It is now understood that iron crosses the blood-brain barrier via a complex metabolic regulatory network and participates in diverse critical biological processes within the central nervous system, including oxygen transport, energy metabolism, and the synthesis and catabolism of myelin and neurotransmitters. During brain development, iron is distributed throughout the brain, playing a pivotal role in key processes such as neuronal development, myelination, and neurotransmitter synthesis. In physiological aging, iron can selectively accumulate in specific brain regions, impacting cognitive function and leading to intracellular redox imbalance, mitochondrial dysfunction, and lipid peroxidation, thereby accelerating aging and associated pathologies. Furthermore, brain iron accumulation may be a primary contributor to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Comprehending the role of iron in brain development, aging, and neurodegenerative diseases, utilizing iron-sensitive Magnetic Resonance Imaging (MRI) technology for timely detection or prediction of abnormal neurological states, and implementing appropriate interventions may be instrumental in preserving normal central nervous system function.

Frailty syndrome often coexists with multimorbidity, sharing several risk factors and outcomes. Therefore, considering multimorbidity when exploring frailty biomarkers may deepen our understanding of these conditions' pathophysiology. In this regard, most studies focused on inflammation, but markers of mitochondrial dysfunction, such as mitochondrial DNA damage, cell respiratory impairment, and oxidative stress, are less explored. The FRAMITO project aims to evaluate mitochondrial dysfunction in frailty, with and without multimorbidity. This cross-sectional study will enroll 75 individuals aged ≥65 years from inpatient and outpatient clinics at the Geriatrics Units of the University Hospital of Ferrara (Ferrara, Italy) and Fondazione IRCCS San Gerardo dei Tintori (Monza, Italy). Participants will be categorized into three groups: 25 without frailty and multimorbidity, 25 with frailty but not multimorbidity, and 25 with frailty and multimorbidity. Blood samples will be collected to isolate Peripheral Blood Mononuclear Cells. Frailty biomarkers will be identified using untargeted metabolomics and functional studies on mitochondrial dysfunctions in PBMCs and their subpopulations, evaluating mitochondrial DNA damage, mitochondrial and glycolytic cellular bioenergetics, and intracellular reactive oxygen species. This project will advance our understanding of mitochondrial dysfunctions in frailty, particularly when combined with multimorbidity, revealing potential synergistic effects. CLINICALTRIAL.GOV REGISTRATION NUMBER: NCT06433427.

Perioperative neurocognitive disorders (PND) are common and costly complications in elderly surgical patients, yet the involvement of specific neural circuits in their etiology remains poorly understood. We hypothesized that neural projections from the medial prefrontal cortex (mPFC) to the amygdala contribute to PND pathogenesis.

Using chemogenetic approaches, we selectively suppressed or excited the mPFC and its projections to the amygdala in a murine model exposed to sevoflurane. We assessed cognitive deficits, synaptic plasticity (AMPA receptor activity, long-term potentiation [LTP]), mitochondrial stress, neuroinflammatory markers, and neuronal apoptosis in the amygdala. Additional interventions included pharmacological suppression of AMPA receptors, glutamate biosynthesis, and mitochondrial stress within the amygdala.

Sevoflurane exposure activated the mPFC-amygdala circuit. Chemogenetic suppression of the mPFC attenuated sevoflurane-induced cognitive deficits, AMPA receptor hyperexcitation, mitochondrial dysfunction, neuroinflammation, and neuronal apoptosis in the amygdala. Retrograde inhibition of mPFC projections to the amygdala alleviated cognitive impairments, whereas retrograde excitation exacerbated them. Suppressing AMPA receptors, glutamate synthesis, or mitochondrial stress in the amygdala similarly reduced cognitive deficits and pathological alterations. Notably, mPFC suppression rescued sevoflurane-induced LTP impairment in the amygdala.

These findings demonstrate that sevoflurane activates the mPFC-amygdala circuit, driving PND-associated cognitive deficits and neuropathological changes. Targeting this circuit or downstream mechanisms (AMPA signaling, mitochondrial stress) may mitigate sevoflurane-induced PND. This study provides empirical evidence implicating specific neural circuitry in anesthetic-related neurocognitive dysfunction.

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.

Background/Objectives: This review has been prepared to promote interest in the interdisciplinary study of mitochondrial dysfunction (MD) and atherosclerosis. This review aims to describe the state of this problem and indicate the direction for further implementation of this knowledge in clinical medicine. Methods: Extensive research of the literature was implemented to elucidate the role of the molecular mechanisms of MD in the pathogenesis of atherosclerosis. Results: A view on the pathogenesis of atherosclerosis through the prism of knowledge about MD is presented. MD is the cause and primary mechanism of the onset and progression of atherosclerosis. It is proposed that this problem be considered in the context of a continuum. Conclusions: MD and atherosclerosis are united by common molecular mechanisms of pathogenesis. Knowledge of MD should be used to argue for a healthy lifestyle as the primary way to prevent atherosclerosis. The development of new approaches to diagnosing and treating MD in atherosclerosis is an urgent task and challenge for modern science.

Most mitochondrial proteins encoded in the nuclear genome are synthesized in the cytoplasm. These proteins subsequently undergo maturation through the cleavage of a signal sequence at the N-terminus by one or two mitochondrial signal peptidases, which is essential for their function within mitochondria. The present study demonstrates that adipocyte-specific knockout of one mitochondrial signal peptidase, mitochondrial intermediate peptidase (MIPEP), resulted in disordered mitochondrial proteostasis of MIPEP substrate proteins and their defective maturation. MIPEP deficiency in white and brown adipocytes suppressed the expression of adipocyte differentiation, lipid metabolism, and mitochondrial biogenesis genes. These alterations led to lipoatrophy in white adipose tissue and the whitening of brown adipose tissue. Additionally, it induced an atypical mitochondrial unfolded protein response and local inflammation in white and brown adipose tissue. Furthermore, it induced fatty liver and splenomegaly and caused systemic impairments in glucose metabolism and inflammation. These findings indicate that maturation defects of certain mitochondrial proteins and subsequent proteostasis disorders in white and brown adipocytes cause chronic and systemic inflammatory and metabolic dysfunctions.

