Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.

Cognitive disability and neurodegeneration are prominent symptoms of Mucopolysaccharidosis VII (MPS VII), a lysosomal storage disorder caused by β-glucuronidase enzyme deficiency. Yet, the mechanism of neurodegeneration in MPS VII remains unclear thereby limiting the scope of targeted therapy. We aimed to bridge this knowledge gap by employing the β-glucuronidase-deficient (CG2135-/-) Drosophila model of MPS VII. Taking cues from our initial observation that the adult CG2135-/- flies displayed enhanced susceptibility to starvation, we investigated potential impairments in the autophagy-lysosomal clearance machinery in their brain to dissect the underlying cause of neurodegeneration. We found that both autophagosome biogenesis and lysosome-mediated autophagosomal turnover were impaired in the CG2135-/- fly brain. This was evidenced by lower Atg8a-II levels, reduced Atg1 and Ref(2)P expression along with accumulation of lipofuscin-like inclusions and multilamellar bodies. Mitophagy was also found to be defective in their brain, resulting in buildup of enlarged mitochondria with distorted cristae and reduced membrane potential. This, in turn, compromised mitochondrial function, as reflected by drastically reduced brain ATP levels. Energy depletion triggered apoptosis in neuronal as well as non-neuronal cells of the CG2135-/- fly brain, where apoptotic dopaminergic neurons were also detected. Interestingly, resveratrol treatment corrected the mitophagy defect and prevented ATP depletion in the CG2135-/- fly brain, providing an explanation for its neuroprotective effects. Collectively, our study reveals a pharmacologically targetable mechanistic link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in MPS VII.

The study aims to investigate the therapeutic effects of the aqueous extract of Atractylodes macrocephala Koidz. (AEA) on dexamethasone (Dex) -induced sarcopenia in mice and to explore its possible mechanisms of action.

This study utilized bioinformatics analysis to explore the primary pathogenic mechanisms of age-related sarcopenia and Dex-induced muscle atrophy. In animal experiments, a mouse model of muscle atrophy was established using Dex, and different doses of AEA were administered for treatment. The therapeutic effects of AEA were evaluated through tests of motor ability and histological analysis, and the molecular mechanisms predicted by bioinformatics were verified by measuring the expression levels of related genes.

Bioinformatics analysis suggests that there may be shared pathogenic mechanisms related to mitochondrial function and structure between age-related sarcopenia and Dex-induced muscle atrophy. Dex significantly reduced the mass, function, and cross-sectional area of muscle fibers in mice, and also induced changes in muscle fiber types. In contrast, AEA significantly ameliorated the aforementioned atrophic effects caused by Dex. The modulation of mitochondrial biogenesis and dynamics may be a crucial mechanism by which AEA exerts its anti-sarcopenia effects.

AEA can significantly alleviate the symptoms of Dex-induced skeletal muscle atrophy in mice by improving mitochondrial function, indicating its potential for clinical application in the prevention and treatment of age-related sarcopenia.

Ovarian tumours are these days one of the biggest oncogynecological problems. In addition to surgery, the treatment of ovarian cancer includes also chemotherapy in which platinum preparations are one of the most used chemotherapeutic drugs. The principle of antineoplastic effects of cisplatin (cis-diamminedichloroplatinum(II), CDDP) is its binding to the DNA and the formation of adducts. While DNA adducts induce the process of apoptosis, or inhibit the process of DNA replication, which prevents further division of tumour cells, various molecular mechanisms can reverse this process. On the other hand, with increasing scientific knowledge, it is becoming clearer that chemotherapy resistance is a very complex process. In this regard, factors and the amount of their expression may regulate the effect of resistance to chemotherapy. This review focuses on new molecular mechanisms and factors such as mitochondrial dynamics, epithelial-mesenchymal transition (EMT), cluster of differentiation, exosomes and others, that could be involved in the emergence of CDDP resistance.

Mitochondria are involved in a wide array of critical cellular processes from energy production to cell death. The morphology (size and shape) of mitochondrial compartments is highly responsive to both intracellular and extracellular conditions, making these organelles highly dynamic. Nutrient levels and stressors both inside and outside the cell inform the balance of mitochondrial fission and fusion and the recycling of mitochondrial components known as mitophagy. The study of mitochondrial morphology and its implications in human disease and microbial engineering have gained significant attention over the past decade. The yeast Saccharomyces cerevisiae offers a valuable model system for studying mitochondria due to its ability to survive without respiring, its genetic tractability, and the high degree of mitochondrial similarity across eukaryotic species. Here, we review how the interplay between mitochondrial fission, fusion, biogenesis, and mitophagy regulates the dynamic nature of mitochondrial networks in both yeast and mammalian systems with an emphasis on yeast as a model organism. Additionally, we examine the crucial role of inter-organelle interactions, particularly between mitochondria and the endoplasmic reticulum, in regulating mitochondrial dynamics. The dysregulation of any of these processes gives rise to abnormal mitochondrial morphologies, which serve as the distinguishing features of numerous diseases, including Parkinson's disease, Alzheimer's disease, and cancer. Notably, yeast models have contributed to revealing the underlying mechanisms driving these human disease states. In addition to furthering our understanding of pathologic processes, aberrant yeast mitochondrial morphologies are of increasing interest to the seemingly distant field of metabolic engineering, following the discovery that compartmentalization of certain biosynthetic pathways within mitochondria can significantly improve chemical production. In this review, we examine the utility of yeast as a model organism to study mitochondrial morphology in both healthy and pathologic states, explore the nascent field of mitochondrial morphology engineering, and discuss the methods available for the quantification and classification of these key mitochondrial morphologies.

