Mitochondrial health is maintained in a steady state through mitochondrial dynamics and autophagy processes. Recent studies have identified healthy mitochondria as crucial regulators of cellular function and survival. This process involves adenosine triphosphate (ATP) synthesis by mitochondrial oxidative phosphorylation (OXPHOS), regulation of calcium metabolism and inflammatory responses, and intracellular oxidative stress management. In the skeletal system, they participate in the regulation of cellular behaviors and the responses of osteoblasts, osteoclasts, chondrocytes, and osteocytes to external stimuli. Indeed, mitochondrial damage or dysfunction occurs in the development of a few bone diseases. For example, mitochondrial damage may lead to an imbalance in osteoblasts and osteoclasts, resulting in osteoporosis, osteomalacia, or poor bone production, and chondrocyte death and inflammatory infiltration in osteoarthritis are the main causes of cartilage degeneration due to mitochondrial damage. However, the opposite exists for osteosarcoma, where overactive mitochondrial metabolism is able to accelerate the proliferation and migration of osteosarcoma cells, which is a major disease feature. Bone is a dynamic organ and osteocytes play a fundamental role in all regions of bone tissue and are involved in regulating bone integrity. This review examines the impact of mitochondrial physiological function on osteocyte health and summarizes the microscopic molecular mechanisms underlying its effects. It highlights that targeted therapies focusing on osteocyte mitochondria may be beneficial for osteocyte survival, providing a new insight for the diagnosis, prevention, and treatment of diseases associated with osteocyte death.

Numerous chemotherapeutic drugs are commercially available for cancer treatment; however, their efficacy is often compromised by diminishing therapeutic effectiveness and unpredictable adverse effects. The lack of specific targeting limits their optimal therapeutic potential. Mitochondria are the primary sites of cellular energy production and play a critical role in cell survival and death. Furthermore, numerous studies have found an apparent association between mitochondrial metabolism and carcinogenesis and progression. Therefore, significant attention has been directed toward nanocarriers specifically designed for mitochondrial delivery, aiming to enhance the precision of chemotherapeutic agent transport to these critical organelles. Among these, triphenylphosphonium has emerged as a prominent mitochondrial targeting agent due to its superior targeting capabilities. This approach not only reduces the required drug dosage but also minimizes adverse effects on healthy tissues. This review provides a concise analysis of nanotechnology's contributions to cancer therapy, emphasizing its potential for targeting at both cellular and sub-cellular levels. Additionally, it delves into mitochondrial targeting, with a particular focus on nanocarriers engineered for efficient mitochondrial drug delivery. Moreover, it focuses on strategies employed by researchers to introduce TPP in nanocarrier systems for mitochondrial delivery and concludes by addressing challenges associated with TPP including hemolytic activity and how researchers mitigate this issue.

Glioblastoma (GBM), the most common primary brain tumor, lacks effective treatments. Emerging evidence suggests mitochondria as a promising therapeutic target, albeit successfully targeting represents a major challenge. Recently, we discovered a group of triterpenes that can self-assemble into nanoparticles (NPs) for cancer treatment. However, unmodified triterpene NPs lack affinity for mitochondria. In this study, using oleanolic acid (OA) as an example, we demonstrated that tertiary amine modification enabled triterpene NPs to selectively target the mitochondria through interaction with translocase of outer mitochondrial membrane 70 (TOM70) leading to effective killing of GBM cells via pyroptosis. We showed that the NPs could be engineered for preferentially penetrating brain tumors through surface conjugation of iRGD, and treatment with the resulting NPs significantly prolonged the survival of tumor-bearing mice. We found that the efficacy could be further improved by encapsulating lonidamine, a mitochondrial hexokinase inhibitor. Furthermore, the observed mitochondria targeting effect through tertiary amine modification could be extended to other triterpenes, including lupeol and glycyrrhetinic acid. Collectively, this study reveals a novel strategy for targeting the mitochondria through tertiary amine modification of triterpenes, offering a promising avenue for the effective treatment of GBM.

Mitochondria are vital for energy production, metabolic regulation, and cellular signaling. Their dysfunction is strongly implicated in neurological, cardiovascular, and muscular degenerative diseases, where energy deficits and oxidative stress accelerate disease progression. Platelet extracellular vesicles (PEVs), once called "platelet dust", have emerged as promising agents for mitigating mitochondrial dysfunction. Like other extracellular vesicles (EVs), PEVs carry diverse molecular cargo and surface markers implicated in disease processes and therapeutic efficacy. Notably, they may possibly contain intact or partially functional mitochondrial components, making them tentatively attractive for targeting mitochondrial damage. Although direct research on PEVs-mediated mitochondrial rescue remains limited, current evidence suggests that PEVs can modulate diseases associated with mitochondrial dysfunction and potentially enhance mitochondrial health. This review explores the therapeutic potential of PEVs in neurodegenerative and cardiovascular disorders, highlighting their role in restoring mitochondrial health. By examining recent advancements in PEVs research, we aim to shed light on novel strategies for utilizing PEVs as therapeutic agents. Our goal is to underscore the importance of further fundamental and applied research into PEVs-based interventions, as innovative tools for combating a wide range of diseases linked to mitochondrial dysfunction.

Mitochondrial dysfunction and increased reactive oxygen species (ROS) generation play an import role in different human pathologies. In this context, mitochondrial targeting of potentially protective antioxidants by their coupling to the lipophilic triphenylphosphonium cation (TPP) is widely applied. Employing a six‑carbon (C6) linker, we recently demonstrated that mitochondria-targeted phenolic antioxidants derived from gallic acid (AntiOxBEN2) and caffeic acid (AntiOxCIN4) counterbalance oxidative stress in primary human skin fibroblasts by activating ROS-protective mechanisms. Here we demonstrate that C6-TPP (but not AntiOxBEN2 and AntiOxCIN4) induce cell death in human skin fibroblasts. This indicates that C6-TPP cytoxocity is counterbalanced by the antioxidant moieties of AntiOxBEN2 and AntiOxCIN4. Remarkably, C6-TPP and AntiOxBEN2 (but not AntiOxCIN4) induced a glycolytic switch, as exemplified by a reduced cellular oxygen consumption rate (OCR), increased extracellular acidification rate (ECAR), elevated extracellular lactate levels, and higher protein levels of glucose transporter 1 (GLUT-1). This switch involved activation of AMP-activated protein kinase (AMPK) and fully compensated for the loss in mitochondrial ATP production by sustaining cellular ATP content. When glycolytic switch induction was prevented (i.e. by using a glucose-free, galactose-containing medium), AntiOxBEN2 induced cell death whereas AntiOxCIN4 did not. We conclude that, despite their similar chemical structure and antioxidant capacity, AntiOxBEN2 and AntiOxCIN4 display both common (redox-adaptive) and specific (bioenergetic-adaptive) effects.

