicator of high disease severity.

Results

We enrolled 24 MDs patients (50 % males, mean age 47.2 ± 14.3 years), the most prevalent mutation was the MT-TL1 m.3243A>G (37.5 %). In MDs patients all dimensional echocardiographic parameters were similar to controls. Conversely, albeit normal, Tissue Doppler septal systolic (p = 0.002) and early diastolic velocities (p = 0.016) were significantly lower and E/e’ ratio was higher (p = 0.032) in MDs. Moreover, LV-GLS was significantly reduced in MDs as compared to their counterparties (20.2 ± 1.6 vs 22.6 ± 1.5, p < 0.001). Similarly, LA reservoir and conduit strain were significantly lower in MDs (31.7 ± 7.0 vs 35.9 ± 6.6, p = 0.038; 19.7 ± 5.6 vs 23.1 ± 6.0, p = 0.049 respectively), while LA contractile strain was similar between the two groups. Lower values of LV-GLS were observed in patients with NMDAS > 21 vs patients with NMDAS ≤ 21 (19.0 ± 1.2 vs 21.0 ± 1.3, p = 0.001).

Conclusions

In patients with MDs and no overt cardiomyopathy Tissue Doppler and speckle tracking analysis unveil worse LV systolic and diastolic function indices as compared to controls. Reduced LV-GLS values were found especially in those with worse disease burden.

Background

Mechanisms behind multiple organ involvement in lupus, is still an enigma for researchers. Mitochondrial dysfunction and oxidative stress are known to be important aspects in lupus etiology however, their role in lupus organ manifestation is yet to be understood. The present study is based on the understanding of interplay between AMPK/PGC-1α/SIRT-1 axis, mitochondrial complexes, and anti-oxidants levels, which might be involved in lupus organ pathology.

Methodology

Pristane-induced Balb/c mice lupus model (PIL) was utilised and evaluation of anti-oxidants, mitochondrial complexes, pro-inflammatory cytokines levels, biochemical parameters were performed by standard procedures. Tissues were studied by haematoxylin and eosin staining followed by immunohistochemistry. The AMPK/PGC-1α/SIRT-1 expression was analysed by using qPCR and flowcytometry. Analysis of reactive oxygen species (ROS) among WBCs was performed by using various dyes (DCFDA, Mitosox, JC-1) on flowcytometry.

Result

Significant presence of immune complexes (Tissue sections), ANA (Serum), and pro-inflammatory cytokines (plasma), diminished anti-oxidants and altered biochemical parameters depict the altered pathology in PIL which was accompanied by dysregulated mitochondrial complex activity. Differential expression of the AMPK/PGC-1α/SIRT-1 axis was detected in tissue and correlation with mitochondrial and antioxidant activity emerged as negative in PIL group while positive in controls. Close association was observed between ROS, mitochondrial membrane potential, and AMPK/PGC-1α/SIRT-1 axis in WBCs.

Conclusion

This study concludes that mitochondria play a dual role in lupus organ pathology, contributing to organ damage while also potentially protecting against damage through the regulation of interactions between antioxidants and the AMPK axis expression.

HIV infection and its treatment are associated with mitochondrial dysfunction and metabolic derangement. However, longitudinal changes in oxidative phosphorylation activities [Complex I (C1) and Complex IV (C4)], or venous lactate/pyruvate ratios (LPR), and their relationships with insulin resistance (IR), remain unclear in youth living with perinatally-acquired HIV (YPHIV). We measured venous LPR, C1, and C4 activities in blood cells and homeostatic model assessment for IR (HOMA-IR) over two years. Limited longitudinal differences in mitochondrial-related measures and IR were observed in YPHIV vs youth perinatally HIV-exposed but uninfected. There were no systematic differences in C1, C4, or HOMA-IR between the groups.