Diabetic kidney disease (DKD) is recognized worldwide as a leading cause of end-stage renal failure. Although therapies that target glomerular hemodynamics and can inhibit disease progression have been developed, there is currently no fundamental cure for the disease. Mitochondria play an important role in cellular respiration, producing adenosine triphosphate (ATP) by oxidative phosphorylation, and are essential for renal function, especially in proximal tubular cells (PTCs). In diabetic conditions, maintaining mitochondrial health is vital for preserving renal function. Under diabetic conditions, excessive reactive oxygen species (ROS) can damage mitochondrial DNA (mtDNA), leading to renal dysfunction. Strategies targeting mitochondrial function, such as AMP-activated protein kinase (AMPK) activation and modulation of nitric oxide (NO) availability, are promising for suppressing diabetic nephropathy. The immune response to DKD, initiated by detecting damage- and pathogen-associated molecular patterns, has a significant impact on the progression of DKD, including leakage of mtDNA and RNA, leading to inflammation through various pathways. This contributes to renal impairment characterized by hyperfiltration, endothelial dysfunction, and albuminuria. Mitochondrial energy metabolism and dynamics induced by hyperglycemia precede the onset of albuminuria and histological changes in the kidneys. The increased mitochondrial fission and decreased fusion that occur under diabetic conditions result in ATP depletion and exacerbate cellular dysfunction. Therapeutic strategies focused on restoring mitochondrial function are promising for slowing the progression of DKD and reduce the adverse effects on renal function. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 (GLP-1) receptor agonists, already in clinical use, have been shown to be protective for mitochondria, and nuclear factor erythroid 2-related factor 2 (Nrf2) activation and mitochondrial dynamics are promising drug discovery targets for further research.

In developed nations, women have increasingly deferred childbearing, leading to a rise in demand for infertility treatments and the widespread use of assisted reproductive technologies. However, despite advancements in in vitro fertilization (IVF), live birth rates among women over 40 remain suboptimal. Mitochondrial dysfunction is widely recognized as a key factor in the processes driving the age-related deterioration in both the quantity and quality of oocytes. We aim to summarize current insights into ovarian aging, with a particular focus on pathways that impair mitochondrial function, and explore directions for future research.

Electronic databases were searched for articles published up to June 30, 2024.

Ongoing ovulation, luteolysis, and menstruation trigger exogenous reactive oxygen species (ROS)-mediated oxidative stress that damages mitochondrial DNA. This, in turn, reduces nuclear gene expression, compromises mitochondrial oxidative phosphorylation, and diminishes adenosine 5' triphosphate production. Persistent endogenous ROS further exacerbate mitochondrial DNA damage and aneuploidy, ultimately causing irreversible chromosomal abnormalities, leading to oocyte aging.

We have delineated the pathway from oxidative stress to ovarian aging. Early detection and management of ovarian aging present challenges and opportunities to enhance IVF treatment strategies.

Lactate, a product of glycolysis, is formed under aerobic conditions. Extensive work has shown lactate flux in young and exercising humans; however, the effect of age is not known. We tested the hypothesis that postprandial lactate shuttling (PLS) would be diminished in older adults. We used [3-13C]lactate and [6,6-2H]glucose tracers, an oral glucose tolerance test (OGTT), and arterialized blood sampling to determine postprandial lactate rates of appearance (Ra), disappearance (Rd), and oxidation (Rox) in 15 young (28.1 ± 1.4 yr) and 13 older (70.6 ± 2.4 yr) healthy men and women. In young participants, fasting blood [lactate] (≈0.5 mM) rose after the glucose challenge, peaked at 15 min, dipped to a nadir at 30 min, and rose again peaking at 60 min (≈1.0 mM). Initial responses in lactate Ra of older participants were delayed and diminished until 90 min rising by 0.83 mg·kg-1·min-1. Lactate Rox was higher throughout the entire trial in young participants by a difference of ∼0.5 mg·kg-1·min-1. Initial peaks in lactate Ra and concentration in all volunteers demonstrated the presence of an enteric PLS following an OGTT. Notably, in the systemic, but not enteric, PLS phase, lactate Ra correlated highly with glucose Rd (r2 = 0.92). Correspondence of second peaks in lactate Ra and concentration and glucose Rd shows dependence of lactate Ra on glucose Rd. Although results show both enteric and systemic PLS phases in young and older study cohorts, metabolic responses were delayed and diminished in healthy older individuals.NEW & NOTEWORTHY We used isotope tracers, an oral glucose tolerance test, and arterialized blood sampling to determine postprandial lactate flux rates in healthy young and older men and women. Lactate rates of appearance and oxidation and the lactate-pyruvate exchange were delayed and diminished in both enteric and systemic postprandial lactate shuttle phases in older participants.