The risk for developing cardiovascular diseases dramatically increases in older individuals, and aging vasculature plays a crucial role in determining their morbidity and mortality. Aging disrupts endothelial balance between vasodilators and vasoconstrictors, impairing function and promoting pathological vascular remodeling. In this Review, we discuss the impact of key and emerging molecular pathways that transduce aberrant inflammatory signals (i.e., chronic low-grade inflammation-inflammaging), oxidative stress, and mitochondrial dysfunction in aging vascular compartment. We focus on the interplay between these events, which contribute to generating a vicious cycle driving the progressive alterations in vascular structure and function during cardiovascular aging. We also discuss the primary role of senescent endothelial cells and vascular smooth muscle cells, and the potential link between vascular and myeloid cells, in impairing plaque stability and promoting the progression of atherosclerosis. The aim of this summary is to provide potential novel insights into targeting these processes for therapeutic benefit.

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.

In the last decades, major changes in ecosystems related to industrial development and environmental modifications have had a direct impact on mammalian fertility, as well as on biodiversity. It is widely demonstrated that all these changes impair reproductive function. Several studies have connected the increase of reactive oxygen species (ROS) generated in mitochondria to the recently identified decline of fertility due to various factors, including heat stress. The study of antioxidants, and especially of mitochondria targeted antioxidants, has been focused on identifying more efficient and less toxic therapies that could circumvent fertility problems. These antioxidants can be derived from natural compounds in the diet and delivered to the mitochondria in more effective forms, providing a much more natural therapy. The use of mitochondriotropic diet-based antioxidants in assisted reproductive technologies (ART) may be an important way to overcome low fertility, allowing the conservation of animal biodiversity and productivity. This paper provides a concise review of the current state of the art on this topic, with a particular focus on the antioxidants mitoquinone, AntiOxBEN2, AntiOxCIN4, urolithin A and piperine, and their effects on bovine and other animal species.

Intracerebral hemorrhage (ICH) is a major global health issue with high mortality and disability rates. Following ICH, the hematoma exerts direct pressure on brain tissue, and blood entering the brain directly damages neurons and the blood-brain barrier. Subsequently, oxidative stress, inflammatory responses, apoptosis, brain edema, excitotoxicity, iron toxicity, and metabolic dysfunction around the hematoma further exacerbate brain tissue damage, leading to secondary brain injury (SBI). Mitochondria, essential for energy production and the regulation of oxidative stress, are damaged after ICH, resulting in impaired ATP production, excessive reactive oxygen species (ROS) generation, and disrupted calcium homeostasis, all of which contribute to SBI. Therefore, a central factor in SBI is mitochondrial dysfunction. Mitochondrial dynamics regulate the shape, size, distribution, and quantity of mitochondria through fusion and fission, both of which are crucial for maintaining their function. Fusion repairs damaged mitochondria and preserves their health, while fission helps mitochondria adapt to cellular stress and removes damaged mitochondria through mitophagy. When this balance is disrupted following ICH, mitochondrial dysfunction worsens, oxidative stress and metabolic failure are exacerbated, ultimately contributing to SBI. Targeting mitochondrial dynamics offers a promising therapeutic approach to restoring mitochondrial function, reducing cellular damage, and improving recovery. This review explores the latest research on modulating mitochondrial dynamics and highlights its potential to enhance outcomes in ICH patients.

Yangtze finless porpoise (YFP) is a critically endangered species in China. It has been found that YFP is constantly exposed to perfluorooctane sulfonate (PFOS) in aquatic environments, leading to significant bioaccumulation. However, the impacts of PFOS on YFP health and survival are still unknown. To circumvent the limitations in YFP research, this study used YFP umbilical cord fibroblast cell line and exposed the cells to PFOS for 48 h, with objectives to uncover the cytotoxicity and mechanisms of PFOS in YFP. A high-throughput proteomics assay showed that PFOS exposure at 50 μM for 48 h perturbed the proteome structure in YFP umbilical cord fibroblast cells. Functional annotation found the high relevance of oxidative stress, mitochondrial oxidative phosphorylation, and DNA damage to PFOS cytotoxic mechanisms. Concordantly, PFOS exposure significantly increased the deposition of reactive oxygen species (ROS) in YFP cells. The potential of mitochondria to produce ATP was also compromised by PFOS, which was accompanied by the higher permeability of mitochondrial membrane. In addition, exposure of YFP umbilical cord fibroblast cells to 50 μM PFOS damaged the DNA assembly as evidenced by the increase in the percentage of DNA fragmentation. Gene transcription and enzymatic activity of caspases were up-regulated by PFOS, subsequently favoring the occurrence of early and late apoptosis. It was notable that ROS scavenger could successfully mitigate the cytotoxicity of PFOS on oxidative stress and apoptosis, thus pinpointing ROS as the molecular initiating event in apoptosis endpoints. To our knowledge, this is the first study that investigates the detrimental effects of PFOS using YFP umbilical cord fibroblast cells. The data will support an accurate assessment of ecological risks imposed by environmental pollutants on the health and sustainability of YFP, which is especially important under the context of sharp decline in YFP population and national initiative in YFP conservation.