Spermidine is a naturally occurring polyamine present in all cells and is necessary for viability in eukaryotic cells. The cellular levels of spermidine decline as an organism ages, and its supplementation has been found to extend lifespan in yeast, worms, flies, mice, and human cultured cells. The lifespan extending effect of spermidine is thought to be due to its ability to induce autophagy, a turnover of cellular components. Mitochondrial dysfunction is believed to be a major driver of the aging process. We asked whether spermidine could rescue mitochondrial dysfunction using the yeast Saccharomyces cerevisiae lacking mtDNA (ρ0 cells) as a model. Not only was spermidine unable to rescue survival in ρ0 cells, but it appeared to exhibit toxicity resulting in a shortened lifespan. This toxicity appears to not be due to the loss of mitochondrial respiration, elevated oxidative stress, or depleted ATP. Spermidine toxicity could be recapitulated by the genetic or pharmacological inactivation of mitochondrial complex III. It can also be prevented by the impairment of autophagy, through the inactivation of ATG8, or by impairment of mitochondrial complex II through the inactivation of SDH2. Spermidine toxicity in ρ0 cells was present in yeast strains BY4741 and W303, but not D273-10B, demonstrating genetic variance in the phenotype. Thus, caution may be suggested regarding the use of spermidine to alleviate aging in humans. Depending on the genotype of the individual, spermidine could potentially harm the very individuals it is intended to help.

Primary liver cancer (PLC), also known as hepatocellular carcinoma (HCC), is a common type of malignant tumor of the digestive system. Its pathological form has a significant negative impact on the patients' quality of life and ability to work, as well as a significant financial burden on society. Current researches had identified chronic hepatitis B virus infection, aflatoxin B1 exposure, and metabolic dysfunction-associated steatotic liver disease (MASLD) as the main causative factors of HCC. Numerous variables, including inflammatory ones, oxidative stress, apoptosis, autophagy, and others, have been linked to the pathophysiology of HCC. On the other hand, autoimmune regulation, inflammatory response, senescence of the hepatocytes, and mitochondrial dysfunction are all closely related to the pathogenesis of HCC. In fact, a growing number of studies have suggested that mitochondrial dysfunction in hepatocytes may be a key factor in the pathogenesis of HCC. In disorders linked to cancer, mitochondrial dysfunction has gained attention in recent 10 years. As the primary producer of adenosine triphosphate (ATP) in liver cells, mitochondria are essential for preserving cell viability and physiological processes. By influencing multiple pathological processes, including mitochondrial fission/fusion, mitophagy, cellular senescence, and cell death, mitochondrial dysfunction contributes to the development of HCC. We review the molecular mechanisms of HCC-associated mitochondrial dysfunction and discuss new directions for quality control of mitochondrial disorders as a treatment for HCC.

Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.

Klotho is an antiaging protein that is primarily secreted by the kidneys. This study aimed to explore the protective effects of Klotho against calcium oxalate (CaOx) crystal-induced renal aging and the underlying mechanisms involved. We established a mouse model of CaOx crystal deposition via the intraperitoneal injection of glyoxylate (Gly) and constructed an in vitro model by stimulating HK2 cells with calcium oxalate monohydrate (COM). Renal aging levels were assessed through β-galactosidase (SA-β-gal) staining and the detection of senescence-associated markers. By overexpressing Klotho both in vitro and in vivo, we examined oxidative stress, mitochondrial function, and renal aging levels. We then evaluated the role of Nrf2/HO-1 signalling pathway-mediated oxidative stress in CaOx crystal-induced renal aging by applying the oxidative stress scavenger N-acetylcysteine (NAC) and overexpressing or inhibiting Nrf2 in HK2 cells. We subsequently overexpressed Klotho while inhibiting Nrf2 to confirm that Klotho exerts its protective effects through the Nrf2/HO-1 pathway. Finally, we measured the methylation levels of the Klotho promoter and assessed the degree of renal aging induced by CaOx crystals after the inhibition of Klotho DNA methylation. We found that the overexpression of Klotho alleviated CaOx crystal-induced oxidative stress and mitochondrial dysfunction, thereby reducing renal aging. NAC mitigated CaOx crystal-induced renal aging. The overexpression of Nrf2 alleviated CaOx crystal-induced oxidative stress and mitochondrial dysfunction, thus reducing renal aging, whereas the knockdown of Nrf2 exacerbated CaOx crystal-induced oxidative stress and mitochondrial dysfunction, leading to more severe renal aging. The combination of Klotho overexpression and Nrf2 knockdown reversed the protective effects of Klotho. CaOx crystals induced an increase in the DNA methylation levels of Klotho in the kidneys, and the inhibition of DNA methylation alleviated CaOx-induced renal aging. This study revealed that Klotho plays a crucial role in calcium oxalate crystal-induced kidney senescence by influencing kidney oxidative stress and mitochondrial function through the Nrf2/HO-1 pathway.

