Mitochondrion最新文献

Alteration of immune response and synovium microvasculature in Rheumatoid arthritis (RA) progression has been suggested to be associated with mitochondrial functioning. Mitochondria, with maternally inherited DNA, exhibit differential response to the female hormone estrogen. Various epidemiological evidence has also shown the prominence of RA in the female population, depicting the role of estrogen in modulating the pathogenesis of RA. As estrogen regulates the expression of differential proteins and associated signaling pathways of RA, its influence on mitochondrial functioning seems evident. Thus, in this review, the studies related to mitochondria and their relation with estrogen and Rheumatoid arthritis were retrieved. We analyzed the different mitochondrial activities that are altered in RA and the possibility of their estrogenic control. The study expands to in silico analysis, revealing the differential mitochondrial proteins expressed in RA and examining these proteins as potential estrogenic targets. It was found that ALDH2, CASP3, and SOD2 are the major mitochondrial proteins involved in RA progression and are also potent estradiol targets. The analysis establishes the role of mitochondrial proteins in RA progression, which were found to be direct or indirect targets of estrogen, depicting its potential for regulating mitochondrial functions in RA.

Mitochondria are important for maintaining cellular energy metabolism and regulating cellular senescence. Mitochondrial DNA (mtDNA) encodes subunits of the OXPHOS complexes which are essential for cellular respiration and energy production. Meanwhile, mtDNA variants have been associated with the pathogenesis of neurodegenerative diseases, including MELAS, for which no effective treatment has been developed. To alleviate the pathological conditions involved in mitochondrial disorders, mitochondria transfer therapy has shown promise. Wharton's jelly mesenchymal stem cells (WJMSCs) have been identified as suitable mitochondria donors for mitochondria-defective cells, wherein mitochondrial functions can be rescued. Miro1 participates in mitochondria trafficking by anchoring mitochondria to microtubules. In this study, we identified Miro1 over-expression as a factor that could help to enhance the efficiency of mitochondrial delivery. More specifically, we reveal that Miro1 over-expressed WJMSCs significantly improved intercellular communications, cell proliferation rates, and mitochondrial membrane potential, while restoring mitochondrial bioenergetics in mitochondria-defective fibroblasts. Furthermore, Miro1 over-expressed WJMSCs decreased rates of induced apoptosis and ROS production in MELAS fibroblasts; although, Miro1 over-expression did not rescue mtDNA mutation ratios nor mitochondrial biogenesis. This study presents a potentially novel therapeutic strategy for treating mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and other diseases associated with dysfunctional mitochondria, while the pathophysiological relevance of our results should be further verified by animal models and clinical studies.

Ageing is described as an inevitable decline in body functions over time and an increase in susceptibility to age-related diseases. Therefore, the increase of life expectancy is also viewed as a condition in which many elderly will develop age-related diseases and disabilities, such as cardiovascular, metabolic, neurological and oncological ones. Currently, several recognized cellular hallmarks of senescence are taken in consideration to evaluate the level of biological ageing and are the topic to plan preventive/curative anti-ageing interventions, including genomic instability, epigenetic alterations, and mitochondrial dysfunction. In this scenario, alterations in the function/expression of mitochondrial ion channels have been found in ageing and associated to an impairment of calcium cycling and a reduced mitochondrial membrane potential. Although several ion channels have been described at mitochondrial level, undoubtedly the mitochondrial potassium (mitoK) channels are the most investigated. Therefore, this review summarized the evidence that sheds to light a correlation between age-related diseases and alteration of mitoK channels, focusing the attention of the main age-related diseases, i.e. cardiovascular, neurological and oncological ones.

Space is a challenging environment that deregulates individual homeostasis. The main external hazards associated with spaceflight include ionizing space radiation, microgravity, isolation and confinement, distance from Earth, and hostile environment. Characterizing the biological responses to spaceflight environment is essential to validate the health risks, and to develop effective protection strategies. Mitochondria energetics is a key mechanism underpinning many physiological, ecological and evolutionary processes. Moreover, mitochondrial stress can be considered one of the fundamental features of space travel. So, we attempt to synthesize key information regarding the extensive effects of spaceflight on mitochondria. In summary, mitochondria are affected by all of the five main hazards of spaceflight at multiple levels, including their morphology, respiratory function, protein, and genetics, in various tissues and organ systems. We emphasize that investigating mitochondrial biology in spaceflight conditions should become the central focus of research on the impacts of spaceflight on human health, as this approach will help resolve numerous challenges of space health and combat several health disorders associated with mitochondrial dysfunction.