Biomass burning (BB) emissions are one of the largest sources of carbonaceous aerosol, posing a significant risk as an airway irritant. Important BB markers include wood pyrolysis emissions, such as levoglucosan (LG) that is an anhydrous sugar bearing a six-carbon ring structure (i.e., 1,6-anhydro-β-D-glucopyranose). Atmospheric chemical aging of BB-derived aerosol (BBA) in the presence of nitrogen oxides (NOx) can yield nitro-aromatic compounds, including 4-nitrocatechol (4NC). There is building evidence that NOx-mediated chemical aging of BBA poses a more serious exposure effect than primary pyrolysis emissions. This study provides a comparative toxicological assessment following the exposure to important BBA marker compounds in human lung cells (i.e., A549 and BEAS-2B) to determine whether aromatic 4NC is more toxic than BBA-bound anhydrous carbohydrate (i.e., LG). We determined inhibitory concentration-50 (IC50) and examined reactive oxygen species (ROS) changes, mitochondrial dysfunction, and apoptosis induction in the two cell lines following exposure to LG and 4NC in a dose-response manner. In the BEAS-2B cells, estimated IC50 values for 4NC were 33 and 8.8 μg mL-1, and for LG were 2546 and ∼3 × 107 μg mL-1 at 24 h and 48 h of exposure, respectively. A549 cells exhibited a much higher IC50 value than BEAS-2B cells. LG exposures resulted in mitochondrial stress with viability inhibition, but cells recovered with increasing exposure time. 4NC exposures at 200 μg mL-1 resulted in the induction of apoptosis at 6 h. Mitochondrial dysfunction and ROS imbalance induced the intrinsic apoptotic pathway induction following 4NC exposures. While increased ROS is caused by LG exposure in lung cells, 4NC is a marker of concern during BB emissions, as we observed apoptosis and high mitochondrial ROS in both lung cells at atmospherically-relevant aerosol concentrations. It may be associated with higher airway or inhalation pathologies in higher BBA emissions, such as wildfires or during wood combustion.

Diabetes mellitus (DM) is characterized by chronic hyperglycemia, and despite intensive glycemic control, the risk of heart failure in patients with diabetes remains high. Diabetes-induced heart failure (DHF) presents a unique metabolic challenge, driven by significant alterations in cardiac substrate metabolism, including increased reliance on fatty acid oxidation, reduced glucose utilization, and impaired mitochondrial function. These metabolic alterations lead to oxidative stress, lipotoxicity, and energy deficits, contributing to the progression of heart failure. Emerging research has identified novel mechanisms involved in the metabolic remodeling of diabetic hearts, such as autophagy dysregulation, epigenetic modifications, polyamine regulation, and branched-chain amino acid (BCAA) metabolism. These processes exacerbate mitochondrial dysfunction and metabolic inflexibility, further impairing cardiac function. Therapeutic interventions targeting these pathways-such as enhancing glucose oxidation, modulating fatty acid metabolism, and optimizing ketone body utilization-show promise in restoring metabolic homeostasis and improving cardiac outcomes. This review explores the key molecular mechanisms driving metabolic remodeling in diabetic hearts, highlights advanced methodologies, and presents the latest therapeutic strategies for mitigating the progression of DHF. Understanding these emerging pathways offers new opportunities to develop targeted therapies that address the root metabolic causes of heart failure in diabetes.

Evaluating protein and mitochondrial alterations post-mortem can contribute to determining correlations between fish-processing parameters and ultimate fish muscle quality. The myofibrillar protein alteration during rigor mortis directly affects the texture of fish muscle. To identify the mechanisms behind post-mortem softness and quality deterioration, it is crucial to understand the conditions linked to the breakdown of myofibrillar proteins in fish skeletal muscle. Therefore, monitoring protein breakdown at the molecular level and finding target proteins would be considered a marker for fish freshness. Mitochondria play an important role in executing and regulating cell death processes, including apoptosis and necrosis. The mitochondria are the seat of cellular respiration and experience significant alterations in post-mortem tissues. Processes used to reduce protein degradation, such as optimizing chilling and handling practices, would also minimize mitochondrial changes in fillet quality. Moreover, pH fluctuations are considered a critical point that influences both protein and mitochondrial changes. This review considered the implications of protein and mitochondrial alteration during post-mortem storage in fish fillets and the possible pathways of their interaction on fillet quality. Mitochondrial characteristics, such as membrane integrity, pH, and ATP levels, are important for post-mortem muscle cell changes, serving as an early indicator of fish freshness. Understanding the mechanisms behind protein degradation in fish muscle led to maintaining fillet quality and requires further experiments. Label-free proteomics combined with bioinformatics is crucial for comprehending protein degradation mechanisms to provide customers with safe and fresh fish products while minimizing economic losses associated with fillet deterioration. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Non-alcoholic fatty liver disease (NAFLD) presents a pervasive global pandemic, affecting approximately 25 % of the world's population. This grave health issue not only demands urgent attention but also stands as a significant economic concern on a global scale. The genesis of NAFLD can be primarily attributed to unhealthy dietary habits and a sedentary lifestyle, albeit certain genetic factors have also been recorded to contribute to its occurrence. NAFLD is characterized by fat accumulation in more than 5 % of hepatocytes according to histological analysis, or >5.6 % of lipid volume fraction in total liver weight in patients. The pathophysiology of NAFLD/non-alcoholic steatohepatitis (NASH) is multifactorial and the mechanisms underlying the progression to advanced forms remain unclear, thereby representing a challenge to disease therapy. Despite the substantial efforts from the scientific community and the large number of pre-clinical and clinical trials performed so far, only one drug was approved by the Food and Drug Administration (FDA) to treat NAFLD/NASH specifically. This review provides an overview of available information concerning emerging molecular targets and drug candidates tested in clinical studies for the treatment of NAFLD/NASH. Improving our understanding of NAFLD pathophysiology and pharmacotherapy is crucial not only to explore new molecular targets, but also to potentiate drug discovery programs to develop new therapeutic strategies. This knowledge endeavours scientific efforts to reduce the time for achieving a specific and effective drug for NAFLD or NASH management and improve patients' quality of life.

Diabetic neuropathy is one of the challenging complications of diabetes and is characterized by peripheral nerve damage due to hyperglycemia in diabetes. Mitochondrial dysfunction has been reported as one of the key pathophysiological factor contributing to nerve damage in diabetic neuropathy, clinically manifesting as neurodegenerative changes like functional and sensorimotor deficits. Accumulating evidence suggests a clear correlation between mitochondrial dysfunction and NLRP3 inflammasome activation. Unraveling deeper molecular aspects of mitochondrial dysfunction may provide safer and effective therapeutic alternatives. This review links mitochondrial dysfunction and appraises its role in the pathophysiology of diabetic neuropathy. We have also tried to delineate the role of mitophagy in NLRP3 inflammasome activation in experimental diabetic neuropathy.

Pressure ulcer is common in the bedridden elderly with high mortality and lack of effective treatment. In this study, human-adipose-derived-stem-cells-hyaluronic acid gel (hADSCs-HA gel) was developed and applied topically to treat pressure ulcers, of which efficacy and paracrine mechanisms were investigated through in vivo and in vitro experiments.