Metabolic dysregulation represents one of the major driving forces in aging. Although multiple genetic and pharmacological manipulations are known to extend longevity in model organisms, aging is a complex trait, and targeting one's own genes may be insufficient to prevent age-dependent deterioration. An alternative strategy could be to use enzymes from other species to reverse age-associated metabolic changes. In this review, we discuss a set of enzymes from lower organisms that have been shown to affect various metabolic parameters linked to age-related processes. These enzymes include modulators of steady-state levels of amino acids (METase, ASNase, and ADI), NADPH/NADP+ and/or reduced form of coenzyme Q (CoQH2)/CoQ redox potentials (NDI1, AOX, LbNOX, TPNOX, EcSTH, RquA, LOXCAT, Grubraw, and ScURA), GSH (StGshF), mitochondrial membrane potential (mtON and mito-dR), or reactive oxygen species (DAAO and KillerRed-SOD1). We propose that leveraging non-mammalian enzymes represents an untapped resource that can be used to delay aging and age-related diseases.

Mitochondria are of great importance in cell biology since they are major sites of adenosine triphosphate (ATP) production and are widely involved in different cellular pathways involved in the response to stress. During ATP production, reactive oxygen species (ROS) can be produced. While a small amount of ROS may be important for the regulation of physiological processes, at elevated levels they can turn into harmful agents leading to cellular damage. From a pathological perspective, it could be particularly interesting to focus on mitochondrial function in endothelial cells since they may be involved in the development of aging and in the onset of different diseases, including renal, cardio-metabolic, liver and neurodegenerative ones. However, to date, there are no surveys which address the above issues. To fill this gap, it may be valuable to collect recent findings about the role of mitochondria in the regulation of endothelial function, not only to increase knowledge about it but also for clinical applications. Here, we overview the most recent knowledge about the above issues in the view of characterizing the role of mitochondria in endothelial cells as an innovative potential target for the prevention of aging, as well as the treatment of the above pathological conditions.

Studies of the mitochondrial respiratory chain (MRC) have given important insights into the pathology of mitochondrial and neurodegenerative disorders. Immunohistochemical methods for staining MRC complexes are particularly valuable for assessing quantitative changes in situ, especially in complex tissues with cellular heterogeneity, such as the brain. However, traditional approaches have notable limitations. Chromogen-based staining, while preserving tissue morphology, has been restricted to a single antigen per section, preventing co-assessment of MRC complexes and mitochondrial mass on the same section. Immunofluorescence, which allows multiplex staining of multiple targets, partially addresses this limitation but compromises tissue morphology and can be highly variable in postmortem brain samples. To address these challenges, we have established a dual-antigen, chromogen-based immunohistochemical method that allows simultaneous assessment of each MRC complex and the mitochondrial marker voltage-dependent anion channel 1 (VDAC1) on the same section. As proof of concept, we apply this method on brain tissue from patients with neurological disease caused by mutations in the mitochondrial DNA polymerase gamma (POLG). Our findings demonstrate that this approach is both reliable and robust. Moreover, this method enables more precise identification of MRC deficiencies in neurons and significantly reduces the amount of tissue required for analysis, a critical advantage when working with scarce human brain samples.

Aging is associated with immunosenescence, a decline in immune functions, but also with inflammaging, a chronic, low-grade inflammation, contributing to immunosenescence. Monocytes and macrophages belong to the innate immune system and aging has a profound impact on these cells, leading to functional changes and most importantly, to the secretion of pro-inflammatory cytokines and thereby contributing to inflammaging. Rheumatoid arthritis (RA) is an autoimmune disease and age is an important risk factor for developing RA. RA is associated with the early development of age-related co-morbidities like cardiovascular manifestations and osteoporosis. The immune system of RA patients shows signs of premature aging like age-inappropriate increased production of myeloid cells, accelerated telomeric erosion, and the uncontrolled production of pro-inflammatory cytokines. In this review we discuss the influence of aging on monocytes and macrophages during healthy aging and premature aging in rheumatoid arthritis.

Urinary incontinence increases with age, reducing the elderly quality of life. Understanding its mechanisms and developing treatments are urgent tasks. While healthy striated muscle maintains homeostasis through mitophagy, aging is thought to reduce autophagy activity. This study aimed to detect abnormal mitochondrial accumulation in the rhabdosphincter using transmission electron microscopy (TEM). We collected the rhabdosphincter samples from seven patients undergoing cystectomy and used the rectus abdominis as controls. Both tissues were examined with Hematoxylin and eosin (HE) staining and TEM. ImageJ software was used to measure the mitochondrial area, perimeter, and luminance. HE staining revealed that the rhabdosphincter had fewer muscle fibers and more stromal tissue than the rectus abdominis. TEM images showed more gaps in muscle bundles and signs of mitochondrial damage, vacuolation, and swelling in the rhabdosphincter. Quantitative analysis revealed a larger average mitochondrial area (0.21 μm2 vs. 0.063 μm2, p < 0.01), longer perimeter (1.83 μm vs. 0.94 μm, p < 0.01) and higher luminance (156.6 vs. 90.2, p < 0.01) than those of the rectus abdominis. The rhabdosphincter of elderly individuals showed significant mitochondrial morphological abnormalities, with increased swelling and vacuolation.