Mycobacteria, including Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria (NTM), pose challenges in treatment due to their increased resistance to antibiotics. Following infection, mycobacteria and their components trigger robust innate and inflammatory immune responses intricately associated with the modulation of mitochondrial functions, including oxidative phosphorylation (OXPHOS) and metabolism. Certainly, mitochondrial reactive oxygen species (mtROS) are an inevitable by-product of OXPHOS and function as a bactericidal weapon; however, an excessive accumulation of mtROS are linked to pathological inflammation and necroptotic cell death during mycobacterial infection. Despite previous studies outlining various host pathways involved in regulating mtROS levels during antimicrobial responses in mycobacterial infection, our understanding of the precise mechanisms orchestrating the fine regulation of this response remains limited. Emerging evidence suggests that mycobacterial proteins play a role in targeting the mitochondria of the host, indicating the potential influence of microbial factors on mitochondrial functions within host cells. In this review, we provide an overview of how both host and Mtb factors influence mtROS generation during infection. A comprehensive study of host and microbial factors that target mtROS will shed light on innovative approaches for effectively managing drug-resistant mycobacterial infections.

Peripheral blood mononuclear cells (PBMC) mitochondrial respiration was measured ex vivo from participants without a history of COVID (n = 19), with a history of COVID and full recovery (n = 20), and with PASC (n = 20). Mean mitochondrial basal respiration, ATP-linked respiration, maximal respiration, spare respiration capacity, ATP-linked respiration, and non-mitochondrial respiration were highest in COVID + PASC+ (p ≤ 0.04). Every unit increase in non-mitochondrial respiration, ATP-linked respiration, basal respiration, spare respiration capacity, and maximal respiration increased the predicted odds of PASC between 1 % and 6 %. Mitochondrial dysfunction in PBMCs may be contributing to the etiology of PASC.

Reticulum 3 (RTN3) is an endoplasmic reticulum (ER) protein that has been reported to act in neurodegenerative diseases and lipid metabolism. However, the role of RTN3 in acute kidney injury (AKI) has not been explored. Here, we employed public datasets, patient data, and animal models to explore the role of RTN3 in AKI. The underlying mechanisms were studied in primary renal tubular epithelial cells and in the HK2 cell line. We found reduced expression of RTN3 in AKI patients, cisplatin-induced mice, and cisplatin-treated HK2 cells. RTN3-null mice exhibit more severe AKI symptoms and kidney fibrosis after cisplatin treatment. Mitochondrial dysfunction was also found in cells with RTN3 knockdown or knockout. A mechanistic study revealed that RTN3 can interact with HSPA9 in kidney cells. RTN3 deficiency may disrupt the RTN3–HSPA9–VDAC2 complex and affect MAMs during ER–mitochondrion contact, which further leads to mitochondrial dysfunction and exacerbates cisplatin-induced AKI. Our study indicated that RTN3 was important in the kidney and that a decrease in RTN3 in the kidney might be a risk factor for the aggravation of AKI.

