bims-mistre 2025-06-01 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–06–01
fifteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Epigallocatechin Gallate in Camellia sinensis Ameliorates Skin Aging by Reducing Mitochondrial ROS Production.
Mitochondria-Nuclear Crosstalk: Orchestrating mtDNA Maintenance.
The Ferroptosis-Mitochondrial Axis in Depression: Unraveling the Feedforward Loop of Oxidative Stress, Metabolic Homeostasis Dysregulation, and Neuroinflammation.
The Gut Microbial Metabolite Butyrate Alleviates IL-1β-Induced Mitochondrial Dysfunction and Oxidative Stress in Pancreatic Islets.
Targeting Mitochondrial Dysfunction to Prevent Endothelial Dysfunction and Atherosclerosis in Diabetes: Focus on the Novel Uncoupler BAM15.
Mitotherapy in Alzheimer's and Parkinson's diseases: A systematic review of preclinical studies.
UQCRB regulates mitochondrial energy metabolism by promoting COX5 A in atherosclerotic endothelial dysfunction.
The potential role of mitochondria in age-related health benefits conferred by moderate hypoxia.
From Obesity to Mitochondrial Dysfunction in Peripheral Tissues and in the Central Nervous System.
Targeting the Electron Transport System for Enhanced Longevity.
Melatonin Improves Lipid Homeostasis, Mitochondrial Biogenesis, and Antioxidant Defenses in the Liver of Prediabetic Rats.
The mitochondrial intermembrane space - a permanently proteostasis-challenged compartment.
cGAS-STING targeting offers a novel therapeutic paradigm in cardiovascular diseases.
Mitochondrial medicine: "from bench to bedside" 3PM-guided concept.
Aerobic Capacity Beyond Cardiorespiratory Fitness Linking Mitochondrial Function, Disease Resilience and Healthy Aging.

Pharmaceuticals (Basel). 2025 Apr 23. pii: 612. [Epub ahead of print]18(5):

Epigallocatechin Gallate in Camellia sinensis Ameliorates Skin Aging by Reducing Mitochondrial ROS Production.

Ji Ho Park, Eun Young Jeong, Ye Hyang Kim, So Yoon Cha, Ha Yeon Kim, Yeon Kyung Nam, Jin Seong Park, So Yeon Kim, Yoo Jin Lee, Jee Hee Yoon, Byeonghyeon So, Duyeol Kim, Minseon Kim, Youngjoo Byun, Yun Haeng Lee, Song Seok Shin, Joon Tae Park.

  Background: Reactive oxygen species (ROS) generated by mitochondrial dysfunction damage cellular organelles and contribute to skin aging. Therefore, strategies to reduce mitochondrial ROS production are considered important for alleviating skin aging, but no effective methods have been identified. Methods: In this study, we evaluated substances utilized as cosmetic ingredients and discovered Camellia sinensis (C. sinensis) as a substance that reduces mitochondrial ROS levels. Results:C. sinensis extracts were found to act as senolytics that selectively kill senescent fibroblasts containing dysfunctional mitochondria. In addition, C. sinensis extracts facilitated efficient electron transport in the mitochondrial electron transport chain (ETC) by increasing the efficiency of oxidative phosphorylation (OXPHOS), thereby reducing mitochondrial ROS production, a byproduct of the inefficient ETC. This novel mechanism of C. sinensis extracts led to the restoration of skin aging and the skin barrier. Furthermore, epigallocatechin gallate (EGCG) was identified as an active ingredient that plays a key role in C. sinensis extract-mediated skin aging recovery. Indeed, similar to C. sinensis extracts, EGCG reduced ROS and improved skin aging in an artificial skin model. Conclusions: Our data uncovered a novel mechanism by which C. sinensis extract reverses skin aging by reducing mitochondrial ROS production via selective senescent cell death/increased OXPHOS efficiency. Our results suggest that C. sinensis extract or EGCG may be used as a therapeutic agent to reverse skin aging in clinical and cosmetic applications.