Background/Objectives: The skin, being the body's outermost organ, plays a vital role in protecting against various external stimuli. Ultraviolet generates reactive oxygen species (ROS), promoting the secretion of matrix metalloproteinases (MMPs) and inducing collagen degradation. Many studies have been conducted to identify natural substances that can prevent or delay the harmful effects of UV. Methods: A wound healing assay, DCF-DA reactive oxygen species (ROS) assay, and JC-1 assay were performed to assess the effects of bio-converted eggplant peels (BEPs) on human dermal fibroblasts (HDFs). Western blot analysis was also conducted to understand the underlying mechanisms for their effects. Finally, hematoxylin-eosin staining and immunohistochemistry were also performed in animal studies. Results: Our study evaluated the antioxidant efficacy of BEPs fermented with Lactobacillus plantarum in hydrogen peroxide (H2O2)-HDFs and UVB-induced skin damage in hairless mice. We demonstrated that BEPs exhibited enhanced antioxidant properties compared to non-fermented eggplant peels (EPs). BEPs facilitated wound healing in H2O2-damaged HDFs, reduced ROS levels, and restored mitochondrial membrane potential. BEPs suppressed the phosphorylation of ERK, p38, and JNK as their underlying mechanism. We further demonstrated that dietary supplementation of BEPs also downregulated matrix metalloproteinase 1 (MMP1) expression and upregulated collagen I (COL1) in UVB-damaged hairless mice, indicating that BEPs were more effective compared to EPs. Conclusions: Our studies suggest that BEPs fermented with Lactobacillus plantarum hold significant potential as a protective agent for mitigating UVB-induced damage and promoting skin health.

Mitochondrial dysfunction is increasingly recognized as a central contributor to the pathogenesis of cardiovascular diseases (CVDs), including heart failure, ischemic heart disease, hypertension, and cardiomyopathy. Mitochondria, known as the powerhouses of the cell, play a vital role in maintaining cardiac energy homeostasis, regulating reactive oxygen species (ROS) production and controlling cell death pathways. Dysregulated mitochondrial function results in impaired adenosine triphosphate (ATP) production, excessive ROS generation, and activation of apoptotic and necrotic pathways, collectively driving the progression of CVDs. This review provides a detailed examination of the molecular mechanisms underlying mitochondrial dysfunction in CVDs, including mutations in mitochondrial DNA (mtDNA), defects in oxidative phosphorylation (OXPHOS), and alterations in mitochondrial dynamics (fusion, fission, and mitophagy). Additionally, the role of mitochondrial dysfunction in specific cardiovascular conditions is explored, highlighting its impact on endothelial dysfunction, myocardial remodeling, and arrhythmias. Emerging therapeutic strategies targeting mitochondrial dysfunction, such as mitochondrial antioxidants, metabolic modulators, and gene therapy, are also discussed. By synthesizing recent advances in mitochondrial biology and cardiovascular research, this review aims to enhance understanding of the role of mitochondria in CVDs and identify potential therapeutic targets to improve cardiovascular outcomes.

Mitochondrial dysfunction represents a pivotal characteristic of numerous neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These conditions, distinguished by unique clinical and pathological features, exhibit shared pathways leading to neuronal damage, all of which are closely associated with mitochondrial dysfunction. The high metabolic requirements of neurons make even minor mitochondrial deficiencies highly impactful, driving oxidative stress, energy deficits, and aberrant protein processing. Growing evidence from genetic, biochemical, and cellular investigations associates impaired electron transport chain activity and disrupted quality-control mechanisms, such as mitophagy, with the initial phases of disease progression. Furthermore, the overproduction of reactive oxygen species and persistent neuroinflammation can establish feedforward cycles that exacerbate neuronal deterioration. Recent clinical research has increasingly focused on interventions aimed at enhancing mitochondrial resilience-through antioxidants, small molecules that modulate the balance of mitochondrial fusion and fission, or gene-based therapeutic strategies. Concurrently, initiatives to identify dependable mitochondrial biomarkers seek to detect pathological changes prior to the manifestation of overt symptoms. By integrating the current body of knowledge, this review emphasizes the critical role of preserving mitochondrial homeostasis as a viable therapeutic approach. It also addresses the complexities of translating these findings into clinical practice and underscores the potential of innovative strategies designed to delay or potentially halt neurodegenerative processes.

Idiopathic pulmonary fibrosis (IPF) has been associated with mitochondrial dysfunction. We investigated whether mitochondrial DNA variants in peripheral blood leukocytes (PBLs), which affect proteins of the respiratory chain and mitochondrial function, could be associated with an increased risk and poor prognosis of IPF. From 2020 to 2022, we recruited 36 patients (age: 75.3 ± 8.5; female: 19%) with IPF, and 80 control subjects (age: 72.3 ± 9.0; female: 27%). The mitochondrial genome of peripheral blood leukocytes was determined using next-generation sequencing. During a 45-month follow-up, 10 (28%) patients with IPF remained stable and the other 26 (72%) progressed, with 12 (33%) mortalities. IPF patients had more non-synonymous (NS) variants (substitution/deletion/insertion) in mitochondrial COX3 gene (coding for subunit 3 of complex IV of the respiratory chain), and more mitochondrial tRNA variants located in the anticodon (AC) stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure in PBLs than the control group. The succumbed IPF patients were older, had lower initial diffusion capacity, and higher initial fibrosis score on high-resolution computerized tomography (HRCT) than the alive group. NS variants in mitochondrial COX3 gene and tRNA variants in PBLs were associated with shorter survival. Our study shows that (1) leukocyte mitochondrial COX3 NS variants are associated with risk and prognosis of IPF; (2) leukocyte mitochondrial tRNA variants located in the AC stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure are associated with risk, and the presence of tRNA variants is associated with poor prognosis of IPF.

