bims-drumid 2024-11-17 papers

bims-drumid

Biomed News

on Drugs for mitochondrial diseases

Issue of 2024–11–17
twelve papers selected by
Volkmar Weissig, Midwestern University

Mitochondria: great balls of fire.
Unraveling the role and mechanism of mitochondria in postoperative cognitive dysfunction: a narrative review.
The Relation Between Mitochondrial Membrane Potential and Reactive Oxygen Species Formation.
Mitophagy-Enhanced Nanoparticle-Engineered Mitochondria Restore Homeostasis of Mitochondrial Pool for Alleviating Pulmonary Fibrosis.
Mitochondrial dynamics and energy metabolism interference therapy for promoting photothermal sensitization.
Safeguarding the brain from oxidative damage.
Mitochondrial dysfunction as a therapeutic strategy for neurodegenerative diseases: Current insights and future directions.
Plant-derived compounds as potential neuroprotective agents in Parkinson's disease.
From Plaques to Pathways in Alzheimer's Disease: The Mitochondrial-Neurovascular-Metabolic Hypothesis.
Revealing mitochondrial microenvironmental changes triggered by ferroptosis regulation.
Methodologies for Mitochondrial Omic Profiling During Spaceflight.
Clinical indications for the diagnosis and treatment of functional posterior crossbite in pediatric population: a narrative review with clinical description.

FEBS J. 2024 Nov 14.

Mitochondria: great balls of fire.

Howard T Jacobs, Pierre Rustin, Paule Bénit, Dan Davidi, Mügen Terzioglu.

  Recent experimental studies indicate that mitochondria in mammalian cells are maintained at temperatures of at least 50 °C. While acknowledging the limitations of current experimental methods and their interpretation, we here consider the ramifications of this finding for cellular functions and for evolution. We consider whether mitochondria as heat-producing organelles had a role in the origin of eukaryotes and in the emergence of homeotherms. The homeostatic responses of mitochondrial temperature to externally applied heat imply the existence of a molecular heat-sensing system in mitochondria. While current findings indicate high temperatures for the innermost compartments of mitochondria, those of the mitochondrial surface and of the immediately surrounding cytosol remain to be determined. We ask whether some aspects of mitochondrial dynamics and motility could reflect changes in the supply and demand for mitochondrial heat, and whether mitochondrial heat production could be a factor in diseases and immunity.

Keywords:  cold‐shock; eukaryote origins; heat‐shock; homeothermy; immunity; mitochondria; mitochondrial disease; mitochondrial dynamics; temperature gradients; thermogenesis

DOI:  https://doi.org/10.1111/febs.17316
J Neuroinflammation. 2024 Nov 12. 21(1): 293

Unraveling the role and mechanism of mitochondria in postoperative cognitive dysfunction: a narrative review.

Zhenyong Zhang, Wei Yang, Lanbo Wang, Chengyao Zhu, Shuyan Cui, Tian Wang, Xi Gu, Yang Liu, Peng Qiu.

  Postoperative cognitive dysfunction (POCD) is a frequent neurological complication encountered during the perioperative period with unclear mechanisms and no effective treatments. Recent research into the pathogenesis of POCD has primarily focused on neuroinflammation, oxidative stress, changes in neural synaptic plasticity and neurotransmitter imbalances. Given the high-energy metabolism of neurons and their critical dependency on mitochondria, mitochondrial dysfunction directly affects neuronal function. Additionally, as the primary organelles generating reactive oxygen species, mitochondria are closely linked to the pathological processes of neuroinflammation. Surgery and anesthesia can induce mitochondrial dysfunction, increase mitochondrial oxidative stress, and disrupt mitochondrial quality-control mechanisms via various pathways, hence serving as key initiators of the POCD pathological process. We conducted a review on the role and potential mechanisms of mitochondria in postoperative cognitive dysfunction by consulting relevant literature from the PubMed and EMBASE databases spanning the past 25 years. Our findings indicate that surgery and anesthesia can inhibit mitochondrial respiration, thereby reducing ATP production, decreasing mitochondrial membrane potential, promoting mitochondrial fission, inducing mitochondrial calcium buffering abnormalities and iron accumulation, inhibiting mitophagy, and increasing mitochondrial oxidative stress. Mitochondrial dysfunction and damage can ultimately lead to impaired neuronal function, abnormal synaptic transmission, impaired synthesis and release of neurotransmitters, and even neuronal death, resulting in cognitive dysfunction. Targeted mitochondrial therapies have shown positive outcomes, holding promise as a novel treatment for POCD.