Pressure ulcers were established on the backs of C57BL/6 mice and treated topically with hADSCs-HA gel, hADSCs, hyaluronic acid, and normal saline respectively. The rate of wound closure was observed continuously during the following 14 days and the wound samples were obtained for Western blot, histopathology, immunohistochemistry, and proteomic analysis. Human dermal fibroblasts (HDFs) and human venous endothelial cells (HUVECs) under normal or hypoxic conditions were treated with conditioned medium of human ADSCs (ADSC-CM), then CCK-8, scratch test, tube formation, and Western blot were conducted to evaluate the paracrine effects of hADSCs and to explore the underlying mechanism.

The in vivo data demonstrated that hADSCs-HA gel significantly accelerated the healing of pressure ulcers by enhancing collagen expression, angiogenesis, and skin proliferation. The in vitro data revealed that hADSCs strengthened the proliferation and wound healing capabilities of HDFs and HUVECs, meanwhile promoted collagen secretion and tube formation through paracrine mode. ADSC-CM was also proved to exert protective effects on hypoxic HDFs and HUVECs. Besides, the results of proteomic analysis and Western blot elucidated that lipid metabolism and PPARβ/δ pathway mediated the healing effect of hADSCs-HA gel on pressure ulcers.

Our research showed that topical application of hADSCs-HA gel played an important role in dermal regeneration and angiogenesis. Therefore, hADSCs-HA gel exhibited the potential as a novel stem-cell-based therapeutic strategy of treating pressure ulcers in clinical practices.

In recent years, impairing mitochondria in cancer cells gained attention as alternative cancer therapy. In this context, non-steroidal anti-inflammatory (NSAID) drugs are interesting candidates to damage mitochondria in cancer cells. However, routing NSAIDs specifically into the mitochondria remained a major challenge and less explored. Herein, we have synthesized a small library of Meclofenamic acid and Naproxen derivatives having ester and amide linkage with substituted triphenylphosphonium cations for mitochondria targeting. Screening in cervical cancer (HeLa), breast cancer (MCF7) and colon cancer (HCT-116) cells revealed a Meclofenamic acid derivative having ester linkage with tri (4-methoxyphenyl) phosphonium cation (8A3) which induced mitochondrial damage through mitochondrial outer membrane permeabilization (MOMP) followed by generation of reactive oxygen species (ROS) in the HCT-116 cells. This 8A3-mediated mitochondrial impairment triggered apoptosis by inhibiting Cox-2, reduction in Bcl-2/Bcl-xl expression and Caspase-3/9 cleavage leading to remarkable HCT-116 cell death. This novel mitochondrion targeted Meclofenamic acid derivative has the potential to be used as a chemical biology tool to understand the role of NSAIDs in mitochondria towards cancer therapy.

Mitochondria, recognized as the cellular powerhouses, are indispensable organelles responsible for crucial cellular processes, such as energy metabolism, material synthesis, and signaling transduction. Their intricate involvement in a broad spectrum of diseases, particularly cancer, has propelled the exploration of mitochondria-targeting treatment as a promising strategy for cancer therapy. Since the groundbreaking discovery of cisplatin, the trajectory of research on the development of metal complexes have been marked by continuous advancement, giving rise to a diverse array of metallodrugs characterized by variations in ligand types, metal center properties, and oxidation states. By specifically targeting mitochondria, these metallodrugs exhibit the remarkable ability to elicit various programmed cell death pathways, encompassing apoptosis, autophagy, and ferroptosis. This review primarily focuses on recent developments in transition metal-based mitochondria-targeting agents, offering a comprehensive exploration of their capacity to induce distinct cell death modes. The aim is not only to disseminate knowledge but also to stimulate an active field of research toward new clinical applications and novel anticancer mechanisms.

Parkinson's disease is characterized by its distinct pathological features; loss of dopamine neurons in the substantia nigra pars compacta and accumulation of Lewy bodies and Lewy neurites containing modified α-synuclein. Beneficial effects of L-DOPA and dopamine replacement therapy indicate dopamine deficit as one of the main pathogenic factors. Dopamine and its oxidation products are proposed to induce selective vulnerability in dopamine neurons. However, Parkinson's disease is now considered as a generalized disease with dysfunction of several neurotransmitter systems caused by multiple genetic and environmental factors. The pathogenic factors include oxidative stress, mitochondrial dysfunction, α-synuclein accumulation, programmed cell death, impaired proteolytic systems, neuroinflammation, and decline of neurotrophic factors. This paper presents interactions among dopamine, α-synuclein, monoamine oxidase, its inhibitors, and related genes in mitochondria. α-Synuclein inhibits dopamine synthesis and function. Vice versa, dopamine oxidation by monoamine oxidase produces toxic aldehydes, reactive oxygen species, and quinones, which modify α-synuclein, and promote its fibril production and accumulation in mitochondria. Excessive dopamine in experimental models modifies proteins in the mitochondrial electron transport chain and inhibits the function. α-Synuclein and familiar Parkinson's disease-related gene products modify the expression and activity of monoamine oxidase. Type A monoamine oxidase is associated with neuroprotection by an unspecific dose of inhibitors of type B monoamine oxidase, rasagiline and selegiline. Rasagiline and selegiline prevent α-synuclein fibrillization, modulate this toxic collaboration, and exert neuroprotection in experimental studies. Complex interactions between these pathogenic factors play a decisive role in neurodegeneration in PD and should be further defined to develop new therapies for Parkinson's disease.

Formaldehyde (FA) is both a highly reactive environmental genotoxin and an endogenously produced metabolite that functions as a signaling molecule and one-carbon (1C) store to regulate 1C metabolism and epigenetics in the cell. Owing to its signal-stress duality, cells have evolved multiple clearance mechanisms to maintain FA homeostasis, acting to avoid the established genotoxicity of FA while also redirecting FA-derived carbon units into the biosynthesis of essential nucleobases and amino acids. The highly compartmentalized nature of FA exposure, production, and regulation motivates the development of chemical tools that enable monitoring of transient FA fluxes with subcellular resolution. Here we report a mitochondrial-targeted, activity-based sensing probe for ratiometric FA detection, MitoRFAP-2, and apply this reagent to monitor endogenous mitochondrial sources and sinks of this 1C unit. We establish the utility of subcellular localization by showing that MitoRFAP-2 is sensitive enough to detect changes in mitochondrial FA pools with genetic and pharmacological modulation of enzymes involved in 1C and amino acid metabolism, including the pervasive, less active genetic mutant aldehyde dehydrogenase 2*2 (ALDH2*2), where previous, non-targeted versions of FA sensors are not. Finally, we used MitoRFAP-2 to comparatively profile basal levels of FA across a panel of breast cancer cell lines, finding that FA-dependent fluorescence correlates with expression levels of enzymes involved in 1C metabolism. By showcasing the ability of MitoRFAP-2 to identify new information on mitochondrial FA homeostasis, this work provides a starting point for the design of a broader range of chemical probes for detecting physiologically important aldehydes with subcellular resolution and a useful reagent for further studies of 1C biology.