Keywords:  Camellia sinensis; reactive oxygen species (ROS); senescence rejuvenation; skin aging recovery

DOI:  https://doi.org/10.3390/ph18050612
Environ Mol Mutagen. 2025 May 26.

Mitochondria-Nuclear Crosstalk: Orchestrating mtDNA Maintenance.

Ghazal Darfarin, Janice Pluth.

  The mitochondria (mt) and nucleus engage in a dynamic bidirectional communication to maintain cellular homeostasis, regulating energy production, stress response, and cell fate. Anterograde signaling directs mt function, while retrograde signaling conveys metabolic and stress-related changes from mt to the nucleus. Central to this crosstalk is mitochondrial DNA (mtDNA), which encodes key oxidative phosphorylation components. MtDNA integrity is preserved through quality control mechanisms, including fusion and fission dynamics, mitophagy, and nuclear-encoded DNA repair. Disruption in these pathways contributes to mt dysfunction, oxidative stress, and genetic instability-hallmarks of aging and diseases. Additionally, redox signaling and NAD+ homeostasis integrate mt and nuclear responses, modulating transcriptional programs that support mt biogenesis and stress adaptation. This review explores the molecular mechanisms coordinating mito-nuclear interactions, emphasizing their role in maintaining mtDNA integrity and cellular equilibrium. Understanding these processes provides insights into how mt dysfunction drives aging and disease, paving the way for targeted therapeutic strategies.

Keywords:  anterograde and retrograde signaling; cellular homeostasis; mitochondrial biogenesis; mitochondrial dynamics; mtDNA maintenance, mitochondrial‐nuclear communication; redox signaling

DOI:  https://doi.org/10.1002/em.70013
Antioxidants (Basel). 2025 May 20. pii: 613. [Epub ahead of print]14(5):

The Ferroptosis-Mitochondrial Axis in Depression: Unraveling the Feedforward Loop of Oxidative Stress, Metabolic Homeostasis Dysregulation, and Neuroinflammation.

Xu Liu, Qiang Luo, Yulong Zhao, Peng Ren, Yu Jin, Junjie Zhou.

  Emerging evidence links ferroptosis-mitochondrial dysregulation to depression pathogenesis through an oxidative stress-energy deficit-neuroinflammation cycle driven by iron overload. This study demonstrates that iron accumulation initiates ferroptosis via Fenton reaction-mediated lipid peroxidation, compromising neuronal membrane integrity and disabling the GPx4 antioxidant system. Concurrent mitochondrial complex I/IV dysfunction impairs ATP synthesis, creating an AMPK/mTOR signaling imbalance and calcium dyshomeostasis that synergistically impair synaptic plasticity. Bidirectional crosstalk emerges: lipid peroxidation derivatives oxidize mitochondrial cardiolipin, while mitochondrial ROS overproduction activates ACSL4 to amplify ferroptotic susceptibility, forming a self-reinforcing neurodegenerative loop. Prefrontal-hippocampal metabolomics reveal paradoxical metabolic reprogramming with glycolytic compensation suppressing mitochondrial biogenesis (via PGC-1α/TFAM downregulation), trapping neurons in bioenergetic crisis. Clinical data further show that microglial M1 polarization through cGAS-STING activation sustains neuroinflammation via IL-6/TNF-α release. We propose a "ferroptosis-mitochondrial fragmentation-metabolic maladaptation" triad as mechanistic subtyping criteria for depression. Preclinical validation shows that combinatorial therapy (iron chelators + SIRT3 agonists) rescues neuronal viability by restoring mitochondrial integrity and energy flux. This work shifts therapeutic paradigms from monoaminergic targets toward multimodal strategies addressing iron homeostasis, organelle dynamics, and metabolic vulnerability-a framework with significant implications for developing neuroprotective antidepressants.