The nuclear-encoded enzyme polymerase gamma (Pol-γ) is crucial in the replication of the mitochondrial genome (mtDNA), which in turn is vital for mitochondria and hence numerous metabolic processes and energy production in eukaryotic cells. Variants in the POLG gene, which encodes the catalytic subunit of Pol-γ, can significantly impair Pol-γ enzyme function. Pol-γ-associated disorders are referred to as POLG-spectrum disorders (POLG-SDs) and are mainly autosomal-recessively inherited. Clinical manifestations include muscle weakness and fatigue, and severe forms of the disease can lead to premature death in infancy, childhood, and early adulthood, often associated with seizures, liver failure, or intractable epilepsy. Here, we analyzed fibroblasts from a compound heterozygous patient with the established pathogenic variant c.2419C>T; p.(Arg807Cys) and a previously undescribed variant c.678G>C; p.(Gln226His) with a clinical manifestation compatible with POLG-SDs, sensory ataxic neuropathy, and infantile muscular atrophy. We conducted a battery of functional studies for Pol-γ and mitochondrial dysfunction on the patient's fibroblasts, to test whether the novel variant c.678G>C; p.(Gln226His) may be causative in human disease.

We analyzed skin-derived fibroblasts in comparison to a first-degree relative (the mother of the patient), an asymptomatic carrier harboring only the established c.2419C>T; p.(Arg807Cys) mutation. Assessments of mitochondrial function included measurements of mtDNA content, mRNA levels of mitochondrial genes, mitochondrial mass, and mitochondrial morphology.

A 13-year-old male presented with symptoms starting at three years of age, including muscle weakness and atrophy in the lower extremities and facial muscles, which later extended to the upper limbs, voice, and back muscles, without further progression. The patient also reported fatigue and muscle pain after physical activity, with no sensory deficits. Extensive diagnostic tests such as electromyography, nerve conduction studies, muscle biopsy, and MRI were unremarkable. Exome sequencing revealed that he carried the compound heterozygous variants in POLG c.678G>C; p.(Gln226His) and c.2419C>T; p.(Arg807Cys), but no other potential genetic pathogenic causes. In comparison to a first-degree relative (his mother) who only carried the c.2419C>T; p.(Arg807Cys) pathogenic mutation, in vitro analyses revealed a significant reduction in mtDNA content (~50%) and mRNA levels of mtDNA-encoded proteins. Mitochondrial mass was reduced by approximately 20%, and mitochondrial interconnectivity within cells was impaired, as determined by fluorescence microscopy and mitochondrial staining.

Our findings suggest that the c.678G>C; p.(Gln226His) variant, in conjunction with the c.2419C>T; p.(Arg807Cys) mutation, may compromise mtDNA replication and mitochondrial function and could result in clinically significant mitochondriopathy. As this study is based on one patient compared to a first-degree relative (but with an identical mitochondrial genome), the pathogenicity of c.678G>C; p.(Gln226His) of POLG should be confirmed in future studies, in particular, in conjunction with other POLG-variants.

Regenerative capacity of skeletal muscles decreases with age. Deficiency in cystic fibrosis transmembrane conductance regulator (CFTR) is associated with skeletal muscle weakness as well as epithelial cell senescence. However, whether and how CFTR plays a role in skeletal muscle regeneration and aging were unclear.

Vastus lateralis biopsy samples from male and female human subjects (n = 23) of 7- to 86-year-old and gastrocnemii tissues from mice of 4- to 29-month-old were examined for CFTR expression. Skeletal muscle tissues or cultured myoblasts from mice carrying CFTR mutation (DF508) at 4- to 18-month-old were used for assessment of muscle mass, contractile force and regenerative capacity as well as myogenic and autophagy signalling. Overexpression of LC3-β, an autophagy mediator, was conducted to reverse myogenic defects in DF508 myoblasts. Adenoviruses containing CFTR gene or pharmaceuticals that enhance CFTR (VX809) were locally injected into the gastrocnemius or femoris quadricep to rescue age-related skeletal muscle defects in mice.

mRNA levels of CFTR in human vastus lateralis exhibited significantly negative correlations with age (r = -0.87 in males and -0.62 in females, p < 0.05). Gastrocnemius mRNA level of CFTR decreased by 77.7 ± 4.6% in 29-month-old wild-type mice compared to the 4-month-old. At 18-month-old, DF508 mice showed significantly reduced lean mass (by 35.6%), lower specific twitch force of the gastrocnemius (by 46.2%), decrease in fast/slow-twitch muscle isoform ratio as well as downregulation of myogenic (e.g., MYOD and MYOG) or autophagy/mitophagy (e.g., LC3-β) genes, compared to age-matched wild-types. Post-injury gastrocnemius regeneration was found impaired in DF508 mice. Myoblast cultures from DF508 mice showed defective myogenic differentiation, which was reversed by overexpressing LC3-β. In aged (> 15-month-old) mice, overexpressing CFTR or VX809 restored the expression of autophagy or myogenic genes, increased mitochondrial LC3-β level and improved skeletal muscle mass and function.

Age-related reduction in skeletal muscle expression of CFTR impairs autophagy and myogenesis, exacerbating skeletal muscle aging. Enhancing CFTR might be a potential treatment strategy for age-related skeletal muscle disorders.

This open question research article highlights mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), which have emerged as crucial cellular structures that challenge our traditional understanding of organelle function. This review highlights the critical importance of MAMs as a frontier in cell biology with far-reaching implications for health, disease and ageing. MAMs serve as dynamic communication hubs between the ER and mitochondria, orchestrating essential processes such as calcium signalling, lipid metabolism and cellular stress responses. Recent research has implicated MAM dysfunction in a wide array of conditions, including neurodegenerative diseases, metabolic disorders, cardiovascular diseases and cancer. The significant lack of biological knowledge behind MAM function emphasizes the need to study these enigmatic subcellular sites in greater detail. Key open questions include the mechanisms controlling MAM formation and disassembly, the full complement of MAM-associated proteins and how MAMs contribute to cellular decision-making and ageing processes. Advancing our understanding of MAMs through interdisciplinary approaches and cutting-edge technologies promises to reveal new insights into fundamental cellular signalling pathways and potentially lead to innovative therapeutic strategies for a range of diseases. As such, MAM research represents a critical open question in biology with the potential to transform our understanding of cellular life and human health.