Non-alcoholic fatty liver disease (NAFLD) is a major health problem. However, no effective treatments are currently available. Thus, there is a critical need to develop novel drugs that can prevent and treat NAFLD with few side effects. In this study, Tussilagone (TUS), a natural sesquiterpene isolated from Tussilago farfara L, was explored in vitro and in vivo for its potential to treat NAFLD. Our results showed that in vitro TUS reduced oleic acid palmitate acid-induced triglyceride and cholesterol synthesis in HepG2cells, reduced intracellular lipid droplet accumulation, improved glucose metabolism disorders and increased energy metabolism and reduced oxidative stress levels. In vivo, TUS significantly reduced fat accumulation and improved liver injury in high-fat diet (HFD)-induced mice. TUS treatment significantly increased liver mitochondrial counts and antioxidant levels compared to the HFD group of mice. In addition, TUS was found to reduce the expression of genes involved in lipid synthesis sterol regulatory element binding protein-1 (SREBP1), fatty acid synthase (FASN), and stearoy-CoA desaturase 1 (SCD1) in vitro and in vivo. Our results suggest that TUS may be helpful in the treatment of NAFLD, suggesting that TUS is a promising compound for the treatment of NAFLD. Our findings provided novel insights into the application of TUS in regulating lipid metabolism.

Treating female canine mammary gland tumors is crucial owing to their propensity for rapid progression and metastasis, significantly impacting the overall health and well-being of dogs. Mitoquinone (MitoQ), an antioxidant, has shown promise in inhibiting the migration, invasion, and clonogenicity of human breast cancer cells. Thus, we investigated MitoQ's potential anticancer properties against canine mammary gland tumor cells, CMT-U27 and CF41.Mg. MitoQ markedly suppressed the proliferation and migration of both CMT-U27 and CF41.Mg cells and induced apoptotic cell death in a dose-dependent manner. Furthermore, treatment with MitoQ led to increased levels of pro-apoptotic proteins, including cleaved-caspase3, BAX, and phospho-p53. Cell cycle analysis revealed that MitoQ hindered cell progression in the G1 and S phases in CMT-U27 and CF41.Mg cells. These findings were supported using western blot analysis, demonstrating elevated levels of cleaved caspase-3, a hallmark of apoptosis, and decreased expression of cyclin-dependent kinase (CDK) 2 and cyclin D4, pivotal regulators of the cell cycle. In conclusion, MitoQ exhibits in vitro antitumor effects by inducing apoptosis and arresting the cell cycle in canine mammary gland tumors, suggesting its potential as a preventive or therapeutic agent against canine mammary cancer.

Untargeted metabolomics and proteomics were employed to investigate the intracellular response of yak rumen epithelial cells (YRECs) to conditions mimicking subacute rumen acidosis (SARA) etiology, including exposure to short-chain fatty acids (SCFA), low pH5.5 (Acid), and lipopolysaccharide (LPS) exposure for 24 h.

These treatments significantly altered the cellular morphology of YRECs. Metabolomic analysis identified significant perturbations with SCFA, Acid and LPS treatment affecting 259, 245 and 196 metabolites (VIP > 1, P < 0.05, and fold change (FC) ≥ 1.5 or FC ≤ 0.667). Proteomic analysis revealed that treatment with SCFA, Acid, and LPS resulted in differential expression of 1251, 1396, and 242 proteins, respectively (FC ≥ 1.2 or ≤ 0.83, P < 0.05, FDR < 1%). Treatment with SCFA induced elevated levels of metabolites involved in purine metabolism, glutathione metabolism, and arginine biosynthesis, and dysregulated proteins associated with actin cytoskeleton organization and ribosome pathways. Furthermore, SCFA reduced the number, morphology, and functionality of mitochondria, leading to oxidative damage and inhibition of cell survival. Gene expression analysis revealed a decrease the genes expression of the cytoskeleton and cell cycle, while the genes expression associated with inflammation and autophagy increased (P < 0.05). Acid exposure altered metabolites related to purine metabolism, and affected proteins associated with complement and coagulation cascades and RNA degradation. Acid also leads to mitochondrial dysfunction, alterations in mitochondrial integrity, and reduced ATP generation. It also causes actin filaments to change from filamentous to punctate, affecting cellular cytoskeletal function, and increases inflammation-related molecules, indicating the promotion of inflammatory responses and cellular damage (P < 0.05). LPS treatment induced differential expression of proteins involved in the TNF signaling pathway and cytokine-cytokine receptor interaction, accompanied by alterations in metabolites associated with arachidonic acid metabolism and MAPK signaling (P < 0.05). The inflammatory response and activation of signaling pathways induced by LPS treatment were also confirmed through protein interaction network analysis. The integrated analysis reveals co-enrichment of proteins and metabolites in cellular signaling and metabolic pathways.

In summary, this study contributes to a comprehensive understanding of the detrimental effects of SARA-associated factors on YRECs, elucidating their molecular mechanisms and providing potential therapeutic targets for mitigating SARA.

Accumulating evidence highlights the pivotal role of mitochondria in cardiovascular diseases (CVDs). Understanding the molecular mechanisms underlying mitochondrial dysfunction is crucial for developing targeted therapeutics. Recent years have seen substantial advancements in unraveling mitochondrial regulatory pathways in both normal and pathological states and the development of potent drugs. However, specific delivery of drugs into the mitochondria is still a challenge. We present recent findings on regulators of mitochondrial dynamics and reactive oxygen species (ROS), critical factors influencing mitochondrial function in CVDs. We also discuss advancements in drug delivery strategies aimed at overcoming the technical barrier in targeting mitochondria for CVD treatment.