The mitochondrial DNA (mtDNA) is replicated and canonically functions within intracellular mitochondria, but recent discoveries reveal that the mtDNA has another exciting extracellular life. mtDNA fragments and mitochondria-containing vesicular structures are detected at high concentrations in cell-free forms, in different biofluids. Commonly referred to as cell-free mtDNA (cf-mtDNA), the field is currently without a comprehensive classification system that acknowledges the various biological forms of mtDNA and whole mitochondria existing outside the cell. This absence of classification hampers the creation of precise and consistent quantification methods across different laboratories, which is crucial for unraveling the molecular and biological characteristics of mtDNA. In this article, we integrate recent findings to propose a classification for different types of Extracellular mtDNA [ex-mtDNA]. The major biologically distinct types include: Naked mtDNA [N-mtDNA], mtDNA within non-mitochondrial Membranes [M-mtDNA], Extracellular mitochondria [exM-mtDNA], and mtDNA within Mitochondria enclosed in a Membrane [MM-mtDNA]. We outline the challenges associated with accurately quantifying these ex-mtDNA types, suggest potential physiological roles for each ex-mtDNA type, and explore how this classification could establish a foundation for future research endeavors and further analysis and definitions for ex-mtDNA. By proposing this classification of circulating mtDNA forms, we draw a parallel with the clinically recognized forms of cholesterol, such as HDL and LDL, to illustrate potential future significance in a similar manner. While not directly analogous, these mtDNA forms may one day be as biologically relevant in clinical interpretation as cholesterol fractions are currently. We also discuss how advancing methodologies to reliably quantify distinct ex-mtDNA forms could significantly enhance their utility as health or disease biomarkers, and how their application may offer innovative therapeutic approaches.

The purpose of our study is to develop age-related phosphorylated tau (p-tau) inhibitors, for Alzheimer’s disease (AD). There are wide-ranging therapeutic molecules available in the market and tested for age-related p-tau inhibition to enhance phosphatase activity and microtubule stability in AD neurons. Until now there are no such small molecules claimed to show promising results to delay the disease process of AD. However, a recently developed molecule, DDQ, has been shown to reduce abnormal protein–protein interactions and protect neurons from mutant protein-induced toxicities in the disease process. In addition, DDQ reduced age- and Aβ-induced oxidative stress, mitochondrial dysfunction, and synaptic toxicity. To date, there are no published reports on the p-tau interaction of DDQ and Sirt3 upregulation with CREB-mediated mitophagy activation in AD neurons. In the current study, HT22 cells were transfected with mutant Tau (mTau) cDNA and treated with the novel molecule DDQ. Cell survival, immunoblotting, and immunofluorescence analysis were conducted to assess cell viability and synaptic and mitophagy proteins in treated and untreated cell groups. As expected, we found cell survival was decreased in mTau-HT22 cells when compared with control HT22 cells. However, cell survival was increased in DDQ-treated mTau-HT22 cells when compared with mTau HT22 cells. P-tau and total tau proteins were significantly reduced in DDQ-treated mTau-HT22 cells, and MAP2 levels were increased. Anti-aging proteins like Sirt3, and CREB levels were increased in DDQ-treated HT22 cells and also in mTau-HT22 cells treated DDQ. Mitophagy proteins were decreased in mTau-HT22 cells and these were increased in DDQ-treated mTau-HT22 cells. These observations strongly suggest that DDQ has anti-p-tau and anti-aging properties, via Sirt3 overexpression and increased mitophagy proteins. Our study findings may have implications for healthy aging to the development of p-tau targeted therapeutics in AD and tauopathies.

Mitochondrial dynamics and autophagy play essential roles in normal cellular physiological activities, while abnormal mitochondrial dynamics and mitochondrial autophagy can cause cancer and related disorders. Abnormal mitochondrial dynamics usually occur in parallel with mitochondrial autophagy. Both have been reported to have a synergistic effect and can therefore complement or inhibit each other. Progress has been made in understanding the classical mitochondrial PINK1/Parkin pathway and mitochondrial dynamical abnormalities. Still, the mechanisms and regulatory pathways underlying the interaction between mitophagy and mitochondrial dynamics remain unexplored. Like other existing reviews, we review the molecular structure of proteins involved in mitochondrial dynamics and mitochondrial autophagy, and how their abnormalities can lead to the development of related diseases. We will also review the individual or synergistic effects of abnormal mitochondrial dynamics and mitophagy leading to cellular proliferation, differentiation and invasion. In addition, we explore the mechanisms underlying mitochondrial dynamics and mitochondrial autophagy to contribute to targeted and precise regulation of mitochondrial function. Through the study of abnormal mitochondrial dynamics and mitochondrial autophagy regulation mechanisms, as well as the role of early disease development, effective targets for mitochondrial function regulation can be proposed to enable accurate diagnosis and treatment of the associated disorders.