bims-mistre 2025-01-05 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–01–05
eight papers selected by
Ellen Siobhan Mitchell, MitoQ

Basic Science and Pathogenesis.
EGCG activates Keap1/P62/Nrf2 pathway, inhibits iron deposition and apoptosis in rats with cerebral hemorrhage.
Berberine alleviates AGEs-induced ferroptosis by activating NRF2 in the skin of diabetic mice.
Basic Science and Pathogenesis.
Basic Science and Pathogenesis.
Basic Science and Pathogenesis.
Repairing muscle with broccoli-derived sulforaphane: A preclinical evaluation for the treatment of mitochondrial myopathies.
Basic Science and Pathogenesis.

Alzheimers Dement. 2024 Dec;20 Suppl 1 e086909

Basic Science and Pathogenesis.

Gherardo Baudo.

BACKGROUND: Findings have demonstrated that mitochondrial dysfunction is vital to Alzheimer's Disease (AD) pathogenesis and progression. This study explored an innovative treatment strategy involving transfer of polymer-functionalized, healthy mitochondria to AD neurons. We hypothesized that this organelle transplantation approach would restore mitochondrial function and bioenergetics, preventing aberrant neuronal dynamics associated with AD.
METHOD: Neuronal cells (SH-SY5Y) were stimulated with amyloid-β (Aβ1-42). Mitochondria were functionalized with dextran-triphenylphosphonium (Dex-TPP/Mt) and administered to neurons. Internalization of Dex-TPP/Mt was assessed, as was the effect of mitochondrial transfer on Aβ-treated SH-SY5Y cell ROS levels, mitochondrial membrane potential, mitochondrial dynamics, ATP levels, and apoptosis.
RESULT: Dex-TPP/Mt underwent efficient internalization into Aβ-treated SH-SY5Y cells. The treatment reduced intracellular ROS levels and restored mitochondrial membrane potential. Mitochondrial quality control was also re-established, as mitochondrial fusion and fission processes were balanced and mitophagy reduced. Dex-TPP/Mt treated neurons also increased ATP levels. Notably, mitochondrial transfer modulated the Bax/Bcl-2 ratio, inhibited caspase-3 activation, and suppressed the pJNK pathway, highlighting reduced neuronal apoptosis that was confirmed by Annexin V assay.
CONCLUSION: Mitochondrial transfer has potential as a therapeutic approach for AD. The treatment highlighted herein effectively mitigated the impact of Aβ on neuronal health by targeting mitochondrial dysfunction and oxidative stress. This opens several avenues for similar strategies aimed at addressing dysregulated bioenergetics and mitochondrial dynamics in AD.

DOI: https://doi.org/10.1002/alz.086909
Sci Rep. 2024 Dec 28. 14(1): 31474

EGCG activates Keap1/P62/Nrf2 pathway, inhibits iron deposition and apoptosis in rats with cerebral hemorrhage.

Liang Hao, Aobo Zhang, Dongsheng Lv, LuLu Cong, Zhimin Sun, Liqiang Liu.

  Intracerebral hemorrhage (ICH) is a common cerebrovascular disease characterized by a high incidence, disability rate, and mortality. Epigallocatechin gallate (EGCG), a key catechin compound found in green tea, has received increasing attention for its potential neuroprotective and therapeutic effects in neurological disorders. Studies have indicated that EGCG may influence various signaling pathways and molecular targets, including the inhibition of oxidative stress, reduction of inflammatory responses, suppression of cell apoptosis, regulation of cell survival, and enhancement of autophagy. Although the exact mechanism of action of EGCG is not fully understood, it has become a focal point of research in various disciplines due to its promising potential. This study aims to investigate the effects of EGCG on oxidative stress, iron deposition, and cell apoptosis in rats with ICH, as well as to uncover the underlying mechanisms. An ICH rat model was created to simulate cerebral hemorrhage, while an in vitro model utilizing primary cortical neurons was developed. The neurons were pre-treated with EGCG before being exposed to Erastin and RSL3 to induce iron death. The levels of oxidative stress, iron deposition, and cell apoptosis were evaluated in both models. In the ICH model, EGCG was discovered to enhance the activation of the Keap1/P62/Nrf2 signaling pathway in both in vivo and in vitro studies. Furthermore, EGCG significantly elevated the levels of GPX4 and XCT proteins, as well as the nuclear expression of Nrf2. It was noted that the Nrf2 inhibitor ML385 partially decreased the expression of these proteins. Through the activation of the Keap1/P62/Nrf2 pathway, EGCG inhibits inflammation, oxidative stress and iron deposition in rats with cerebral hemorrhage. EGCG inhibits oxidative stress, iron deposition and apoptosis in rats with ICH by activating Keap1/P62/Nrf2 pathway.