The mitochondrial deacetylase sirtuin-3 (SIRT3) is necessary for the increased bone resorption and enhanced function of mitochondria in osteoclasts that occur with advancing age; how SIRT3 drives bone resorption remains elusive.

To determine the role of SIRT3 in osteoclast mitochondria, we used mice with conditional loss of Sirt3 in osteoclast lineage and mice with germline deletion of either Sirt3 or its known target Pink1.

SIRT3 stimulates mitochondrial quality in osteoclasts in a PINK1-independent manner, promoting mitochondrial activity and osteoclast maturation and function, thereby contributing to bone loss in female but not male mice. Quantitative analyses of global proteomes and acetylomes revealed that deletion of Sirt3 dramatically increased acetylation of osteoclast mitochondrial proteins, particularly ATPase inhibitory factor 1 (ATPIF1), an essential protein for mitophagy. Inhibition of mitophagy via mdivi-1 recapitulated the effect of deletion of Sirt3 or Atpif1 in osteoclast formation and mitochondrial function.

Decreasing mitophagic flux in osteoclasts may be a promising pharmacotherapeutic approach to treat osteoporosis in older adults.

Despite clinical and scientific advancements, heart failure is the major cause of morbidity and mortality worldwide. Both mitochondrial dysfunction and inflammation contribute to the development and progression of heart failure. Although inflammation is crucial to reparative healing following acute cardiomyocyte injury, chronic inflammation damages the heart, impairs function, and decreases cardiac output. Mitochondria, which comprise one third of cardiomyocyte volume, may prove a potential therapeutic target for heart failure. Known primarily for energy production, mitochondria are also involved in other processes including calcium homeostasis and the regulation of cellular apoptosis. Mitochondrial function is closely related to morphology, which alters through mitochondrial dynamics, thus ensuring that the energy needs of the cell are met. However, in heart failure, changes in substrate use lead to mitochondrial dysfunction and impaired myocyte function. This review discusses mitochondrial and cristae dynamics, including the role of the mitochondria contact site and cristae organizing system complex in mitochondrial ultrastructure changes. Additionally, this review covers the role of mitochondria-endoplasmic reticulum contact sites, mitochondrial communication via nanotunnels, and altered metabolite production during heart failure. We highlight these often-neglected factors and promising clinical mitochondrial targets for heart failure.

The liver, the largest internal organ and a metabolic hub, undergoes significant declines due to aging, affecting mitochondrial function and increasing the risk of systemic liver diseases. How the mitochondrial three-dimensional (3D) structure changes in the liver across aging, and the biological mechanisms regulating such changes confers remain unclear. In this study, we employed Serial Block Face-Scanning Electron Microscopy (SBF-SEM) to achieve high-resolution 3D reconstructions of murine liver mitochondria to observe diverse phenotypes and structural alterations that occur with age, marked by a reduction in size and complexity. We also show concomitant metabolomic and lipidomic changes in aged samples. Aged human samples reflected altered disease risk. To find potential regulators of this change, we examined the Mitochondrial Contact Site and Cristae Organizing System (MICOS) complex, which plays a crucial role in maintaining mitochondrial architecture. We observe that the MICOS complex is lost during aging, but not Sam50. Sam50 is a component of the sorting and assembly machinery (SAM) complex that acts in tandem with the MICOS complex to modulate cristae morphology. In murine models subjected to a high-fat diet, there is a marked depletion of the mitochondrial protein SAM50. This reduction in Sam50 expression may heighten the susceptibility to liver disease, as our human biobank studies corroborate that Sam50 plays a genetically regulated role in the predisposition to multiple liver diseases. We further show that changes in mitochondrial calcium dysregulation and oxidative stress accompany the disruption of the MICOS complex. Together, we establish that a decrease in mitochondrial complexity and dysregulated metabolism occur with murine liver aging. While these changes are partially be regulated by age-related loss of the MICOS complex, the confluence of a murine high-fat diet can also cause loss of Sam50, which contributes to liver diseases. In summary, our study reveals potential regulators that affect age-related changes in mitochondrial structure and metabolism, which can be targeted in future therapeutic techniques.

