bims-mistre 2025-08-24 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–08–24
ten papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondrial Quality Control in Health and Disease.
Metabolic Messenger: growth differentiation factor 15.
Mitochondria as a Therapeutic Target in Neurodegeneration: Strategies for Restoring Cellular Homeostasis.
Loss of Drosophila ribosomal protein S6 kinase II causes mitochondrial dysfunction and cell death.
Different association of GDF15 and FGF21 with glycemic status and aging in the context of obesity.
SIRT3 mitigates osteoarthritis by suppressing ferroptosis through activating AMPK signaling pathway.
Urolithin A protects against domoic acid-induced cognitive deficits via promoting estrogen receptor-α-mediated mitochondrial biogenesis signaling in mice.
NDUFB9 ameliorates CUMS-induced depression-like behavior by promoting mitophagy.
What Is the Potential Relevance of Growth and Differentiation Factor-15 in Neurologic Disease?
NADPH Oxidase Inhibition Promotes Brain Resilience by Attenuating Tauopathy and Neuroinflammation in Alzheimer's Disease.

MedComm (2020). 2025 Aug;6(8): e70319

Mitochondrial Quality Control in Health and Disease.

Lin Ye, Xinzhi Fu, Qi Li.

  Mitochondria are central regulators of cellular energy metabolism, and their functional integrity is essential for maintaining cellular homeostasis. Mitochondrial quality control (MQC) encompasses a coordinated network of mitochondrial biogenesis, dynamics (fusion and fission), and selective autophagy (mitophagy), which together sustain mitochondrial structure and function. Under physiological conditions, MQC ensures the removal of dysfunctional mitochondria, restricts excessive reactive oxygen species production, and modulates apoptosis, thereby supporting the high energy demands of organs such as the heart and brain. Disruption of MQC contributes to the onset and progression of various diseases, including neurodegenerative disorders, cardiovascular pathologies, and metabolic syndromes, largely through accumulation of damaged mitochondria and impaired metabolic signaling. While the core components of MQC have been characterized, the mechanistic interplay among its modules and their disease-specific alterations remain incompletely defined. This review provides an integrated overview of the molecular pathways governing mitochondrial biogenesis, dynamics, and mitophagy, with a focus on their cross-talk in maintaining mitochondrial homeostasis. We further discuss how MQC dysfunction contributes to disease pathogenesis and examine emerging therapeutic approaches aimed at restoring mitochondrial quality. Understanding the regulatory logic of MQC not only elucidates fundamental principles of cellular stress adaptation but also informs novel strategies for disease intervention.

Keywords:  disease intervention; mitochondria; mitochondrial quality control; therapeutic strategies

DOI:  https://doi.org/10.1002/mco2.70319
Nat Metab. 2025 Aug 18.

Metabolic Messenger: growth differentiation factor 15.

Samuel N Breit, Vicky W Tsai.

Growth differentiation factor 15 (GDF15; also known as macrophage-inhibitory cytokine-1) is a stress-responsive cytokine that is overexpressed under a broad range of conditions. It has a role in regulating appetite and body weight and is an aetiological factor in anorexia-cachexia syndromes, as well as nausea and vomiting during pregnancy. Long after its original cloning, its receptor was identified as GFRAL, a distant member of the GDNF receptor family within the TGFβ superfamily, with RET as its co-receptor. Both of these are highly localized to specific hindbrain regions. Although many of GFRAL's metabolic changes may be linked to its effect on suppressing appetite, recent findings suggest that GDF15 also independently regulates energy expenditure and insulin sensitivity. Here, we review recent literature and provide updates on the current understanding of GDF15 biology and its therapeutic applications in health and metabolic diseases.

DOI: https://doi.org/10.1038/s42255-025-01353-3
Curr Neuropharmacol. 2025 Aug 12.

Mitochondria as a Therapeutic Target in Neurodegeneration: Strategies for Restoring Cellular Homeostasis.

Bartosz Twarowski, Iwona Piątkowska-Chmiel, Mariola Herbet.