Photodynamic therapy (PDT), as an emerging cancer treatment, requires the development of highly desirable photosensitizers (PSs) with integrated functional groups to achieve enhanced therapeutic efficacy. Coordination-driven self-assembly (CDSA) would provide an alternative approach for combining multiple PSs synergistically. Here, we demonstrate a simple yet powerful strategy of combining conventional chromophores (tetraphenylethylene, porphyrin, or Zn-porphyrin) with pyridinium salt PSs together through condensation reactions, followed by CDSA to construct a series of novel metallo-supramolecular PSs (S1-S3). The generation of reactive oxygen species (ROS) is dramatically enhanced by the direct combination of two different PSs, and further reinforced in the subsequent ensembles. Among all the ensembles, S2 with two porphyrin cores shows the highest ROS generation efficiency, specific interactions with lysosome, and strong emission for probing cells. Moreover, the cellular and living experiments confirm that S2 has excellent PDT efficacy, biocompatibility, and biosafety. As such, this study will enable the development of more efficient PSs with potential clinical applications.

Due to the pivotal role of mitochondria in the generation of adenosine triphosphate (ATP) and the regulation of cellular homeostasis, mitochondrial dysfunction may exert a profound impact on various physiological systems, potentially precipitating a spectrum of distinct diseases. Consequently, research pertaining to mitochondrial therapeutics has assumed increasing significance, warranting heightened scrutiny. In recent years, the field of mitochondrial therapy has witnessed noteworthy advancements, with active exploration into diverse pharmacological agents aimed at ameliorating mitochondrial function. Elamipretide (SS-31), a novel synthetic mitochondrial-targeted antioxidant, has emerged as a promising candidate with extensive therapeutic potential. Its notable attributes encompass the mitigation of oxidative stress, the suppression of inflammatory processes, the maintenance of mitochondrial dynamics, and the prevention of cellular apoptosis. As such, SS-31 may emerge as a viable choice for the treatment of mitochondrial dysfunction-related ailments in the foreseeable future. This article extensively expounds upon the superiority of SS-31 over natural antioxidants and traditional mitochondrial-targeted antioxidants, delves into its mechanisms of modulating mitochondrial function, and comprehensively summarizes its applications in alleviating mitochondrial dysfunction-associated disorders. Furthermore, we offer a comprehensive outlook on the expansive prospects of SS-31's future development and application.

Ferroptosis is a new form of regulated cell death caused by iron-dependent accumulation of lethal polyunsaturated phospholipids peroxidation. It has received considerable attention owing to its putative involvement in a wide range of pathophysiological processes such as organ injury, cardiac ischemia/reperfusion, degenerative disease and its prevalence in plants, invertebrates, yeasts, bacteria, and archaea. To counter ferroptosis, living organisms have evolved a myriad of intrinsic efficient defense systems, such as cyst(e)ine-glutathione-glutathione peroxidase 4 system (cyst(e)ine-GPX4 system), guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin (BH4) system (GCH1/BH4 system), ferroptosis suppressor protein 1/coenzyme Q10 system (FSP1/CoQ10 system), and so forth. Among these, GPX4 serves as the only enzymatic protection system through the reduction of lipid hydroperoxides, while other defense systems ultimately rely on small compounds to scavenge lipid radicals and prevent ferroptotic cell death. In this article, we systematically summarize the chemical biology of lipid radical trapping process by endogenous chemicals, such as coenzyme Q10 (CoQ10), BH4, hydropersulfides, vitamin K, vitamin E, 7-dehydrocholesterol, with the aim of guiding the discovery of novel ferroptosis inhibitors.

Despite immense potential as anti-aging interventions, applications of current senolytics are limited due to low sensitivity and specificity. We demonstrate the specific loss of complex I-linked coupled respiration and the inability to maintain mitochondrial membrane potential upon respiratory stimulation as a specific vulnerability of senescent cells. Further decreasing the mitochondrial membrane potential of senescent cells with a mitochondrial uncoupler synergistically enhances the in vitro senolytic efficacy of BH3 mimetic drugs, including Navitoclax, by up to two orders of magnitude, whereas non-senescent cells remain unaffected. Moreover, a short-term intervention combining the mitochondrial uncoupler BAM15 with Navitoclax at a dose two orders of magnitude lower than typically used rescues radiation-induced premature aging in an in vivo mouse model, as demonstrated by reduced frailty and improved cognitive function for at least eight months. Our study shows compromised mitochondrial functional capacity is a senescence-specific vulnerability that can be targeted by mild uncoupling in vitro and in vivo.

The in vitro production (IVP) of bovine embryos has gained popularity worldwide and in recent years and its use for producing embryos from genetically elite heifers and cows has surpassed the use of conventional superovulation-based embryo production schemes. There are, however, several issues with the IVP of embryos that remain unresolved. One limitation of special concern is the low efficiency of the IVP of embryos. Exposure to reactive oxygen species (ROS) is one reason why the production of embryos with IVP is diminished. These highly reactive molecules are generated in small amounts through normal cellular metabolism, but their abundances increase in embryo culture because of oocyte and embryo exposure to temperature fluctuations, light exposure, pH changes, atmospheric oxygen tension, suboptimal culture media formulations, and cryopreservation. When uncontrolled, ROS produce detrimental effects on the structure and function of genomic and mitochondrial DNA, alter DNA methylation, increase lipid membrane damage, and modify protein activity. Several intrinsic enzymatic pathways control ROS abundance and damage, and antioxidants react with and reduce the reactive potential of ROS. This review will focus on exploring the efficiency of supplementing several of these antioxidant molecules on oocyte maturation, sperm viability, fertilization, and embryo culture.