Global attention is riveted on neurodegenerative diseases due to their unresolved aetiologies and lack of efficacious therapies. Two key factors implicated include mitochondrial impairment and microglial ageing. Several viral infections, including Herpes simplex virus-1 (HSV-1), human immunodeficiency virus (HIV) and Epstein-Barr virus, are linked to heightened risk of these disorders. Surprisingly, numerous studies indicate viruses induce these aforementioned precipitating events. Epstein-Barr virus, Hepatitis C Virus, HIV, respiratory syncytial virus, HSV-1, Japanese Encephalitis Virus, Zika virus and Enterovirus 71 specifically impact mitochondrial function, leading to mitochondrial malfunction. These vital organelles govern various cell activities and, under specific circumstances, trigger microglial ageing. This article explores the role of viral infections in elucidating the pathogenesis of neurodegenerative ailments. Various viruses instigate microglial ageing via mitochondrial destruction, causing senescent microglia to exhibit activated behaviour, thereby inducing neuroinflammation and contributing to neurodegeneration.

Age-related atrophy of skeletal muscle, is characterized by loss of mass, strength, endurance, and oxidative capacity during aging. Notably, bioenergetics and protein turnover studies have shown that mitochondria mediate this decline in function. Although exercise has been the only therapy to mitigate sarcopenia, the mechanisms that govern how exercise serves to promote healthy muscle aging are unclear. Mitochondrial aging is associated with decreased mitochondrial capacity, so we sought to investigate how aging affects mitochondrial structure and potential age-related regulators. Specifically, the three-dimensional (3D) mitochondrial structure associated with morphological changes in skeletal muscle during aging requires further elucidation. We hypothesized that aging causes structural remodeling of mitochondrial 3D architecture representative of dysfunction, and this effect is mitigated by exercise. We used serial block-face scanning electron microscopy to image human skeletal tissue samples, followed by manual contour tracing using Amira software for 3D reconstruction and subsequent analysis of mitochondria. We then applied a rigorous in vitro and in vivo exercise regimen during aging. Across 5 human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria we less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.

It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and cartilage. Consequently, gaining a comprehensive understanding of the regulatory patterns governing mitochondrial function and its underlying mechanisms holds promise for mitigating the progression of osteoarthritis, intervertebral disc degeneration, and osteoporosis. Mitochondrial hormesis, referred to as mitohormesis, represents a cellular adaptive stress response mechanism wherein mitochondria restore homeostasis and augment resistance capabilities against stimuli by generating reactive oxygen species (ROS), orchestrating unfolded protein reactions (UPRmt), inducing mitochondrial-derived peptides (MDP), instigating mitochondrial dynamic changes, and activating mitophagy, all prompted by low doses of stressors. The varying nature, intensity, and duration of stimulus sources elicit divergent degrees of mitochondrial stress responses, subsequently activating one or more signaling pathways to initiate mitohormesis. This review focuses specifically on the effector molecules and regulatory networks associated with mitohormesis, while also scrutinizing extant mechanisms of mitochondrial dysfunction contributing to bone and cartilage degeneration through oxidative stress damage. Additionally, it underscores the potential of mechanical stimulation, intermittent dietary restrictions, hypoxic preconditioning, and low-dose toxic compounds to trigger mitohormesis, thereby alleviating bone and cartilage degeneration.

The Sit4 protein phosphatase plays a key role in orchestrating various cellular processes essential for maintaining cell viability during aging. We have previously shown that SIT4 deletion promotes vacuolar acidification, mitochondrial derepression, and oxidative stress resistance, increasing yeast chronological lifespan. In this study, we performed a proteomic analysis of isolated vacuoles and yeast genetic interaction analysis to unravel how Sit4 influences vacuolar and mitochondrial function. By employing high-resolution mass spectrometry, we show that sit4Δ vacuolar membranes were enriched in Vps27 and Hse1, two proteins that are part of the endosomal sorting complex required for transport-0. In addition, SIT4 exhibited a negative genetic interaction with VPS27, as sit4∆vps27∆ double mutants had a shortened lifespan compared to sit4∆ and vps27∆ single mutants. Our results also show that Vps27 did not increase sit4∆ lifespan by improving protein trafficking or vacuolar sorting pathways. However, Vps27 was critical for iron homeostasis and mitochondrial function in sit4∆ cells, as sit4∆vps27∆ double mutants exhibited high iron levels and impaired mitochondrial respiration. These findings show, for the first time, cross-talk between Sit4 and Vps27, providing new insights into the mechanisms governing chronological lifespan.

Aortic dissection (AD) is a disease with rapid onset but with no effective therapeutic drugs yet. Previous studies have suggested that glucose metabolism plays a critical role in the progression of AD. Transketolase (TKT) is an essential bridge between glycolysis and the pentose phosphate pathway. However, its role in the development of AD has not yet been elucidated. In this study, we aimed to explore the role of TKT in AD.

We collected AD patients' aortic tissues and used high-throughput proteome sequencing to analyze the main factors influencing AD development. We generated an AD model using BAPN in combination with angiotensin II (Ang II) and pharmacological inhibitors to reduce TKT expression. The effects of TKT and its downstream mediators on AD were elucidated using human aortic vascular smooth muscle cells (HAVSMCs).