  Ageing is a complex biological process marked by a gradual decline in bodily functions at the cellular, tissue, and organ levels, resulting from molecular damage and environmental influences. It increases disease risk, particularly in older adults with neurodegenerative conditions characterized by progressive neuronal loss and neurological symptoms such as cognitive and motor impairments. Key mechanisms include abnormal protein accumulation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Disruption of cellular homeostasis prevents the maintenance of internal conditions such as pH and glucose levels. Mitochondria, known as the cell's "powerhouses," are essential for ATP production, DNA protection, and metabolic regulation, supporting cellular structures. Their dysfunction plays a crucial role in the progression of neurodegenerative diseases. Factors like chronic inflammation, ATP deficiency, excessive production of reactive oxygen species (ROS), and calcium imbalance leads to oxidative stress and neuronal damage, exacerbating neurodegeneration. Current therapies mainly focus on symptom relief, emphasizing the urgent need for new treatment strategies. Given the key role of mitochondrial dysfunction, therapies aiming to restore mitochondrial homeostasis are gaining increasing attention. Mitochondrial antioxidants such as MitoQ, MitoTEMPO, and SkQ1 have shown neuroprotective, anti-inflammatory, and antioxidant properties. Research into their therapeutic potential may lead to the development of effective drugs that restore mitochondrial function and improve quality of life of the patienst.

Keywords:  Mitochondrial antioxidants; mitochondrial dysfunction.; neurodegenerative diseases; neuropharmacology; toxicology

DOI:  https://doi.org/10.2174/011570159X389970250727031306
Dis Model Mech. 2025 Aug 01. pii: dmm052374. [Epub ahead of print]18(8):

Loss of Drosophila ribosomal protein S6 kinase II causes mitochondrial dysfunction and cell death.

Ting Deng, Lajos Kalmar, Samantha Loh, Olivier E Pardo, L Miguel Martins.

  Mitochondria are dynamic organelles that are critical for energy production in high-demand tissues, such as the brain and muscle, with fusion and fission maintaining network integrity. The dysregulation of these processes underlies pathologies, such as neurodegenerative diseases. Ribosomal S6 kinases (RSK1-4) are effectors of extracellular signal-regulated kinases (ERKs), with roles in cell survival and metabolism. Here, we show that RSKs are essential for mitochondrial health. In human cells, siRNAs targeting any RSK isoform (RSK1-4) induced mitochondrial fragmentation and reduced viability. In Drosophila melanogaster, CRISPR-mediated loss of S6kII (the sole RSK orthologue) caused mitochondrial dysfunction and tissue degeneration in high-energy-demand organs, including the indirect flight muscle and brain, accompanied by autophagic activation. Notably, we rescued these defects by expressing human RSK4, underscoring functional conservation. Our findings establish RSKs as critical regulators of mitochondrial integrity, linking ERK signalling to organelle dynamics. This work identifies RSKs as regulators of mitochondrial health in energy-demanding tissues, providing insights into the mechanisms underlying neurodegeneration and strategies to target ERK/RSK-driven mitochondrial dysfunction.

Keywords:   Drosophila ; Cell death; Kinase; Mitochondria

DOI:  https://doi.org/10.1242/dmm.052374
Geroscience. 2025 Aug 19.

Different association of GDF15 and FGF21 with glycemic status and aging in the context of obesity.

Laura Salmón-Gómez, Victoria Catalán, Beatriz Ramírez, Maite Aguas-Ayesa, Amaia Rodríguez, Sara Becerril, Jorge Baixauli, Sonsoles Gutiérrez-Medina, Carmen Mugueta, Inmaculada Colina, Carolina M Perdomo, Camilo Silva, Javier Escalada, Gema Frühbeck, Javier Gómez-Ambrosi.

  Growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) are stress-induced cytokines increased in age-related and metabolic disorders. The aim of the present study was to analyze the association between circulating concentrations of GDF15 and FGF21 in obesity and type 2 diabetes (T2D) in the context of aging. Serum samples from 405 participants (33 with normal weight and normoglycemia (NG), 156 with obesity and NG, 157 with obesity and impaired glucose tolerance (IGT), and 59 with obesity and T2D) aged 47 ± 13 years, were recruited to study the serum GDF15 and FGF21 concentrations and their relationship with obesity, T2D, and aging. Adipokines (leptin and adiponectin) and other cardiometabolic risk factors were also measured. The circulating concentrations of GDF15 and FGF21 were significantly increased with obesity and further increased with IGT and T2D. Both GDF15 and FGF21 showed positive associations with glucose (r = 0.25, P < 0.001 and r = 0.40, P < 0.001, respectively) and insulin (r = 0.16, P < 0.01 and r = 0.27, P < 0.001, respectively) levels. Similarly, GDF15 and FGF21 were positively correlated with age (r = 0.55, P < 0.001 and r = 0.15, P < 0.01, respectively). Interestingly, the FGF21/adiponectin and GDF15/adiponectin ratios emerged as good biomarkers for the presence of T2D (AUC = 0.807 and 0.779, respectively). Our findings support that obesity, T2D, and aging increase the concentrations of both GDF15 and FGF21. Furthermore, GDF15 concentrations are more associated with aging while FGF21 levels are more related to the metabolic status. Finally, we propose the FGF21/adiponectin ratio as a novel biomarker for the detection of the presence of T2D.

Keywords:  Aging; FGF21; FGF21/adiponectin ratio; GDF15; Obesity; Type 2 diabetes

DOI:  https://doi.org/10.1007/s11357-025-01830-3
Cell Signal. 2025 Aug 14. pii: S0898-6568(25)00478-4. [Epub ahead of print]135 112063

SIRT3 mitigates osteoarthritis by suppressing ferroptosis through activating AMPK signaling pathway.

Weiyu Tian, Zijing Yang, Mingkai Yu, Tao Ma, Zefan Guo, Wenhao Weng, Xuanchen Ren, Wenxuan Li, Weishan Wang, Nannan Pang, Zhendong Zhang.

   BACKGROUND: Osteoarthritis (OA) is characterized by cartilage degeneration and inflammatory environments that promote chondrocyte death via mechanisms including ferroptosis. SIRT3-AMPK activation inhibits inflammatory and catabolic responses in chondrocytes. However, its potential effect on chondrocyte ferroptosis remains unclear.
OBJECTIVE: This study aimed to elucidate the effects of SIRT3 on ferroptosis in chondrocytes under inflammatory conditions and the underlying mechanisms involving the AMPK/mTOR signaling pathway.
METHODS: Mendelian randomization was used to analyze the epidemiological relationship between SIRT3 expression and the occurrence of knee OA. ATDC5 cells were treated with IL-1β, TNF-α, or ferroptosis agonist/antagonist. SIRT3 was overexpressed in ATDC5 cells. The effects of SIRT3 on extracellular matrix metabolism, mitochondrial function, and ferroptosis were detected by Western blot, immunofluorescence, JC-1 staining, quantitative real-time PCR, and Alcian blue staining. In vivo experiments were conducted using mice subjected to destabilization of the medial meniscus to mimic OA. Then, micro-CT, histological analyses, and protein expression detections were conducted.
RESULTS: Mendelian randomization identified SIRT3 expression as a protective factor in the development of knee OA. In vitro, IL-1β and TNF-α induced ferroptosis and oxidative stress in ATDC5 cells while down-regulating SIRT3. Treatment with the ferroptosis agonist Erastin or the antagonist Fer-1 resulted in decreased or increased protein levels of SIRT3, respectively. SIRT3 overexpression mitigated the degradation of the extracellular matrix, alleviated oxidative stress, modulated mitochondrial functions, and prevented ferroptosis in ATDC5 cells under IL-1β treatment in vitro. Furthermore, the effects of SIRT3 may be mediated by the AMPK/mTOR signaling pathway. In vivo, SIRT3 overexpression mitigated OA severity, evidenced by improved joint integrity and reduced cartilage degradation.
CONCLUSIONS: SIRT3 inhibits ferroptosis and regulates mitochondrial function via the AMPK/mTOR signaling pathway, thereby alleviating OA. Targeting the SIRT3-AMPK axis presents a promising therapeutic method for OA treatment.