Keywords:  depression; disorder of energy metabolism; ferroptosis; iron dysregulation; lipid metabolism disorders; mitochondrial dysfunction; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox14050613
FASEB J. 2025 Jun 15. 39(11): e70623

The Gut Microbial Metabolite Butyrate Alleviates IL-1β-Induced Mitochondrial Dysfunction and Oxidative Stress in Pancreatic Islets.

Signe Schultz Pedersen, Richard Denis Maxime De Mets, Joana Mendes Lopes de Melo, Andrea Irazoki, Patrick E MacDonald, Michala Prause, Nils Billestrup.

  Butyrate, a gut microbiota-derived metabolite, supports cellular health. In pancreatic beta cells, inflammation and oxidative stress disrupt mitochondrial function, contributing to dysfunction. This study explores how butyrate influences mitochondrial function and redox balance to protect beta cells from interleukin-1beta (IL-1β)-induced stress. Pancreatic mouse islets were treated with IL-1β and/or butyrate for 10 days to model chronic inflammation in type 2 diabetes, and their effects on mitochondrial health and oxidative stress were studied. Butyrate protected against IL-1β-induced impairment of insulin secretion by enhancing mitochondrial function, as evidenced by an increased glucose-stimulated oxygen consumption rate and a higher mitochondrial membrane potential compared to IL-1β treatment alone. IL-1β increased mitochondrial mass, but the mitochondria appeared smaller and rounded, indicating fragmentation. In contrast, butyrate co-treatment promoted mitochondrial hyperfusion, as evidenced by elongated mitochondria, higher levels of fusion proteins Opa1 and Mfn2, and lower levels of fission protein Fis1 compared to IL-1β alone. Furthermore, butyrate reduced IL-1β-induced reactive oxygen species (ROS) production, antioxidant enzyme gene expression, and protein oxidation, indicating protection against oxidative stress. Butyrate co-treatment further enhanced redox balance by increasing reduced glutathione (GSH) levels and the ratio of GSH to oxidized glutathione (GSSG). These findings suggest that butyrate acts as a potent modulator of mitochondrial function and redox balance, counteracting IL-1β-induced dysfunction and providing a potential therapeutic strategy for improving insulin secretion in inflammatory conditions.

Keywords:  beta cells; butyrate; cytokine; inflammation; mitochondria; oxidative stress

DOI:  https://doi.org/10.1096/fj.202403388R
Int J Mol Sci. 2025 May 11. pii: 4603. [Epub ahead of print]26(10):

Targeting Mitochondrial Dysfunction to Prevent Endothelial Dysfunction and Atherosclerosis in Diabetes: Focus on the Novel Uncoupler BAM15.

Woong Bi Jang, Vinoth Kumar Rethineswaran, Sang-Mo Kwon.

  Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia, leading to endothelial dysfunction and accelerated atherosclerosis. Mitochondrial dysfunction, oxidative stress, and dysregulated lipid metabolism contribute to endothelial cell (EC) injury, promoting plaque formation and increasing cardiovascular disease risk. Current lipid-lowering therapies have limited effectiveness in restoring endothelial function, highlighting the need for novel strategies. Mitochondrial uncoupling has emerged as a promising approach, with BAM15-a newly identified mitochondrial uncoupler-showing potential therapeutic benefits. BAM15 enhances fatty acid oxidation (FAO), reduces reactive oxygen species, and protects ECs from hyperglycemia-induced apoptosis. Unlike conventional uncouplers, BAM15 demonstrates improved tolerability and efficacy without severe off-target effects. It restores mitochondrial function, improves endothelial survival, and supports metabolic homeostasis under hyperglycemic conditions. This review uniquely integrates emerging evidence on mitochondrial dysfunction, endothelial metabolism, and FAO to highlight the novel role of BAM15 in restoring vascular function in diabetes. We provide the first focused synthesis of BAM15's mechanistic impact on EC bioenergetics and position it within the broader landscape of mitochondrial-targeted therapies for diabetic vascular complications. Further research is needed to elucidate the molecular mechanism through which BAM15 modulates EC metabolism and to evaluate its long-term vascular effects in diabetic models.