Keywords:  Cell apoptosis; EGCG; Ferroptosis; Intracerebral hemorrhage; Oxidative stress

DOI:  https://doi.org/10.1038/s41598-024-82938-y
Exp Biol Med (Maywood). 2024 ;249 10280

Berberine alleviates AGEs-induced ferroptosis by activating NRF2 in the skin of diabetic mice.

Chunjie Jiang, Guojuan Lao, Jianmin Ran, Ping Zhu.

  Advanced glycation end products (AGEs) have adverse effects on the development of diabetic complications. Berberine (BBR), a natural alkaloid, has demonstrated its ability to promote the delayed healing of skin wounds. However, the impact of BBR on AGEs-induced ferroptosis in skin cells and the underlying molecular mechanisms remains unexplored. This study investigated the involvement of ferroptosis in AGEs-induced keratinocyte death, and the impact of BBR on ferroptosis in a db/db mouse model with long-term hyperglycemia was elucidated. A remarkable reduction in cell viability was observed along with increased malondialdehyde (MDA) production in AGEs-induced HaCaT cells. Intracellular reactive oxygen species (ROS) and iron levels were elevated in cells exposed to AGEs. Meanwhile, the protein expression of glutathione peroxidase 4 (GPX4) and ferritin light chain (FTL) was significantly decreased in AGEs-treated cells. However, pretreatment with BBR markedly protected cell viability and inhibited MDA levels, attenuating the intracellular ROS and iron levels and increased expression of GPX4 and FTL in vitro. Significantly diminished antiferroptotic effects of BBR on AGEs-treated keratinocytes were observed upon the knockdown of the nuclear factor E2-related factor 2 (NRF2) gene. In vivo, GPX4, FTL, and FTH expression in the epidermis of diabetic mice was significantly reduced, accompanied by enhanced lipid peroxidation. Treatment with BBR effectively rescued lipid peroxidation accumulation and upregulated GPX4, FTL, FTH, and NRF2 levels in diabetic skin. Collectively, the findings indicate that ferroptosis may play a significant role in AGEs-induced keratinocyte death. BBR protects diabetic keratinocytes against ferroptosis, partly by activating NRF2.

Keywords:  NRF2; advanced glycation end productions; berberine; ferroptosis; keratinocytes

DOI:  https://doi.org/10.3389/ebm.2024.10280
Alzheimers Dement. 2024 Dec;20 Suppl 1 e091488

Basic Science and Pathogenesis.

Wenzhang Wang.

BACKGROUND: Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial proteostasis regulated by chaperones and proteases in each compartment of mitochondria is critical for mitochondrial function, and it is suspected that mitochondrial proteostasis deficits may be involved in mitochondrial dysfunction in AD.
METHOD: An unbiased screening of intraneuronal Aβ42 protein-interactome was perfumed in AD cell culture. Mitochondrial protease activity and mitochondria functions were investigated in AD models in vitro and in vivo, while cognitive behaviors of AD transgenic mice were analyzed by memory capacity tests.
RESULT: We identified LONP1, an ATP-dependent protease in the matrix, as a top Aβ42 interacting mitochondrial protein through and found significantly decreased LONP1 expression and extensive mitochondrial proteostasis deficits in AD experimental models both in vitro and in vivo, as well as in the brain of AD patients. Impaired METTL3-m6A signaling contributed at least in part to Aβ42-induced LONP1 reduction. Moreover, Aβ42 interaction with LONP1 impaired the assembly and protease activity of LONP1 both in vitro and in vivo. Importantly, LONP1 knockdown caused mitochondrial proteostasis deficits and dysfunction in neurons, while restored expression of LONP1 in neurons expressing intracellular Aβ and in the brain of CRND8 APP transgenic mice rescued Aβ-induced mitochondrial deficits and cognitive deficits.
CONCLUSION: These results demonstrated a critical role of LONP1 in disturbed mitochondrial proteostasis and mitochondrial dysfunction in AD and revealed a novel mechanism underlying intracellular Aβ42-induced mitochondrial toxicity through its impact on LONP1 and mitochondrial proteostasis.