Keywords:  AMPK/mTOR; Chondrocyte; Ferroptosis; Osteoarthritis; SIRT3

DOI:  https://doi.org/10.1016/j.cellsig.2025.112063
Free Radic Biol Med. 2025 Aug 14. pii: S0891-5849(25)00904-9. [Epub ahead of print]

Urolithin A protects against domoic acid-induced cognitive deficits via promoting estrogen receptor-α-mediated mitochondrial biogenesis signaling in mice.

Peng Chen, Jiexin Lei, Ruixiang Li, Ru Liu, Benhong Zhou.

  Recent studies have indicated that stress in the endoplasmic reticulum (ER) plays a role in the development of domoic acid-induced neurodegeneration. Urolithin A (Uro A) is an active metabolite of the plant polyphenol ellagic acid, which is generated by intestinal flora and offers positive health and biological benefits. Recent research has indicated that anthocyanins possess estrogenic properties and can boost the expression of estrogen receptor-α (ERα). In this study, we examined the effects of Uro A on cognitive deficits resulting from hippocampal mitochondrial dysfunction in mice exposed to domoic acid (DA) and explored the underlying mechanisms. Oral administration of Uro A to the DA-treated mice significantly improved their performance in behavioral tasks, such as step-through passive avoidance, Morris water maze, and open field test. These advancements were, to some extent, driven by the stimulation of mitochondrial biogenesis signaling through estrogen receptor-α and also by lowered expression levels of p47phox and gp91phox. A reduction in reactive oxygen species and protein carbonylation was noted, along with the inhibition of the signaling pathway related to ER stress. Moreover, Uro A greatly reduced ER stress-induced apoptosis, which prevented synaptic damage and restored the expression of memory-related proteins. The partial attenuation of the neuroprotective effects of Uro A in the mice given a combination of Uro A and DA, following the knockdown of ERα via short hairpin RNA, suggests that Uro A exerts its effects via several routes. Our findings imply that Uro A can be used to prevent and treat cognitive deficits associated with excitotoxicity and other brain disorders.

Keywords:  Cognitive deficits; ERα; Endoplasmic reticulum stress; Mitochondrial biogenesis; Urolithin A

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.024
Transl Psychiatry. 2025 Aug 18. 15(1): 292

NDUFB9 ameliorates CUMS-induced depression-like behavior by promoting mitophagy.

Ye Sun, Liya Li, Xianglong Yang, Shengming Yin, Zhaoyang Xiao.

Major depressive disorder (MDD) is characterized by persistent low mood and anhedonia. Mitochondrial dysfunction is linked to MDD, but the mechanisms are unclear. In this study, transcriptomic analysis of MDD patients' peripheral blood found three key genes: TFAM, SURF1, and NDUFB9. Single-cell transcriptomic analysis of the prefrontal cortex (PFC) in MDD patients identified seven cell types. Analysis showed strong interactions between excitatory and inhibitory neurons in the PFC, with the three genes mainly in inhibitory neurons and NDUFB9 having the highest expression. We then established a chronic unpredictable mild stress (CUMS) mouse model. CUMS exposure induced depressive-like behaviors in mice, as evidenced by decreased sucrose preference, increased immobility time in the forced swim, and reduced activity and frequency of entries into the central area in the open field. Moreover, CUMS-exposed mice exhibited mitochondrial dysfunction in the prefrontal cortex (PFC). Notably, the expressions of TFAM, SURF1, and NDUFB9 were decreased in the PFC of CUMS mice, with the most significant decrease observed in NDUFB9. Subsequently, the overexpression of NDUFB9 in CUMS-treated mice significantly alleviated depressive-like behaviors, restored mitochondrial function and reduced the death of inhibitory neurons. It also enhanced mitophagy by PINK1/Parkin pathway. Inhibiting autophagy and mitophagy confirmed mitophagy's pivotal role in NDUFB9-mediated restoration. Co-IP and protein half-life assays revealed that NDUFB9 stabilizes PINK1, thereby promoting mitophagy. In conclusion, our findings reveal a novel role of NDUFB9 on alleviating depression-like behavior by enhancing mitophagy, suggesting that targeting NDUFB9 could offer a promising therapeutic strategy for MDD.