Keywords:  atherosclerosis; diabetes mellitus; endothelial dysfunction; mitochondrial dysfunction; mitochondrial uncoupling

DOI:  https://doi.org/10.3390/ijms26104603
BMC Neurol. 2025 May 27. 25(1): 227

Mitotherapy in Alzheimer's and Parkinson's diseases: A systematic review of preclinical studies.

Aynur Modiri, Leila Hosseini, Nasrin Abolhasanpour, Hosein Azizi, Reza Naghdi Sadeh.

   BACKGROUND: Alzheimer's disease (AD) and Parkinson's disease (PD) are prevalent neurodegenerative disorders and strongly affect both the patients' lives and their caregivers. Strategy to improve and restore mitochondrial function, as well as to treat mitochondria-associated diseases, as observed in the pathophysiology of AD and PD. The current study aimed to investigate the potential of mitotherapy in AD and PD in preclinical studies.
METHODS: We conducted a systematic search of articles in English related to mitotherapy in AD and PD animal models published until October 2024 in the selected bibliographic databases, including PubMed, Scopus, EMBASE, and Google Scholar, and the reference lists of relevant review articles published. The quality of the final selected studies was assessed using the Collaborative Approach to Meta-Analysis and Review of Animal Studies (CAMARADES) checklists and the SYRCLE risk of bias tool. The initial search resulted in 231 studies, and after screening the titles and abstracts, 30 studies were recognized. Finally, 7 studies met the inclusion criteria.
RESULTS: Despite restricted knowledge of the mitotherapy mechanisms, evidence shows that exogenous mitochondria exert neuroprotective effects via improving mitochondrial function, reducing oxidative stress and inflammation in preclinical models of AD and PD.
CONCLUSION: This systematic review summarizes the preclinical studies on mitotherapy and provides evidence favoring mitochondria transplantation's protective effects in animal PD and AD models.

Keywords:  Alzheimer's disease; Mitochondrial dysfunction; Mitochondrial transfer; Parkinson's disease

DOI:  https://doi.org/10.1186/s12883-025-04241-1
Naunyn Schmiedebergs Arch Pharmacol. 2025 May 30.

UQCRB regulates mitochondrial energy metabolism by promoting COX5 A in atherosclerotic endothelial dysfunction.

Rui Dai, Xiaotong Lei, Xiaojun Liu, Chen Bian.

  Mitochondrial dysfunction plays a critical role in the onset and progression of Atherosclerosis (AS). The ubiquinol-cytochrome c reductase binding protein (UQCRB) is an essential subunit of the mitochondrial respiratory chain. The objective of this study was to investigate whether UQCRB improves endothelial dysfunction in AS by upregulating cytochrome c oxidase subunit 5A (COX5A), thereby regulating mitochondrial energy metabolism, reducing inflammation, and preventing apoptosis. To explore the biological role of UQCRB in AS, we found that UQCRB was significantly downregulated in AS, based on bioinformatics analysis and clinical patient data. In vitro, overexpression of UQCRB significantly increased COX5A protein expression in response to oxidized low-density lipoprotein (OX-LDL), enhanced mitochondrial membrane potential, boosted ATP production, and reduced reactive oxygen species (ROS) levels. Furthermore, the secretion of inflammatory cytokines, including TNF-α, IL-1β, and IL-6, was decreased, and the apoptosis rate was significantly reduced. Additionally, the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was lowered, while the level of phosphorylated AMP-activated protein kinase (AMPK) was increased. The small molecule compound Terpestacin targeting UQCRB down-regulated the expression of COX5A in the AS mouse model, exacerbated endothelial dysfunction, and increased inflammation. These findings further corroborated the in vitro results. In conclusion, UQCRB enhances mitochondrial energy metabolism and activates the AMPK pathway while reducing inflammation and apoptosis through the upregulation of COX5A. This study identifies UQCRB as a novel therapeutic target and provides a theoretical foundation for the development of strategies to prevent and treat atherosclerosis.