Cholecystokinin (CCK) is a major neuropeptide in the brain that functions as a neurotransmitter, hormone, and growth factor. The peptide and its receptors are widely expressed in the brain. CCK signaling modulates synaptic plasticity and can improve or impair memory formation, depending on the brain areas studies and the receptor subtype activated. Studies have shown in a series of animal models of neurodegenerative diseases that CCK receptor agonists show neuroprotective effects and can effectively alleviate oxidative stress, alleviate chronic inflammation of the central nervous system, improve neuronal synaptic plasticity, prevent neuronal loss, and improve cognitive dysfunction in Alzheimer's disease (AD) model mice and motor activity in animal models of Parkinson's disease. In addition, CCK plays important roles in the amygdala to regulate anxiety and depressive states. Activation of interneurons or inhibition of excitatory neurons can improve anxiety levels. This review summarizes the effects on memory formation and synaptic plasticity, the neuroprotective effects of cholecystokinin and its analogs in neurological diseases such as Alzheimer and Parkinson's disease, and the effects on anxiety and neuronal activity in the amygdala.

Background/Objectives: Sarcopenia, characterized by the progressive loss of muscle mass and strength, is linked to physical disability, metabolic dysfunction, and an increased risk of mortality. Exercise therapy is currently acknowledged as a viable approach for addressing sarcopenia. Nevertheless, the molecular mechanisms behind exercise training or physical activity remain poorly understood. The disruption of mitochondrial homeostasis is implicated in the pathogenesis of sarcopenia. Exercise training effectively delays the onset of sarcopenia by significantly maintaining mitochondrial homeostasis, including promoting mitophagy, improving mitochondrial biogenesis, balancing mitochondrial dynamics, and maintaining mitochondrial redox. Exerkines (e.g., adipokines, myokines, hepatokines, and osteokines), signaling molecules released in response to exercise training, may potentially contribute to skeletal muscle metabolism through ameliorating mitochondrial homeostasis, reducing inflammation, and regulating protein synthesis as a defense against sarcopenia. Methods: In this review, we provide a detailed summary of exercise-induced exerkines and confer their benefit, with particular focus on their impact on mitochondrial homeostasis in the context of sarcopenia. Results: Exercise induces substantial adaptations in skeletal muscle, including increased muscle mass, improved muscle regeneration and hypertrophy, elevated hormone release, and enhanced mitochondrial function. An expanding body of research highlights that exerkines have the potential to regulate processes such as mitophagy, mitochondrial biogenesis, dynamics, autophagy, and redox balance. These mechanisms contribute to the maintenance of mitochondrial homeostasis, thereby supporting skeletal muscle metabolism and mitochondrial health. Conclusions: Through a comprehensive investigation of the molecular mechanisms within mitochondria, the context reveals new insights into the potential of exerkines as key exercise-protective sensors for combating sarcopenia.

Challenges such as difficult wound healing, ischemic necrosis of skin flaps, and skin aging are prevalent in plastic surgery. Previous research has indeed suggested that these challenges in plastic surgery are often linked to cellular energy barriers. As the powerhouses of the cell, mitochondria play a critical role in sustaining cellular vitality and health. Fundamentally, issues like ischemic and hypoxic damage to organs and tissues, as well as aging, stem from mitochondrial dysfunction, which leads to a depletion of cellular energy. Hence, having an adequate number of high-quality, healthy mitochondria is vital for maintaining tissue stability and cell survival. In recent years, there has been preliminary exploration into the protective effects of mitochondrial transplantation against cellular damage in systems such as the nervous, cardiovascular, and respiratory systems. For plastic surgery, mitochondrial transplantation is an extremely advanced research topic. This review focuses on the novel applications and future prospects of mitochondrial transplantation in plastic surgery, providing insights for clinicians and researchers, and offering guidance to patients seeking innovative and effective treatment options.

Mitochondria are the energy factories of cells, and their functions are closely related to cell homeostasis. The mitochondrial unfolded protein response (mtUPR) is a newly discovered mechanism for regulating mitochondrial homeostasis. When unfolded/ misfolded proteins accumulate in mitochondria, the mitochondria release signals that regulate the transcription of certain proteins in the nucleus, thereby inducing the correct folding or degradation of proteins in mitochondria. Many studies have also shown that an abnormality of mtUPR is closely related to the occurrence and development of diseases. Here, we summarized the pathways regulating mtUPR signaling and reviewed the research progress on mtUPR in diseases. Finally, we summarized the currently identified agonists and inhibitors of the mtUPR and discussed the potential of the mtUPR as a therapeutic target for diseases.