DOI: https://doi.org/10.1038/s41398-025-03502-4
Neurology. 2025 Sep 09. 105(5): e214131

What Is the Potential Relevance of Growth and Differentiation Factor-15 in Neurologic Disease?

Eduardo Benarroch.

Growth and differentiation factor-15 (GDF-15) is a multifunctional cytokine that is a distant member of both the transforming growth factor-beta (TGF-β) superfamily and glial cell-derived neurotrophic factor (GDNF) family.1-6 GDF-15 is released in physiologic conditions, such as pregnancy or muscle exercise, but its levels increase particularly in the setting of cellular stress associated with mitochondrial dysfunction and tissue injury.7,8 GDF-15 is a central inhibitor of appetite9,10 and regulates energy homeostasis,2-5 inflammation,11 and carcinogenesis12 (Figure). The effects of GDF-15 signaling can be beneficial or detrimental, depending on their timing, magnitude, and duration.5 Circulating levels of GDF-15 increase with aging and can be markedly elevated in several pathologic conditions, including obesity, diabetes, renal disease, cardiovascular disease, and cancer, where they are typically associated with poor outcomes.13-17 The role of GDF-15 in the pathogenesis and as a biomarker and therapeutic target in these disorders has been extensively reviewed4-6 and will not be further discussed here. Circulating GDF-15 levels also increase in patients with diabetic peripheral neuropathy,18 mitochondrial myopathy,19 neurodegenerative disorders,20-22 and glioma.23 Although experimental evidence suggests that GDF-15 may have a potential neuroprotective role against neurodegeneration22,24 and a detrimental role in glioma,24 its role as a biomarker and therapeutic target in neurologic disorders is yet to be established.

DOI: https://doi.org/10.1212/WNL.0000000000214131
Adv Sci (Weinh). 2025 Aug 18. e05495

NADPH Oxidase Inhibition Promotes Brain Resilience by Attenuating Tauopathy and Neuroinflammation in Alzheimer's Disease.

Jihyeon Lee, Seunghwan Sim, Yinglan Jin, Hyejun Park, Eun Young Byeon, Su Jin Kim, Sujin Yun, Hye Eun Lee, Da Un Jeong, Jung Min Suh, In Hye Lee, Ho-Young Lee, Yongseok Choi, Yun Soo Bae.

  Alzheimer's disease (AD) associates closely associated with the activation of NADPH oxidase (Nox) isozymes. CRB-2131, a novel oxadiazole derivative, is identified as a potently suppresses Nox isozymes. It inhibits reactive oxygen species production (ROS) by hippocampal neuronal and microglial cells and reduces microglial activation. Prophylactic (starting at 3.5 months of age) and therapeutic (starting at 6 months of age) oral administration with CRB-2131 for 10 weeks in 5XFAD mice reduced hippocampal superoxide levels, lipid peroxidation, Tau phosphorylation, and neuroinflammation. Prophylactic and therapeutic CRB-2131 treatment of 5XFAD mice restored their impaired cognition as shown by the novel-object recognition, Y-maze, and Morris water-maze tests. CRB-2131 treatment increased mature neurons, reduced apoptotic mature neurons, and elevated immature neurons in the hippocampus. Positron-emission tomography/computed-tomography imaging confirmed that CRB-2131 stimulated neuronal regeneration. CRB-2131 suppresses brain oxidation, tauopathy, and neuroinflammation, thereby preventing mature neuron death and promoting neuron regeneration. Ultimately, this fosters a resilient brain and protects cognition.

Keywords:  NADPH oxidase inhibitor; alzheimer's disease; brain resilience; neuroinflammation; tauopathy

DOI:  https://doi.org/10.1002/advs.202505495