We found that glucose metabolism plays an important role in the development of AD and that TKT is upregulated in patients with AD. Western blot and immunohistochemistry confirmed that TKT expression was upregulated in mice with AD. Reduced TKT expression attenuated AD incidence and mortality, maintained the structural integrity of the aorta, aligned elastic fibers, and reduced collagen deposition. Mechanistically, TKT was positively associated with impaired mitochondrial bioenergetics by upregulating AKT/MDM2 expression, ultimately contributing to NDUFS1 downregulation.

Our results provide new insights into the role of TKT in mitochondrial bioenergetics and AD progression. These findings provide new intervention options for the treatment of AD.

Recent advances in microphysiological systems (MPS), also known as organs-on-a-chip (OoC), enable the recapitulation of more complex organ and tissue functions on a smaller scale in vitro. MPS therefore provide the potential to better understand human diseases and physiology. To date, numerous MPS platforms have been developed for various tissues and organs, including the heart, liver, kidney, blood vessels, muscle, and adipose tissue. However, only a few studies have explored using MPS platforms to unravel the effects of aging on human physiology and the pathogenesis of age-related diseases. Age is one of the risk factors for many diseases, and enormous interest has been devoted to aging research. As such, a human MPS aging model could provide a more predictive tool to understand the molecular and cellular mechanisms underlying human aging and age-related diseases. These models can also be used to evaluate preclinical drugs for age-related diseases and translate them into clinical settings. Here, we provide a review on the application of MPS in aging research. First, we offer an overview of the molecular, cellular, and physiological changes with age in several tissues or organs. Next, we discuss previous aging models and the current state of MPS for studying human aging and age-related conditions. Lastly, we address the limitations of current MPS and present future directions on the potential of MPS platforms for human aging research.

Mitochondrial quality control (MQC) plays a significant role in the progression of liver fibrosis, with key processes such as mitochondrial fission, fusion, mitophagy and biogenesis maintaining mitochondrial homeostasis. To understand the molecular mechanisms underlying epigenetic regulation of mitochondrial quality control in liver fibrosis, with the aim of uncovering novel therapeutic targets for treating, mitigating, and potentially reversing liver fibrosis, in light of the most recent advances in this field.

We searched PubMed, Web of Science, and Scopus for published manuscripts using terms "mitochondrial quality control" "mitochondrial fission" "mitochondrial fusion" "mitochondrial biogenesis" "mitophagy" "liver fibrosis" "epigenetic regulation" "DNA methylation" "RNA methylation" "histone modification" and "non-coding RNA". Manuscripts were collated, studied and carried forward for discussion where appropriate.

Mitochondrial fission, fusion, biogenesis, and mitophagy regulate the homeostasis of mitochondria, and the imbalance of mitochondrial homeostasis can induce liver fibrosis. Epigenetic regulation, including DNA methylation, RNA methylation, histone modifications, and non-coding RNAs, plays a significant role in regulating the processes of mitochondrial homeostasis.

Mitochondrial quality control and epigenetic mechanisms are intricately linked to the pathogenesis of liver fibrosis. Understanding these molecular interactions provides insight into potential therapeutic strategies. Further research is necessary to translate these findings into clinical applications, with a focus on developing epigenetic drugs to ameliorate liver fibrosis by modulating MQC and epigenetic pathways.

We previously reported evidence that oxidative stress during aging leads to adverse protein profile changes of brain cortical microvessels (MVs: end arterioles, capillaries, and venules) that affect mRNA/protein stability, basement membrane integrity, and ATP synthesis capacity in mice. As an extension of our previous study, we also found that proteins which comprise the blood-brain barrier (BBB) and regulate mitochondrial quality control were also significantly decreased in the mice's cortical MVs with aging. Interestingly, the neuroinflammatory protein fibrinogen (Fgn) was increased in mice brain MVs, which corresponds with clinical reports indicating that the plasma Fgn concentration increased progressively with aging. In this study, protein-protein interaction network analysis indicated that high expression of Fgn is linked with downregulated expression of both BBB- and mitochondrial fission/fusion-related proteins in mice cortical MVs with aging. To investigate the mechanism of Fgn action, we observed that 2 mg/mL or higher concentration of human plasma Fgn changed cell morphology, induced cytotoxicity, and increased BBB permeability in primary human brain microvascular endothelial cells (HBMECs). The BBB tight junction proteins were significantly decreased with increasing concentration of human plasma Fgn in primary HBMECs. Similarly, the expression of phosphorylated dynamin-related protein 1 (pDRP1) and other mitochondrial fission/fusion-related proteins were also significantly reduced in Fgn-treated HBMECs. Interestingly, DRP1 knockdown by shRNA(h) resulted in the reduction of both BBB- and mitochondrial fission/fusion-related proteins in HBMECs. Our results suggest that elevated Fgn downregulates DRP1, leading to mitochondrial-dependent endothelial and BBB dysfunction in the brain microvasculature.