The ubiquitous human exposure to nanoplastics (NPs) increasingly raises concerns regarding impact on our health. However, little is known on the biological effects of complex mixtures of weathered NPs with heterogenous size and irregular shape present in the environment. In this study, the bioenergetic effects of four such NPs mixtures on human intestinal Caco-2 cells were investigated. To this aim, Caco-2 cells were exposed to polydisperse nanoPET (<800 nm) and nanoPS (mixture of 100 and 750 nm) samples with and without ultraviolet (UV) weathering at low concentration range (102-107 particles/mL) for 48 h. Mitochondrial respiration, glycolytic functions and ATP production rates of exposed cells were measured by Seahorse XFe96 Analyzer. Among four NPs samples, polydisperse nanoPET with irregular shapes induced significant stimulation of mitochondrial respiration, glycolysis and ATP production rates in Caco-2 cells. Spherical nanoPS caused significant stimulation on glycolytic functions of Caco-2 cells at the highest concentration used (106 particles/mL). ATR-FTIR spectra and carbonyl index indicated formation of carbonyl groups in nanoPET and nanoPS after UV weathering. UV weathering could alleviate bioenergetic stress caused by NPs in Caco-2 cells and even shifted the energy pathways from mitochondrial respiration to glycolysis due to electrostatic repulsion between negatively charged UV-aged NPs and cell membranes. This research is the first to study in-vitro bioenergetic responses of NPs samples with multidimensional features (polymer type, irregular shape, heterogenous size, UV-weathering) on human health. It highlights that effects between pristine and weathered NPs are different at a bioenergetic level, which has important implications for the risk assessment of NPs on human health.

Mitochondrion has appeared as one of the important targets for anti-cancer therapy. Subsequently, small molecule anti-cancer drugs are directed to the mitochondria for improved therapeutic efficacy. However, simultaneous imaging and impairing mitochondria by a single probe remained a major challenge. To address this, herein Chimeric Small Molecules (CSMs) encompassing drugs, fluorophore and mitochondria homing moiety were designed and synthesized through a concise strategy. Screening of the CSMs in a panel of cancer cell lines (HeLa, MCF7, A549, and HCT-116) revealed that one of the CSMs comprising Indomethacin V exhibited remarkable cervical cancer cell (HeLa) killing (IC50 =0.97 μM). This lead CSM homed into the mitochondria of HeLa cells within 1 h followed by mitochondrial damage and reactive oxygen species (ROS) generation. This novel Indomethacin V-based CSM-mediated mitochondrial damage induced programmed cell death (apoptosis). We anticipate these CSMs can be used as tools to understand the drug effects in organelle chemical biology in diseased states.

Transcription factor EB (TFEB) is an important endogenous defensive protein that responds to ischemic stimuli. Acute ischemic stroke is a growing concern due to its high morbidity and mortality. Most survivors suffer from disabilities such as numbness or weakness in an arm or leg, facial droop, difficulty speaking or understanding speech, confusion, impaired balance or coordination, or loss of vision. Although TFEB plays a neuroprotective role, its potential effect on ischemic stroke remains unclear. This article describes the basic structure, regulation of transcriptional activity, and biological roles of TFEB relevant to ischemic stroke. Additionally, we explore the effects of TFEB on the various pathological processes underlying ischemic stroke and current therapeutic approaches. The information compiled here may inform clinical and basic studies on TFEB, which may be an effective therapeutic drug target for ischemic stroke.

This study examined the potential influence of mitochondrial calcium sequestering ability on calpain-1 autolysis and proteolysis in vitro. We first tested whether mitochondria can sequester calcium in an in vitro setting. Isolated bovine mitochondria (0, 0.5, or 2 mg/mL) were incubated in a buffer containing varying calcium levels (0, 50, or 100 μM). An inverse relationship between mitochondrial content and measured free calcium was observed (P < 0.05), confirming that mitochondria can sequester calcium within the concentration range tested. In the first in vitro experiment, intact mitochondria (0, 0.5, or 2 mg/mL) were incorporated into an in vitro model simulating postmortem muscle conditions, and calpain-1 autolysis and proteolysis were evaluated over a 168-h period. Adding intact mitochondria to the in vitro model decreased calpain-1 autolysis and proteolysis during the first 4 h of incubation (P < 0.05), likely through reducing calcium availability. However, accentuated calpain-1 autolysis and proteolysis were observed at 24 h. To further explore these effects, mitochondrial integrity was evaluated at varying pH and calcium levels. Mitochondrial integrity decreased as pH declined (P < 0.05), especially in the presence of calcium. Based on these results, we conducted a second in vitro experiment involving disrupted mitochondria. Unlike intact mitochondria, which exerted a suppressive effect on calpain-1 autolysis and proteolysis early on, disrupted mitochondria increased both parameters at most time points (P < 0.05). Overall, it appears that intact mitochondria initially cause a delay in calpain-1 autolysis and proteolysis, but as their integrity diminishes, both processes are enhanced.

Oleanolic acid (OA), a pentacyclic triterpenoid, exhibits a broad spectrum of biological activities, including antitumor, antiviral, antibacterial, anti-inflammatory, hepatoprotective, hypoglycemic, and hypolipidemic effects. Since its initial isolation and identification, numerous studies have reported on the structural modifications and pharmacological activities of OA and its derivatives. Despite this, there has been a dearth of comprehensive reviews in the past two decades, leading to challenges in subsequent research on OA. Based on the main biological activities of OA, this paper comprehensively summarized the modification strategies and structure-activity relationships (SARs) of OA and its derivatives to provide valuable reference for future investigations into OA.

While bioorthogonal reactions are routinely employed in living cells and organisms, their application within individual organelles remains limited. In this review, we highlight diverse examples of bioorthogonal reactions used to investigate the roles of biomolecules and biological processes as well as advanced imaging techniques within cellular organelles. These innovations hold great promise for therapeutic interventions in personalized medicine and precision therapies. We also address existing challenges related to the selectivity and trafficking of subcellular dynamics. Organelle-targeted bioorthogonal reactions have the potential to significantly advance our understanding of cellular organization and function, provide new pathways for basic research and clinical applications, and shape the direction of cell biology and medical research.

Exposure to persistent new organic pollutants in the environment often leads to high mortality and causes serious economic losses to the aquaculture industry. Currently, perfluorooctane sulfonate (PFOS) is persistent and bio-accumulative in the environment, causing potential risks to aquatic ecosystems, but its toxicity mechanism to aquatic organisms is still unclear. As a natural flavonoid compound, quercetin (QU) has many biological activities such as anti-oxidation, anti-inflammatory, anti-apoptosis and immune regulation. Whether it can be used as a candidate medicine to alleviate PFOS toxicity needs to be further explored. Therefore, in this study, we treated (Ctenopharyngodon idellus) grass carp hepatocytes (L8824) with PFOS (200 μM) and/or QU (60 μM) for 24 h. The results showed that PFOS significantly increased the release of LDH and active oxygen (ROS) in L8824 cells, and led to the decrease of mitochondrial membrane potential (ΔΨm) and ATP content, the increase of mitochondrial ROS, the disorder of mitochondrial dynamics, and the initiation of Bcl-2/Bax-mediated apoptosis. Surprisingly, QU can alleviate the above PFOS-induced grass carp hepatocyte toxicity. In addition, in order to further explore the protective mechanism of QU, we used the molecular docking to predict the binding site between QU and AMPK, and found that there was a high binding capacity between QU and AMPK. In addition, we used Compound C (CC) and 3-Methyladenine (3-MA) to intervene. The results showed that CC and 3-MA intervention aggravated mitochondrial dysfunction and apoptosis factor expression in the QU+PFOS group. These data indicate that PFOS induces oxidative stress, mitochondrial dysfunction, and apoptosis. The regulation of AMPK/mTOR mediated mitophagy by QU may be a new therapeutic strategy to alleviate the hepatotoxicity of PFOS grass carp. This study provides theoretical basis and reference for exploring the toxic mechanism and biological toxic effects of PFOS, and provides a scheme for improving the economic benefits of aquaculture.