The process of aging is a natural phenomenon characterized by gradual deterioration in biological functions and systemic homeostasis, which can be modulated by both genetic and environmental factors. Numerous investigations conducted on model organisms, including nematodes, flies, and mice, have elucidated several pivotal aging pathways, such as insulin signaling and AMPK signaling. However, it remains uncertain whether the regulation of the aging process is uniform or diverse across different tissues and whether manipulating the same aging factor can result in consistent outcomes in various tissues. In this study, we utilize the Drosophila organism to investigate tissue-specific proteome signatures during the aging process. Although distinct proteins undergo changes in aged tissues, certain common altered functional networks are constituently identified across different tissues, including the decline of the mitochondrial ribosomal network, autophagic network, and anti-ROS defense networks. Furthermore, downregulation of insulin receptor (InR) in the midguts, muscle, and central nervous system (CNS) of flies leads to a significant extension in fly lifespans. Notably, despite manipulating the same aging gene InR, diverse alterations in proteins are observed across different tissues. Importantly, knockdown of InR in the midguts leads to a distinct proteome compared with other tissues, resulting in enhanced actin nucleation and glutathione metabolism, while attenuating age-related elevation of serine proteases. Consequently, knockdown of InR results in rejuvenation of the integrity of the midgut barrier and augmentation of anti-ROS defense capabilities. Our findings suggest that the barrier function of the midgut plays a pivotal role in defending against aging, underscoring the paramount importance of maintaining optimal gut physiology to effectively delay the aging process. Moreover, when considering age-related changes across various tissues, it is more reasonable to identify functional networks rather than focusing solely on individual proteins.

Immunosenescence, the age-related decline in immune function, is a complex biological process with profound implications for health and longevity. This phenomenon, characterized by alterations in both innate and adaptive immunity, increases susceptibility to infections, reduces vaccine efficacy, and contributes to the development of age-related diseases. At the cellular level, immunosenescence manifests as decreased production of naive T and B cells, accumulation of memory and senescent cells, thymic involution, and dysregulated cytokine production. Recent advances in molecular biology have shed light on the underlying mechanisms of immunosenescence, including telomere attrition, epigenetic alterations, mitochondrial dysfunction, and changes in key signaling pathways such as NF-κB and mTOR. These molecular changes lead to functional impairments in various immune cell types, altering their proliferative capacity, differentiation, and effector functions. Emerging research suggests that lifestyle factors may modulate the rate and extent of immunosenescence at both cellular and molecular levels. Physical activity, nutrition, stress management, and sleep patterns have been shown to influence immune cell function, inflammatory markers, and oxidative stress in older adults. This review provides a comprehensive analysis of the molecular and cellular mechanisms underlying immunosenescence and explores how lifestyle interventions may impact these processes. We will examine the current understanding of immunosenescence at the genomic, epigenomic, and proteomic levels, and discuss how various lifestyle factors can potentially mitigate or partially reverse aspects of immune aging. By integrating recent findings from immunology, gerontology, and molecular biology, we aim to elucidate the intricate interplay between lifestyle and immune aging at the molecular level, potentially informing future strategies for maintaining immune competence in aging populations.

Mitochondrial DNA encodes essential components of the respiratory chain complexes, serving as the foundation of mitochondrial respiratory function. Mutations in mtDNA primarily impair energy metabolism, exerting far-reaching effects on cellular physiology, particularly in the context of aging. The intrinsic vulnerability of mtDNA is increasingly recognized as a key driver in the initiation of aging and the progression of its related diseases. In the field of aging research, it is critical to unravel the intricate mechanisms underpinning mtDNA mutations in living organisms and to elucidate the pathological consequences they trigger. Interestingly, certain effects, such as oxidative stress and apoptosis, may not universally accelerate aging as traditionally perceived. These phenomena demand deeper investigation and a more nuanced reinterpretation of current findings to address persistent scientific uncertainties. By synthesizing recent insights, this review seeks to clarify how pathogenic mtDNA mutations drive cellular senescence and systemic health deterioration, while also exploring the complex dynamics of mtDNA inheritance that may propagate these mutations. Such a comprehensive understanding could ultimately inform the development of innovative therapeutic strategies to counteract mitochondrial dysfunctions associated with aging.

Aging is accompanied by a decline in muscle mass, strength, and physical function, a condition known as sarcopenia. Muscle disuse attributed to decreased physical activity, hospitalization, or illness (e.g. sarcopenia) results in a rapid decline in muscle mass in aging individuals and effectively accelerates sarcopenia. Consuming protein at levels above (at least 50-100% higher) the current recommended intakes of ∼0.8 g protein/kg bodyweight/d, along with participating in both resistance and aerobic exercise, will aid in the preservation of muscle mass. Physiological muscle adaptations often accompany the observable changes in physical independence an older adult undergoes. Muscle fibre adaptations include a reduction in type 2 fibre size and number, a loss of motor units, reduced sensitivity to calcium, reduced elasticity, and weak cross-bridges. Mitochondrial function and structure are impaired in relation to aging and are worsened with inactivity and disease states but could be overcome by engaging in exercise. Intramuscular connective tissue adaptations with age are evident in animal models; however, the adaptations in collagenous tissue within human aging are less clear. We know that the satellite muscle cell pool decreases with age, and there is a reduced capacity for muscle repair/regeneration. Finally, a pro-inflammatory state associated with age has detrimental impacts on the muscle. The purpose of this review is to highlight the physiological adaptations driving muscle aging and their potential mitigation with exercise/physical activity and nutrition.

The accumulation of damaged mitochondria has long been considered a hallmark of the aging process. Among various factors, age-related mitochondrial alterations comprise bioenergetic impairments and disturbances in reactive oxygen species (ROS) control, thereby negatively affecting mitochondrial performance and ultimately accelerating aging. Previous studies have revealed that polyamine spermidine appears to exert health-protective and lifespan-promoting effects. Notably, recent findings have also described a spermidine-induced improvement in age-associated mitochondrial dysfunction, but the beneficial effects of spermidine on aged mitochondria have not been entirely examined yet. Here, we show that spermidine positively regulates several parameters related to mitochondrial bioenergetics and mitochondrial redox homeostasis in young and aged human-induced pluripotent stem cell-derived neurons. We report that spermidine treatment increases adenosine triphosphate production and mitochondrial membrane potential, which is accompanied by an attenuation in mitochondrial ROS levels in both age groups. Furthermore, we demonstrate a spermidine-mediated amelioration in mitochondrial respiration in both young and aged neurons. Overall, our findings suggest that nutritional spermidine supplementation might represent an attractive therapeutic approach to enhance mitochondrial function, consequently decelerating aging.