Mitochondria are required for energy production and even give brown adipose tissue (BAT) its characteristic color due to their high iron content and abundance. The physiological function and bioenergetic capacity of mitochondria are connected to the structure, folding, and organization of its inner-membrane cristae. During the aging process, mitochondrial dysfunction is observed, and the regulatory balance of mitochondrial dynamics is often disrupted, leading to increased mitochondrial fragmentation in aging cells. Therefore, it is hypothesized that significant morphological changes in BAT mitochondria and cristae will be present with aging. A quantitative 3D electron microscopy approach is developed to map cristae network organization in mouse BAT to test this hypothesis. Using this methodology, the 3D morphology of mitochondrial cristae is investigated in adult (3-month) and aged (2-year) murine BAT tissue via serial block face-scanning electron microscopy (SBF-SEM) and 3D reconstruction software for manual segmentation, analysis, and quantification. Upon investigation, an increase is found in mitochondrial volume, surface area, and complexity and decreased sphericity in aged BAT, alongside significant decreases in cristae volume, area, perimeter, and score. Overall, these data define the nature of the mitochondrial structure in murine BAT across aging.

Vascular aging, featuring endothelial dysfunction and large elastic artery stiffening, is a major risk factor for the development of age-associated cardiovascular diseases (CVDs). Vascular aging is largely mediated by an excessive production of reactive oxygen species (ROS) and increased inflammation leading to reduced bioavailability of the vasodilatory molecule nitric oxide and remodeling of the arterial wall. Other cellular mechanisms (i.e., mitochondrial dysfunction, impaired stress response, deregulated nutrient sensing, cellular senescence), termed "hallmarks" or "pillars" of aging, may also contribute to vascular aging. Gonadal aging, which largely impacts women but also impacts some men, modulates the vascular aging process. Regular physical activity, including both aerobic and resistance exercise, is a first-line strategy for reducing CVD risk with aging. Although exercise is an effective intervention to counter vascular aging, there is considerable variation in the vascular response to exercise training with aging. Aerobic exercise improves large elastic artery stiffening in both middle-aged/older men and women and enhances endothelial function in middle-aged/older men by reducing oxidative stress and inflammation and preserving nitric oxide bioavailability; however, similar aerobic exercise training improvements are not consistently observed in estrogen-deficient postmenopausal women. Sex differences in adaptations to exercise may be related to gonadal aging and declines in estrogen in women that influence cellular-molecular mechanisms, disconnecting favorable signaling in the vasculature induced by exercise training. The present review will summarize the current state of knowledge on vascular adaptations to regular aerobic and resistance exercise with aging, the underlying mechanisms involved, and the moderating role of biological sex.

Diabetes Mellitus (DM) is referred to as hyperglycemia in either fasting or postprandial phases. Oxidative stress, which is defined by an excessive amount of reactive oxygen species (ROS) production, increased exposure to external stress, and an excessive amount of the cellular defense system against them, results in cellular damage. Increased DNA damage is one of the main causes of genomic instability, and genetic changes are an underlying factor in the emergence of cancer. Through covalent connections with DNA and proteins, quercetin has been demonstrated to offer protection against the creation of oxidative DNA damage. It has been found that quercetin shields DNA from possible oxidative stress-related harm by reducing the production of ROS. Therefore, Quercetin helps to lessen DNA damage and improve the ability of DNA repair mechanisms. This review mainly focuses on the role of quercetin in repairing DNA damage and compensating for drug resistance in diabetic patients. Data on the target topic was obtained from major scientific databases, including SpringerLink, Web of Science, Google Scholar, Medline Plus, PubMed, Science Direct, and Elsevier. In preclinical studies, quercetin guards against DNA deterioration by regulating the degree of lipid peroxidation and enhancing the antioxidant defense system. By reactivating antioxidant enzymes, decreasing ROS levels, and decreasing the levels of 8-hydroxydeoxyguanosine, Quercetin protects DNA from oxidative damage. In clinical studies, it was found that quercetin supplementation was related to increased antioxidant capacity and decreased risk of type 2 diabetes mellitus in the experimental group as compared to the placebo group. It is concluded that quercetin has a significant role in DNA repair in order to overcome drug resistance in diabetes.