DOI: https://doi.org/10.1002/alz.091488
Alzheimers Dement. 2024 Dec;20 Suppl 1 e087320

Basic Science and Pathogenesis.

Antonella Tramutola, Sara Pagnotta, Fabio Di Domenico, Lucrezia Romana Rolfi, Marzia Perluigi, Eugenio Barone.

BACKGROUND: Brain insulin resistance (bIR) heavily impacts on the core pathological processes of aging and Alzheimer disease (AD) since insulin regulates brain metabolism and cognitive functions. A close link among bIR, oxidative stress (OS) and mitochondrial defects exists, that contributes to brain dysfunctions observed in AD. Intriguingly, several studies suggest that intranasal insulin treatment (INI) enhances cognitive performance and reduced AD neuropathology both in humans and murine models of AD. We focused on the interplay between OS and bIR, by testing the hypothesis that rescuing brain insulin signaling activation by INI results in improved mitochondrial functions and reduced OS-induced damage to proteins in a mouse model of AD (3xTg-AD).
METHOD: 12-month-old 3 × Tg-AD and wild-type (non-Tg) mice were treated with INI (2 UI) or vehicle (saline) every other day for 2 months. Insulin signaling pathway and OS marker levels, i.e., PC, 4-HNE and 3-NT were evaluated in the frontal cortex. Then, due to the link between bIR and nitrosative stress, a redox proteomics approach was used to identify specific protein targets of 3-NT modifications. Mitochondrial functions were evaluated by measuring mitochondrial complexes (OXPHOS) and activities in all experimental groups.
RESULT: INI administration improved insulin signaling and reduced OS levels in 3xTg-AD mice. In particular, a consistent reduction of 3-NT levels was observed. Redox proteomics allowed to identify several proteins with reduced 3-NT modifications, that belong to key pathways, such as protein degradation and energy metabolism, known to be involved in the progression of AD. Remarkably, reduced 3-NT levels on mitochondrial proteins were responsible for an improvement of mitochondrial activity and brain energy metabolism.
CONCLUSION: We propose that INI represents a promising approach to reduce OS-induced damage to proteins and restore mitochondrial bioenergetics in AD brain.

DOI: https://doi.org/10.1002/alz.087320
Alzheimers Dement. 2024 Dec;20 Suppl 1 e088345

Basic Science and Pathogenesis.

Matthew P Neal, Autumn Meek, Donald F Weaver.

BACKGROUND: An explicit molecular level understanding of Alzheimer's Disease (AD) remains elusive. What initiates the disease and why does it progress? Answering these questions will be crucial to the development of much needed new diagnostics and therapeutics. Though the amyloid hypothesis is often debated, recent biologic trial results support a role for Aβ in AD pathogenesis. However, there are other tenable hypotheses, most notably neuroinflammation, but also gliopathy, synaptopathy, mitochondriopathy, and oxidative stress. Is it possible to formulate a model of AD that incorporates multiple proposed hypotheses into a single unifying conceptual approach? We seek to answer this question.
METHOD: We performed a comprehensive series of in silico, in vitro and in vivo studies explicitly evaluating the atomistic-molecular mechanisms of Aβ-mediated neurotoxicities as well as Aβ's antimicrobial and immunomodulatory effects. The molecular effects of Aβ and various cytokines on mitochondria, neuronal membranes and synapses were also explicitly studied.
RESULT: Membranes are a mosaic of lipophilic and hydrophilic (negatively-charged) regions organized in specific geometric patterns. Our studies show that bacterial membranes and neuronal membranes have essentially identical patterns, making neurons inadvertently susceptible to molecules targeting bacterial membranes. From this, a new model of AD emerges: In response to various immunostimulatory events (infection, trauma, ischemia, diabetes, air pollution), Aβ is released as an immunopeptide (kinocidin-type cytokine) which exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not); this inflicts a misdirected attack upon 'self' neurons, arising from the essentially identical membrane surface electrotopologies between neurons (especially at the synapse) and bacteria - causing neuronal death by mistaken identity. Following this self-attack, the resulting necrotic neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a self-perpetuating cycle.
CONCLUSION: We propose that AD occurs because Aβ is an immunopeptide that cannot differentiate neurons from bacteria - a case of mistaken identity that leads to an innate autoimmune response in which Aβ extracellularly attacks neuronal membranes, particularly at the synapse, while also intracellularly attacking mitochondria.