Keywords:  Atherosclerosis; COX5A; Endothelial dysfunction; Inflammation; UQCRB

DOI:  https://doi.org/10.1007/s00210-025-04294-6
Gerontology. 2025 May 26. 1-14

The potential role of mitochondria in age-related health benefits conferred by moderate hypoxia.

Johannes Burtscher, Kamilla Woznica Miskowiak, Katharina Hüfner, Hannelore Ehrenreich, Martin Kopp.

Background Mitochondrial integrity and efficiency deteriorate with age and are linked to cellular senescence. Mitochondria are highly responsive to reduced oxygen availability (hypoxia), which for example occurs when exposed to altitude. We hypothesize that mitochondria are involved in the observed health benefits at moderate altitude. Because the experimental evidence on mitochondrial changes at moderate altitude is limited, we also evaluate dose-response associations of oxygen transport and mitochondrial functions derived from measurements at normoxia and severe hypoxia. Summary We summarize the effects of environmental oxygen availability and changes in cellular oxygen demand/supply on mitochondrial functions and assess, how this may influence aging. Hypotheses are presented how mild hypoxia at moderate altitude (1000 - 2500 m) could improve mitochondrial function and possibly explain the reported lower levels of mortality from several age-related diseases. Key messages It is unknown, whether continuous or intermittent types of hypoxia exposure are more effective in improving mitochondrial functions and promoting healthy aging. The combination of tissue-specific oxygen demand (for example during physical exercise) with mild reductions of ambient oxygen availability may enable the reported health benefits associated with moderate altitude residence.

DOI: https://doi.org/10.1159/000546478
Biomolecules. 2025 Apr 29. pii: 638. [Epub ahead of print]15(5):

From Obesity to Mitochondrial Dysfunction in Peripheral Tissues and in the Central Nervous System.

Francesca Marino, Lidia Petrella, Fabiano Cimmino, Amelia Pizzella, Antonietta Monda, Salvatore Allocca, Roberta Rotondo, Margherita D'Angelo, Nadia Musco, Piera Iommelli, Angela Catapano, Carmela Bagnato, Barbara Paolini, Gina Cavaliere.

  Obesity is a condition of chronic low-grade inflammation affecting peripheral organs of the body, as well as the central nervous system. The adipose tissue dysfunction occurring under conditions of obesity is a key factor in the onset and progression of a variety of diseases, including neurodegenerative disorders. Mitochondria, key organelles in the production of cellular energy, play an important role in this tissue dysfunction. Numerous studies highlight the close link between obesity and adipocyte mitochondrial dysfunction, resulting in excessive ROS production and adipose tissue inflammation. This inflammation is transmitted systemically, leading to metabolic disorders that also impact the central nervous system, where pro-inflammatory cytokines impair mitochondrial and cellular functions in different areas of the brain, leading to neurodegenerative diseases. To date, several bioactive compounds are able to prevent and/or slow down neurogenerative processes by acting on mitochondrial functions. Among these, some molecules present in the Mediterranean diet, such as polyphenols, carotenoids, and omega-3 PUFAs, exert a protective action due to their antioxidant and anti-inflammatory ability. The aim of this review is to provide an overview of the involvement of adipose tissue dysfunction in the development of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and multiple sclerosis, emphasizing the central role played by mitochondria, the main actors in the cross-talk between adipose tissue and the central nervous system.

Keywords:  Alzheimer’s disease; Parkinson’s disease; adipose tissue; mitochondria; multiple sclerosis; neurodegenerative disorders; obesity

DOI:  https://doi.org/10.3390/biom15050638
Biomolecules. 2025 Apr 23. pii: 614. [Epub ahead of print]15(5):

Targeting the Electron Transport System for Enhanced Longevity.

Marko Radovic, Lucas P Gartzke, Simon E Wink, Joris A van der Kleij, Frouwkje A Politiek, Guido Krenning.