Renal iron overload is a common complication of diabetes that leads to oxidative stress and mitochondrial dysfunction in the kidneys. This study investigated the effects of iron chelation using deferiprone on mitochondrial dysfunction and oxidative stress in the renal cortex of a murine model of type 2 diabetes. Diabetic rats were treated with deferiprone (50 mg/kg BW) for 16 weeks. Our results show that iron chelation with deferiprone significantly increased the nuclear accumulation of Nrf2, a transcription factor that regulates the expression of antioxidant enzymes. This led to enhanced antioxidant capacity, reduced production of reactive oxygen species, and improved mitochondrial bioenergetic function in diabetic rats. However, chronic iron chelation led to altered mitochondrial respiration and increased oxidative stress in non-diabetic rats. In conclusion, our findings suggest that iron chelation with deferiprone protects mitochondrial bioenergetics and mitigates oxidative stress in the renal cortex, involving the NRF2 pathway in type 2 diabetes.

Protein function is dependent on charge interactions and charge biased regions, which are involved in a wide range of cellular and biochemical processes. We report the development of a new algorithm implemented in Python and its use to identify charge clusters CC (NegativeCC: NCC, PositiveCC: PCC and MixedCC: MCC) and compare their presence in mitochondrial proteins of plant groups. To characterize the resulting CC, statistical, structural and functional analyses were conducted. The screening of 105 399 protein sequences showed that 2.6 %, 0.48 % and 0.03 % of the proteins contain NCC, PCC and MCC, respectively. Mitochondrial proteins encoded by the nuclear genome of green algae have the biggest proportion of both PCC (1.6 %) and MCC (0.4 %) and mitochondrial proteins coded by the nuclear genome of other plants group have the highest portion of NCC (7.5 %). The mapping of the identified CC showed that they are mainly located in the terminal regions of the protein. Annotation showed that proteins with CC are classified as binding proteins, are included in the transmembrane transport processes, and are mainly located in the membrane. The CC scanning revealed the presence of 2373 and 784 sites and 192 and 149 motif profiles within NCC and PCC, respectively. The investigation of CC within pentatricopeptide repeat-containing proteins revealed that they are involved in correct and specific RNA editing. CC were proven to play a key role in providing insightful structural and functional information of complex protein assemblies which could be useful in biotechnological applications.

In recent years, research has increasingly focused on the biogenesis of extracellular vesicles (EVs) and the sorting mechanisms for their contents. Mitochondria can be selectively loaded into EVs, serving as a way to maintain cellular mitochondrial homeostasis. EV-mediated mitochondrial transfer has also been shown to greatly impact the function of target cells. Based on the mechanism of EV-mediated mitochondrial transfer, therapies can be developed to treat human diseases. This review summarizes the recent advances in the biogenesis and molecular composition of EVs. It also highlights the sorting and trafficking mechanisms of mitochondrial components into EVs. Furthermore, it explores the current role of EV-mediated mitochondrial transfer in the development of human diseases, as well as its diagnostic and therapeutic applications.

A hallmark of neuroinflammatory disorders is mitochondrial dysfunction. Nevertheless, the transcriptional changes underlying this alteration are not well-defined. Microglia activation, a decrease in mitochondrion biogenesis and a subsequent alteration of the redox are common factors in diseases coursing with neuroinflammation. In the last two decades, components of the adenosinergic system have been proposed as potential therapeutic targets to combat neuroinflammation. In this research, we analyzed by RNAseq the gene expression in activated microglia treated with an adenosine A_2A receptor antagonist, SCH 582561, and/or an A₃ receptor agonist, 2-Cl-IB-MECA, since these receptors are deeply related to neurodegeneration and inflammation. The analysis was focused on genes related to inflammation and REDOX homeostasis. It was detected that in the three conditions (microglia treated with 2-Cl-IB-MECA, SCH 582561, and their combination) more than 40 % of the detected genes codified by the mitochondrial genome were differentially expressed (FDR < 0.05) (14/34, 16/34, and 13/34) respectively, being almost all of them (>85 %) upregulated in the microglia treated with adenosinergic compounds. Also, we analyzed the differential expression of genes related to mitochondrial function and oxidative stress codified by the nuclear genome. Additionally, we evaluated the oxygen consumption rate (OCR) of mitochondria in microglia treated with LPS and IFN-γ, both alone and in combination with adenosinergic compounds. The data showed an improvement in mitochondrial function with the antagonist of the adenosine A_2A receptor, compared to the effects of pro-inflammatory stimulus, confirming a functional effect consistent with the RNAseq data.