DOI: https://doi.org/10.1002/alz.088345
Drug Discov Today. 2024 Dec 28. pii: S1359-6446(24)00408-2. [Epub ahead of print] 104283

Repairing muscle with broccoli-derived sulforaphane: A preclinical evaluation for the treatment of mitochondrial myopathies.

Thomas Lilley, Donny M Camera, Faith A A Kwa.

  Skeletal muscle health relies on the production of adenosine triphosphate (ATP) in the mitochondria. ATP production is accompanied by oxidative phosphorylation, which generates reactive oxygen species (ROS). When there is an imbalance in ROS levels, oxidative stress and subsequent mitochondrial dysfunction, mitochondrial myopathies including sarcopenia, chronic progressive external ophthalmoplegia, and proximal myopathy can result. Such incurable myopathies are characterised by aberrant metabolism, limited ATP production, and muscle atrophy. Broccoli-derived sulforaphane has emerged as a novel treatment for mitochondrial myopathies because of its antioxidant and anti-inflammatory properties. This review discusses preclinical models that reveal sulforaphane's potential therapeutic benefits and limitations in treating mitochondrial myopathies.

Keywords:  chronic progressive external ophthalmoplegia; inflammation; oxidative stress; proximal myopathy; sarcopenia; sulforaphane

DOI:  https://doi.org/10.1016/j.drudis.2024.104283
Alzheimers Dement. 2024 Dec;20 Suppl 1 e084633

Basic Science and Pathogenesis.

Dan Gao.

BACKGROUND: Alzheimer's disease (AD), also known as senile dementia, is the most common degenerative disease of the central nervous system. Neuroinflammation is currently believed to be a crucial factor in the progression of AD, while its exact mechanism remains unclear.
METHOD: APP/PS1 AD mice were treated with a natural active ingredient tetrahydroxy stilbene glucoside (TSG) at 40 mg/kg/day and 80 mg/kg/day respectively for 5 consecutive months, and then the Morris water maze test (MWM) and the novel object recognition test were performed to assess the effect of TSG on the cognitive and memory ability of AD mice. Moreover, central microglia activation, peripheral inflammation as well as the correlated cGAS-STING signal pathway were analysed by Immunostaining and ELISA, which was further verified in BV2 cell experiments.
RESULT: Treating with TSG, learning-memory ability of AD mice was distinctly improved. Meanwhile, it was observed that the expressions of serum inflammatory cytokines and the activation of microglia in cerebral cortex and hippocampus were suppressed after TSG treatment, which was probably attributable to the decrease of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) triggered immune response and NLRP3 inflammasome activation. Furthermore, cell culture experiments employing LPS combined with IFN-γ induced microglia activation showed that TSG reversed the polarization status of M1-type microglia to restore the quiescence, and cGAS-STING elevation was observed in the activated microglia and normalized by TSG incubation. In addition, TSG suppressed the production of inflammatory cytokines such as IL-1β, IL-6, TNF- α, IFN- αand IFN-β, as well as the expression of IFN regulatory proteins such as IFIT1 and IRF7 in the LPS/IFN-γ-stimulated inflammatory response in BV2 cell. Finally, it was also verified that TSG are, in part, through a cGAS-STING dependent pathway and triggered NLRP3 inflammasome activation to inhibit neuroinflammation through interfering with cGAS-STING inhibitors.
CONCLUSION: Our findings highlight the health benefits of TSG and its potential application in preventing cognitive disorders by inhibiting neuroinflammation through cGAS-STING signaling pathway in AD.

DOI: https://doi.org/10.1002/alz.084633