The gas molecules O2, NO, H2S, CO, and CH4, have been increasingly used for medical purposes. Other than these gas molecules, H2 is the smallest diatomic molecule in nature and has become a rising star in gas medicine in the past few decades. As a non-toxic and easily accessible gas, H2 has shown preventive and therapeutic effects on various diseases of the respiratory, cardiovascular, central nervous system, and other systems, but the mechanisms are still unclear and even controversial, especially the mechanism of H2 as a selective radical scavenger. Mitochondria are the main organelles regulating energy metabolism in living organisms as well as the main organelle of reactive oxygen species' generation and targeting. We propose that the protective role of H2 may be mainly dependent on its unique ability to penetrate every aspect of cells to regulate mitochondrial homeostasis by activating the Keap1-Nrf2 phase II antioxidant system rather than its direct free radical scavenging activity. In this review, we summarize the protective effects and focus on the mechanism of H2 as a mitochondria-targeting nutrient by activating the Keap1-Nrf2 system in different disease models. In addition, we wish to provide a more rational theoretical support for the medical applications of hydrogen.

Mitochondrially targeted anticancer drugs (mitocans) that disrupt the energy-producing systems of cancer are emerging as new potential therapeutics. Mitochondrially targeted tamoxifen (MitoTam), an inhibitor of mitochondrial respiration respiratory complex I, is a first-in-class mitocan that was tested in the phase I/Ib MitoTam-01 trial of patients with metastatic cancer. MitoTam exhibited a manageable safety profile and efficacy; among 37% (14/38) of responders, the efficacy was greatest in patients with metastatic renal cell carcinoma (RCC) with a clinical benefit rate of 83% (5/6) of patients. This can be explained by the preferential accumulation of MitoTam in the kidney tissue in preclinical studies. Here we report the mechanism of action and safety profile of MitoTam in a case series of RCC patients. All six patients were males with a median age of 69 years, who had previously received at least three lines of palliative systemic therapy and suffered progressive disease before starting MitoTam. We recorded stable disease in four, partial response in one, and progressive disease (PD) in one patient. The histological subtype matched clear cell RCC (ccRCC) in the five responders and claro-cellular carcinoma with sarcomatoid features in the non-responder. The number of circulating tumor cells (CTCs) was evaluated longitudinally to monitor disease dynamics. Beside the decreased number of CTCs after MitoTam administration, we observed a significant decrease of the mitochondrial network mass in enriched CTCs. Two patients had long-term clinical responses to MitoTam, of 50 and 36 weeks. Both patients discontinued treatment due to adverse events, not PD. Two patients who completed the trial in November 2019 and May 2020 are still alive without subsequent anticancer therapy. The toxicity of MitoTam increased with the dosage but was manageable. The efficacy of MitoTam in pretreated ccRCC patients is linked to the novel mechanism of action of this first-in-class mitochondrially targeted drug.

Heart failure is a serious global health challenge, affecting more than 6.2 million people in the United States and is projected to reach over 8 million by 2030. Independent of etiology, failing hearts share common features, including defective calcium (Ca2+) handling, mitochondrial Ca2+ overload, and oxidative stress. In cardiomyocytes, Ca2+ not only regulates excitation-contraction coupling, but also mitochondrial metabolism and oxidative stress signaling, thereby controlling the function and actual destiny of the cell. Understanding the mechanisms of mitochondrial Ca2+ uptake and the molecular pathways involved in the regulation of increased mitochondrial Ca2+ influx is an ongoing challenge in order to identify novel therapeutic targets to alleviate the burden of heart failure. In this review, we discuss the mechanisms underlying altered mitochondrial Ca2+ handling in heart failure and the potential therapeutic strategies.

Motivated by the discovery of main group Lewis acids that could compete or possibly outperform the ubiquitous organoboranes, several groups, including ours, have engaged in the chemistry of Lewis acidic organoantimony compounds as new platforms for anion capture, sensing, and transport. Principal to this approach are the intrinsically elevated Lewis acidic properties of antimony, which greatly favor the addition of halide anions to this group 15 element. The introduction of organic substituents to the antimony center and its oxidation from the + III to the + V state provide for tunable Lewis acidity and a breadth of applications in supramolecular chemistry and catalysis. The performances of these antimony-based Lewis acids in the domain of anion sensing in aqueous media illustrate the favorable attributes of antimony as a central element. At the same time, recent advances in anion binding catalysis and anion transport across phospholipid membranes speak to the numerous opportunities that lie ahead in the chemistry of these unique main group compounds.

Mitochondria play a vital role in maintaining cellular energy homeostasis, regulating apoptosis, and controlling redox signaling. Dysfunction of mitochondria has been implicated in the pathogenesis of various brain diseases, including neurodegenerative disorders, stroke, and psychiatric illnesses. This review paper provides a comprehensive overview of the intricate relationship between mitochondria and brain disease, focusing on the underlying pathological mechanisms and exploring potential therapeutic opportunities. The review covers key topics such as mitochondrial DNA mutations, impaired oxidative phosphorylation, mitochondrial dynamics, calcium dysregulation, and reactive oxygen species generation in the context of brain disease. Additionally, it discusses emerging strategies targeting mitochondrial dysfunction, including mitochondrial protective agents, metabolic modulators, and gene therapy approaches. By critically analysing the existing literature and recent advancements, this review aims to enhance our understanding of the multifaceted role of mitochondria in brain disease and shed light on novel therapeutic interventions.