  Damage to mitochondrial DNA (mtDNA) results in defective electron transport system (ETS) complexes, initiating a cycle of impaired oxidative phosphorylation (OXPHOS), increased reactive oxygen species (ROS) production, and chronic low-grade inflammation (inflammaging). This culminates in energy failure, cellular senescence, and progressive tissue degeneration. Rapamycin and metformin are the most extensively studied longevity drugs. Rapamycin inhibits mTORC1, promoting mitophagy, enhancing mitochondrial biogenesis, and reducing inflammation. Metformin partially inhibits Complex I, lowering reverse electron transfer (RET)-induced ROS formation and activating AMPK to stimulate autophagy and mitochondrial turnover. Both compounds mimic caloric restriction, shift metabolism toward a catabolic state, and confer preclinical-and, in the case of metformin, clinical-longevity benefits. More recently, small molecules directly targeting mitochondrial membranes and ETS components have emerged. Compounds such as Elamipretide, Sonlicromanol, SUL-138, and others modulate metabolism and mitochondrial function while exhibiting similarities to metformin and rapamycin, highlighting their potential in promoting longevity. The key question moving forward is whether these interventions should be applied chronically to sustain mitochondrial health or intermittently during episodes of stress. A pragmatic strategy may combine chronic metformin use with targeted mitochondrial therapies during acute physiological stress.

Keywords:  biomolecules; drug targeting; electron transport system; longevity; mitochondria

DOI:  https://doi.org/10.3390/biom15050614
Int J Mol Sci. 2025 May 13. pii: 4652. [Epub ahead of print]26(10):

Melatonin Improves Lipid Homeostasis, Mitochondrial Biogenesis, and Antioxidant Defenses in the Liver of Prediabetic Rats.

Milena Cremer de Souza, Maria Luisa Gonçalves Agneis, Karoliny Alves das Neves, Matheus Ribas de Almeida, Geórgia da Silva Feltran, Ellen Mayara Souza Cruz, João Paulo Ferreira Schoffen, Luiz Gustavo de Almeida Chuffa, Fábio Rodrigues Ferreira Seiva.

  Type 2 diabetes mellitus represents a major global health burden and is often preceded by a prediabetic state characterized by insulin resistance and metabolic dysfunction. Mitochondrial alterations, oxidative stress, and disturbances in lipid metabolism are central to the prediabetes pathophysiology. Melatonin, a pleiotropic indolamine, is known to regulate metabolic and mitochondrial processes; however, its therapeutic potential in prediabetes remains poorly understood. This study investigated the effects of melatonin on energy metabolism, oxidative stress, and mitochondrial function in a rat model of prediabetes induced by chronic sucrose intake and low-dose streptozotocin administration. Following prediabetes induction, animals were treated with melatonin (20 mg/kg) for four weeks. Biochemical analyses were conducted to evaluate glucose and lipid metabolism, and mitochondrial function was assessed via gene expression, enzymatic activity, and oxidative stress markers. Additionally, hepatic mitochondrial dynamics were examined by quantifying key regulators genes associated with biogenesis, fusion, and fission. Prediabetic animals exhibited dyslipidemia, hepatic lipid accumulation, increased fat depots, and impaired glucose metabolism. Melatonin significantly reduced serum glucose, triglycerides, and total cholesterol levels, while enhancing the hepatic high-density lipoprotein content. It also stimulated β-oxidation by upregulating hydroxyacyl-CoA dehydrogenase and citrate synthase activity. Mitochondrial dysfunction in prediabetic animals was evidenced by the reduced expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha and mitochondrial transcription factor A, both of which were markedly upregulated by melatonin. The indolamine also modulated mithocondrial dynamics by regulating fusion and fission markers, including mitosuin 1 and 2, optic atrophy protein, and dynamin-related protein. Additionally, melatonin mitigated oxidative stress by enhancing the activity of superoxide dismutase and catalase while reducing lipid peroxidation. These findings highlight melatonin's protective role in prediabetes by improving lipid and energy metabolism, alleviating oxidative stress, and restoring mitochondrial homeostasis. This study provides novel insights into the therapeutic potential of melatonin in addressing metabolic disorders, particularly in mitigating mitochondrial dysfunction associated with prediabetes.