We present provocative data that in addition to the expected progressive age-related involution, mammary gland aging can occur in a cyclical pattern and is dictated by maternal ancestry. In cyclical aging, mammary glands of 11 and 19 months old mice share genetic and proteomic signatures, which are enriched in breast cancer-related pathways, but are absent at 3 and 14 months. Since incidence of breast cancer shows a bimodal age distribution at 45 (~11m in mice) and 65 (~ 19m in mice), cyclical aging may contribute to these peaks of cancer susceptibility. Conversely, since the mammary glands at 3 and 14 months cluster together hierarchically, the cancer-associated peaks seem separated by a rejuvenation phase. Since cyclical aging is observed in mice with extended lifespan, these findings raise the possibility that if oncogenic mutations are avoided during the pro-oncogenic phases, through its rejuvenation phase, cyclical aging may impact multiple organs leading to extended longevity.

The domestication of animals marks a pivotal moment in human history, profoundly influencing our demographic and cultural progress. This process has led to significant genetic, behavioral, and physical changes in livestock species compared to their wild ancestors. Understanding the evolutionary history and genetic diversity of livestock species is crucial, and mitochondrial DNA (mtDNA) has emerged as a robust marker for investigating molecular diversity in animals. Its highly conserved gene content across animal species, minimal duplications, absence of introns, and short intergenic regions make mtDNA analysis ideal for such studies. Mitochondrial DNA analysis has uncovered distinct cattle domestication events dating back to 8000 years BC in Southwestern Asia. The sequencing of water buffalo mtDNA in 2004 provided important insights into their domestication history. Caprine mtDNA analysis identified three haplogroups, indicating varied maternal origins. Sheep, domesticated 12,000 years ago, exhibit diverse mtDNA lineages, suggesting multiple domestication events. Ovine mtDNA studies revealed clades A, B, C, and a fourth lineage, group D. The origins of domestic pigs were traced to separate European and Asian events followed by interbreeding. In camels, mtDNA elucidated the phylogeographic structure and genetic differentiation between wild and domesticated species. Horses, domesticated around 3500 BC, show significant mtDNA variability, highlighting their diverse origins. Yaks exhibit unique adaptations for high-altitude environments, with mtDNA analysis providing insights into their adaptation. Chicken mtDNA studies supported a monophyletic origin from Southeast Asia's red jungle fowl, with evidence of multiple origins. This review explores livestock evolution and diversity through mtDNA studies, focusing on cattle, water buffalo, goat, sheep, pig, camel, horse, yak and chicken. It highlights mtDNA's significance in unraveling maternal lineages, genetic diversity, and domestication histories, concluding with insights into its potential application in improving livestock production and reproduction dynamics.

The universe began 13.8 billion years ago, and Earth was born 4.6 billion years ago. Early traces of life were found as soon as 4.1 billion years ago; then, ~200,000 years ago, the human being was born. The evolution of life on earth was to become individual rather than cellular life. The birth of mitochondria made this possible to be the individual life. Since then, individuals have had a limited time of life. It was 1.4 billion years ago that a bacterial cell began living inside an archaeal host cell, a form of endosymbiosis that is the development of eukaryotic cells, which contain a nucleus and other membrane-bound compartments. The bacterium started to provide its host cell with additional energy, and the interaction eventually resulted in a eukaryotic cell, with both archaeal (the host cell) and bacterial (mitochondrial) origins still having genomes. The cells survived high concentrations of oxygen producing more energy inside the cell. Further, the roles of mitochondria in human being's life and aging will be discussed.

Fetal hypoxia has long-term effects on postnatal reproductive functions and the mitochondrial impairments of ovarian granulosa cells may be one of the causes. Melatonin applied to mitigate mitochondrial dysfunction and autophagy in mammalian cells has been reported. However, the potential mechanisms by which fetal hypoxia damages reproductive function in neonatal female mice and the melatonin effects on this problem remain unclear.

This research aimed to explore the mechanism that fetal hypoxia damages reproductive function in neonatal female mice and attempt to improve the reproductive function by treating with melatonin in vivo and in vitro.

We established a fetal hypoxia model and confirmed that fetal hypoxia affects ovarian function by inducing GC excessive autophagy. Transcriptomic analysis, gene interference, cell immunofluorescence, immunohistochemistry and western blot were conducted to explore and verify the underlying mechanisms in mice GCs and KGN cells. Finally, melatonin treatment was executed on hypoxia-treated mice GCs and KGN cells and melatonin injection to fetal-hypoxia-treated mice to determine its effect.

The results of in vitro experiments found that fetal hypoxia led to mitochondrial dysfunction in ovarian GCs causing autophagic cell death. And the PI3K/Akt/FoxO pathway mediated the occurrence of this process by transcriptome analysis of ovarian GCs from normal and fetal hypoxia mice, which was further verified in mice GCs and KGN cells. Additionally, melatonin administration prevented autophagic injuries and mitochondrial impairments in hypoxia-treated mice GCs and KGN cells. Meanwhile, in vivo experiments by melatonin injection ameliorated oxidative stress of ovary in fetal-hypoxia-treated mice and improved their low fertility.

Our data found that fetal hypoxia causes ovarian GCs excessive autophagy leading to low fertility in neonatal female mice and mitigated by melatonin. These results provide a potential therapy for hypoxic stress-related reproductive disorders.