In multiple sclerosis (MS), mitochondrial alterations appear to contribute to disease progression. The sphingosine-1-phosphate receptor modulator siponimod is approved for treating secondary progressive MS. Its preceding compound fingolimod was shown to prevent oxidative stress-induced alterations in mitochondrial morphology. Here, we assessed the effects of siponimod, compared to fingolimod, on neuronal mitochondria in oxidatively stressed hippocampal slices. We have also advanced the model of chronic organotypic hippocampal slices for live imaging, enabling semi-automated monitoring of mitochondrial alterations. The slices were prepared from B6.Cg-Tg(Thy1-CFP/COX8A)S2Lich/J mice that display fluorescent neuronal mitochondria. They were treated with hydrogen peroxide (oxidative stress paradigm) ± 1 nM siponimod or fingolimod for 24 h. Afterwards, mitochondrial dynamics were investigated. Under oxidative stress, the fraction of motile mitochondria decreased and mitochondria were shorter, smaller, and covered smaller distances. Siponimod partly prevented oxidatively induced alterations in mitochondrial morphology; for fingolimod, a similar trend was observed. Siponimod reduced the decrease in mitochondrial track displacement, while both compounds significantly increased track speed and preserved motility. The novel established imaging and analysis tools are suitable for assessing the dynamics of neuronal mitochondria ex vivo. Using these approaches, we showed that siponimod at 1 nM partially prevented oxidatively induced mitochondrial alterations in chronic brain slices.

Sarcopenia, characterized by the insidious reduction of skeletal muscle mass and strength, detrimentally affects the quality of life in elderly cohorts. Present therapeutic strategies are confined to physiotherapeutic interventions, signaling a critical need for elucidation of the etiological underpinnings to facilitate the development of innovative pharmacotherapies. Recent scientific inquiries have associated mitochondrial dysfunction and inflammation with the etiology of sarcopenia. Mitochondria are integral to numerous fundamental cellular processes within muscle tissue, including but not limited to apoptosis, autophagy, signaling via reactive oxygen species, and the maintenance of protein equilibrium. Deviations in mitochondrial dynamics, coupled with compromised oxidative capabilities, autophagic processes, and protein equilibrium, result in disturbances to muscular architecture and functionality. Mitochondrial dysfunction is particularly detrimental as it diminishes oxidative phosphorylation, escalates apoptotic activity, and hinders calcium homeostasis within muscle cells. Additionally, deleterious feedback loops of deteriorated respiration, exacerbated oxidative injury, and diminished quality control mechanisms precipitate the acceleration of muscular senescence. Notably, mitochondria exhibiting deficient energetic metabolism are pivotal in precipitating the shift from normative muscle aging to a pathogenic state. This analytical review meticulously examines the complex interplay between mitochondrial dysfunction, persistent inflammation, and the pathogenesis of sarcopenia. It underscores the imperative to alleviate inflammation and amend mitochondrial anomalies within geriatric populations as a strategy to forestall and manage sarcopenia. An initial overview provides a succinct exposition of sarcopenia and its clinical repercussions. The discourse then progresses to an examination of the direct correlation between mitochondrial dysfunction and the genesis of sarcopenia. Concomitantly, it accentuates potential synergistic effects between inflammatory responses and mitochondrial insufficiencies during the aging of skeletal muscle, thereby casting light upon emergent therapeutic objectives. In culmination, this review distills the prevailing comprehension of the mitochondrial and inflammatory pathways implicated in sarcopenia and delineates extant lacunae in knowledge to orient subsequent scientific inquiry.

Based on studies with a fluorescent reporter dye, Mito Thermo Yellow (MTY), and the genetically encoded gTEMP ratiometric fluorescent temperature indicator targeted to mitochondria, the temperature of active mitochondria in four mammalian and one insect cell line was estimated to be up to 15°C above that of the external environment to which the cells were exposed. High mitochondrial temperature was maintained in the face of a variety of metabolic stresses, including substrate starvation or modification, decreased ATP demand due to inhibition of cytosolic protein synthesis, inhibition of the mitochondrial adenine nucleotide transporter and, if an auxiliary pathway for electron transfer was available via the alternative oxidase, even respiratory poisons acting downstream of oxidative phosphorylation (OXPHOS) complex I. We propose that the high temperature of active mitochondria is an inescapable consequence of the biochemistry of OXPHOS and is homeostatically maintained as a primary feature of mitochondrial metabolism.

Mitochondrial dysfunction is a critical process in renal epithelial cells upon kidney injury. While its implication in kidney disease progression is established, the mechanisms modulating it remain unclear. Here, we describe the role of Lipocalin-2 (LCN2), a protein expressed in injured tubular cells, in mitochondrial dysfunction. We show that LCN2 expression decreases mitochondrial mass and function and induces mitochondrial fragmentation. Importantly, while LCN2 expression favors DRP1 mitochondrial recruitment, DRP1 inhibition antagonizes LCN2's effect on mitochondrial shape. Remarkably, LCN2 promotes mitochondrial fragmentation independently of its secretion or transport iron activity. Mechanistically, intracellular LCN2 expression increases mTOR activity, and rapamycin inhibits LCN2's effect on mitochondrial shape. In vivo, Lcn2 gene inactivation prevents mTOR activation and mitochondrial length decrease observed upon ischemia-reperfusion-induced kidney injury (IRI) in Lcn2+/+ mice. Our data identify LCN2 as a key regulator of mitochondrial dynamics and further elucidate the mechanisms leading to mitochondrial dysfunction.