Keywords:  energy metabolism; melatonin; mitochondrial dynamics; oxidative stress; prediabetes

DOI:  https://doi.org/10.3390/ijms26104652
Biol Chem. 2025 May 27.

The mitochondrial intermembrane space - a permanently proteostasis-challenged compartment.

Matthias Weith, Konstantin Weiss, Dylan Stobbe, Jan Riemer.

  The mitochondrial intermembrane space (IMS) houses proteins essential for redox regulation, protein import, signaling, and energy metabolism. Protein import into the IMS is mediated by dedicated pathways, including the disulfide relay pathway for oxidative folding. In addition, various IMS-traversing import pathways potentially expose unfolded proteins, representing threats to proteostasis. This trafficking of precursors coincides with unique biophysical challenges in the IMS, including a confined volume, elevated temperature, variable pH and high levels of reactive oxygen species. Ultrastructural properties and import supercomplex formation ameliorate these challenges. Nonetheless, IMS proteostasis requires constant maintenance by chaperones, folding catalysts, and proteases to counteract misfolding and aggregation. The IMS plays a key role in stress signaling, where proteostasis disruptions trigger responses including the integrated stress response (ISR) activated by mitochondrial stress (ISRmt) and responses to cytosolic accumulation of mitochondrial protein precursors. This review explores the biology and mechanisms governing IMS proteostasis, presents models, which have been employed to decipher IMS-specific stress responses, and discusses open questions.

Keywords:  IMS; mitochondria; protein import; proteostasis; stress responses

DOI:  https://doi.org/10.1515/hsz-2025-0108
Eur J Pharm Sci. 2025 May 22. pii: S0928-0987(25)00136-8. [Epub ahead of print]211 107137

cGAS-STING targeting offers a novel therapeutic paradigm in cardiovascular diseases.

Yu Wang, Weixue Wang, Yi Zhang, Pu Gao, Joshua S Fleishman, Hongquan Wang.

  Cyclic GMP/AMP (cGAMP) synthase (cGAS), along with the endoplasmic reticulum (ER)-associated stimulator of interferon genes (STING), are crucial elements of the type 1 interferon response. cGAS senses microbial DNA and self-DNA, labeling cGAS-STING as a crucial mechanism in autoimmunity, sterile inflammatory responses, and cellular senescence. However, chronic and aberrant activation of the cGAS/STING axis results in inflammatory and autoimmune diseases. cGAS-STING has emerged as a vital mechanism driving inflammation-related diseases, including cardiovascular diseases (CVDs). Insights into the biology of the cGAS-STING pathway have enabled the discovery of small-molecule agents which have the potential to inhibit the cGAS-STING axis in many human diseases. In this review, we first outline the principal components of the cGAS-STING signaling cascade. From such we discuss recent research that highlights general mechanisms by which cGAS-STING contributes to CVDs. Then, we summarize a list of bioactive small-molecule compounds which modulate the cGAS-STING axis, reviewing their potential clinical applications. Finally, we discuss key limitations of this new proposed therapeutic approach and provide possible techniques to overcome them.These review highlights a novel groundbreaking therapeutic possibilities through targeting cGAS-STING in CVDs.

Keywords:  Cardiovascular diseases; STING;Antagonist; cGAS

DOI:  https://doi.org/10.1016/j.ejps.2025.107137
EPMA J. 2025 Jun;16(2): 239-264

Mitochondrial medicine: "from bench to bedside" 3PM-guided concept.

Qianwen Shao, Marie Louise Ndzie Noah, Olga Golubnitschaja, Xianquan Zhan.