Mitochondria are required for energy production and even give brown adipose tissue (BAT) its characteristic color due to their high iron content and abundance. The physiological function and bioenergetic capacity of mitochondria are connected to the structure, folding, and organization of its inner-membrane cristae. During the aging process, mitochondrial dysfunction is observed, and the regulatory balance of mitochondrial dynamics is often disrupted, leading to increased mitochondrial fragmentation in aging cells. Therefore, we hypothesized that significant morphological changes in BAT mitochondria and cristae would be present with aging. We developed a quantitative three-dimensional (3D) electron microscopy approach to map cristae network organization in mouse BAT to test this hypothesis. Using this methodology, we investigated the 3D morphology of mitochondrial cristae in adult (3-month) and aged (2-year) murine BAT tissue via serial block face-scanning electron microscopy (SBF-SEM) and 3D reconstruction software for manual segmentation, analysis, and quantification. Upon investigation, we found increases in mitochondrial volume, surface area, and complexity and decreased sphericity in aged BAT, alongside significant decreases in cristae volume, area, perimeter, and score. Overall, these data define the nature of the mitochondrial structure in murine BAT across aging.

Evidence from clinical studies and preclinical studies supports that exercise preconditioning can not only reduce the risk of stroke but also improve brain tissue and functional outcome after stroke. It has been demonstrated that autophagy and mitochondrial dynamics are involved in ischemic stroke. However, it is still unclear whether exercise preconditioning-induced neuroprotection against stroke is associated with modulation of autophagy and mitochondrial dynamics. Although age and sex interactively affect ischemic stroke risk, incidence, and outcome, studies based on young male animals are most often used to explore the role of exercise preconditioning in the prevention of ischemic stroke. In the current study, we examined whether exercise preconditioning could modulate autophagy and mitochondrial dynamics in a brain ischemia and reperfusion (I/R) model of female aged mice. The results showed that exercise preconditioning reduced infarct volume and improved neurological deficits. Additionally, increased levels of autophagy-related proteins LC3-II/LC3-I, LC3-II, p62, Atg7, and mitophagy-related proteins Bnip3L and Parkin, as well as increased levels of mitochondrial fusion modulator Mfn2 and mitochondrial fission modulator Drp1 in the ischemic cortex of female aged mice at 12 h after I/R were present. Our results could contribute to a better understanding of exercise preconditioning-induced neuroprotection against ischemic stroke for the elderly.

We previously reported that kenpaullone, which inhibits GSK-3a/b and CDKs inhibited CCCP mediated mitochondrial depolarisation and augments the mitochondrial network. To investigate the actions of this class of drug further, we compared the ability of kenpaullone, alsterpaullone, 1-azakenapaullone, AZD5438, AT7519 (CDK and GSK-3a/b inhibitors) and dexpramipexole and olesoxime (mitochondrial permeability transition pore inhibitors) to prevent CCCP mediated mitochondrial depolarisation and found that AZD5438 and AT7519, were the most effective. Furthermore, treatment with AZD5438 alone increased the complexity of the mitochondrial network. We also found that AZD5438 prevented the rotenone induced decrease in PGC-1alpha and TOM20 levels and that it mediated powerful anti-apoptotic effects and promoted glycolytic respiration. Importantly, experiments in human iPSC derived cortical and midbrain neurons showed AZD5438 mediated significant protective effects, preventing the neuronal cell death, and collapse in the neurite and mitochondrial network associated with rotenone treatment. These results suggest drugs that target GSK-3a/b and CDKs should be developed and assessed further as they may have significant therapeutic potential.

The decline in oocyte quality with age is an irreversible process that results in low fertility. Reproductive aging causes an increase in oocyte aneuploidy leading to a decrease in embryo quality and an increase in the incidence of miscarriage and congenital defects. Here, we show that the dysfunction associated with aging is not limited to the oocyte, as oocyte granulosa cells also show a range of defects related to mitochondrial activity. The addition of Y-27632 and Vitamin C combination drugs to aging germ cells was effective in enhancing the quality of aging cells. We observed that supplement treatment significantly decreased the production of reactive oxygen species (ROS) and restored the balance of mitochondrial membrane potential. Supplementation treatment reduces excessive mitochondrial fragmentation in aging cells by upregulating mitochondrial fusion. Moreover, it regulated the energy metabolism within cells, favoring oxygen respiration and reducing anaerobic respiration, thereby increasing cellular ATP production. In an experiment with aged mice, supplement treatment improved the maturation of oocytes in vitro and prevented the buildup of ROS in aging oocytes in culture. Additionally, this treatment resulted in an increased concentration of anti-mullerian hormone (AMH) in the culture medium. By improving mitochondrial metabolism in aging females, supplement treatment has the potential to increase quality of oocytes during in vitro fertilization.