  Mitochondria are the primary sites for aerobic respiration and play a vital role in maintaining physiologic function at the cellular and organismal levels. Physiologic mitochondrial homeostasis, functions, health, and any kind of mitochondrial impairments are associated with systemic effects that are linked to the human health and pathologies. Contextually, mitochondria are acting as a natural vital biosensor in humans controlling status of physical and mental health in a holistic manner. So far, no any disorder is known as happening to humans independently from a compromised mitochondrial health as the cause (primary mitochondrial dysfunction) or a target of collateral damage (secondary mitochondrial injury). This certainty makes mitochondrial medicine be the superior instrument to reach highly ambitious objectives of predictive, preventive, and personalized medicine (PPPM/3PM). 3PM effectively implements the paradigm change from the economically ineffective reactive medical services to a predictive approach, targeted prevention and treatments tailored to individualized patient profiles in primary (protection against health-to-disease transition) and secondary (protection against disease progression) healthcare. Mitochondrial DNA (mtDNA) properties differ significantly from those of nuclear DNA (nDNA). For example, mtDNA as the cell-free DNA molecule is much more stable compared to nDNA, which makes mtDNA be an attractive diagnostic target circulating in human body fluids such as blood and tear fluid. Further, genetic variations in mtDNA contribute to substantial individual differences in disease susceptibility and treatment response. To this end, the current gene editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas, are still immature in mtDNA modification, and cannot be effectively applied in clinical practice posing a challenge for mtDNA-based therapies. In contrast, comprehensive multiomics technologies offer new insights into mitochondrial homeostasis, health, and functions, which enables to develop more effective multi-level diagnostics and targeted treatment strategies. This review article highlights health- and disease-relevant mitochondrial particularities and assesses involvement of mitochondrial medicine into implementing the 3PM objectives. By discussing the interrelationship between 3PM and mitochondrial medicine, we aim to provide a foundation for advancing early and predictive diagnostics, cost-effective targeted prevention in primary and secondary care, and exemplify personalized treatments creating proof-of-concept approaches for 3PM-guided clinical applications.

Keywords:  Autophagy and mitophagy; Cancer; Cardio-vascular disease; Chronic Fatigue; Cost-effective tailored treatments; Environment; Health policy; Health-to-disease transition; Individualized patient profile; Metabolic disease; Mitochondrial medicine; Neurodegeneration; Predictive Preventive Personalized Medicine (PPPM / 3PM / 3P medicine); Signaling; Stress; Vital biosensor

DOI:  https://doi.org/10.1007/s13167-025-00409-4
FASEB J. 2025 Jun 15. 39(11): e70655

Aerobic Capacity Beyond Cardiorespiratory Fitness Linking Mitochondrial Function, Disease Resilience and Healthy Aging.

Tian Gao, Yang Hu, Huifeng Zhang, Rongpei Shi, Yang Song, Mingge Ding, Feng Gao.

  Aerobic capacity is conventionally equated with cardiorespiratory fitness (CRF), but its physiological essence extends far beyond cardiopulmonary performance. Aerobic capacity is an integrative physiological indicator reflecting the entire process from oxygen uptake and transport to mitochondrial energy conversion, with mitochondrial function constituting its molecular core. Emerging evidence reveals robust associations between diminished aerobic capacity and increased risks of non-communicable chronic diseases and age-related functional decline. However, its potential as a valuable tool for early disease detection and intervention remains undervalued in clinical practice. By synthesizing recent clinical and experimental studies, we highlight the crucial role of aerobic capacity, particularly its mechanistic links to impaired mitochondrial function, which drives disease progression through impaired energy metabolism and chronic inflammation. Furthermore, exercise interventions designed to enhance aerobic capacity have shown promise in improving mitochondrial efficiency, promoting cardiometabolic adaptation, and boosting overall health, thus offering an effective strategy for chronic disease prevention. We advocate for inclusion of aerobic capacity assessments in routine health evaluations and emphasize the need to integrate aerobic capacity optimization into public health frameworks to advance preventive strategies against chronic diseases and promote healthy aging.

Keywords:  aerobic capacity; cardiorespiratory fitness; exercise; mitochondria; non‐communicable diseases

DOI:  https://doi.org/10.1096/fj.202500554R