Keywords:  Cognitive complication; Electron transport chain deficiency; Mitochondria; Mitochondrial dysfunction; Mitophagy; Neuroinflammation; Oxidative stress; Postoperative cognitive dysfunction

DOI:  https://doi.org/10.1186/s12974-024-03285-3
Methods Mol Biol. 2025 ;2878 133-162

The Relation Between Mitochondrial Membrane Potential and Reactive Oxygen Species Formation.

Magdalena Lebiedzinska-Arciszewska, Jan Suski, Massimo Bonora, Barbara Pakula, Paolo Pinton, Jerzy Duszynski, Patrycja Jakubek-Olszewska, Mariusz R Wieckowski.

  Mitochondria are considered one of the main sites of reactive oxygen species (ROS) production in the eukaryotic cells. For this reason, mitochondrial dysfunction associated with increased ROS production underlies various pathological conditions as well as promotes aging. Chronically increased rates of ROS production contribute to oxidative damage to macromolecules, i.e., DNA, proteins, and lipids. Accumulation of unrepaired oxidative damage may result in progressive cell dysfunction, which can finally trigger cell death. The main by-product of mitochondrial oxidative phosphorylation is superoxide, which is generated by the leak of electrons from the mitochondrial respiratory chain complexes leading to one-electron reduction of oxygen. Mitochondrial superoxide dismutase (MnSOD, SOD2) as well as cytosolic superoxide dismutase (Cu/ZnSOD, SOD1), whose smaller pool is localized in the mitochondrial intermembrane space, converts superoxide to H2O2, which can be then degraded by the catalase to harmless H2O.In this chapter, we focus on the relationship between one of the bioenergetic parameters, which is mitochondrial membrane potential, and the rate of ROS formation. We present a set of various methods enabling the characterization of these parameters applicable to isolated mitochondria or intact cells. We also present examples of experimental data demonstrating that the magnitude and direction (increase or decrease) of a change in mitochondrial ROS production depend on the mitochondrial metabolic state.

Keywords:  Confocal microscopy; Hydrogen peroxide; Mitochondria; Oxygen consumption; Resazurin; Superoxide

DOI:  https://doi.org/10.1007/978-1-0716-4264-1_8
ACS Nano. 2024 Nov 15.

Mitophagy-Enhanced Nanoparticle-Engineered Mitochondria Restore Homeostasis of Mitochondrial Pool for Alleviating Pulmonary Fibrosis.

Yi Wang, Li-Fan Hu, Na-Hui Liu, Jing-Song Yang, Lei Xing, Jee-Heon Jeong, Ling Li, Hu-Lin Jiang.

  Pulmonary fibrosis (PF) is an interstitial lung disease tightly associated with the disruption of mitochondrial pool homeostasis, a delicate balance influenced by functional and dysfunctional mitochondria within lung cells. Mitochondrial transfer is an emerging technology to increase functional mitochondria via exogenous mitochondrial delivery; however, the therapeutic effect on mitochondrial transfer is hampered during the PF process by the persistence of dysfunctional mitochondria, which is attributed to impaired mitophagy. Herein, we reported engineering mitochondria mediated by mitophagy-enhanced nanoparticle (Mito-MEN), which promoted synchronal regulation of functional and dysfunctional mitochondria for treating PF. Mitophagy-enhanced nanoparticles (MENs) were fabricated through the encapsulation of Parkin mRNA, and the electrostatic interaction favored MENs to anchor isolated healthy mitochondria for the construction of Mito-MEN. Mito-MEN increased the load of functional exogenous mitochondria by enhancing mitochondrial delivery efficiency and promoted mitophagy of dysfunctional endogenous mitochondria. In a bleomycin (BLM)-induced PF mouse model, Mito-MEN repaired mitochondrial function and efficiently relieved PF-related phenotypes. This study provides a powerful tool for synchronal adjustment of mitochondrial pool homeostasis and offers a translational approach for pan-mitochondrial disease therapies.

Keywords:  alveolar epithelial cells; mitophagy; nanoengineered mitochondria; nanoparticle; pulmonary fibrosis

DOI:  https://doi.org/10.1021/acsnano.4c10328
J Colloid Interface Sci. 2024 Oct 30. pii: S0021-9797(24)02535-9. [Epub ahead of print]680(Pt A): 429-440

Mitochondrial dynamics and energy metabolism interference therapy for promoting photothermal sensitization.

Cuimei Liu, Sihang Cheng, Xue Zhou, Lu Li, Chungang Wang, Lingyu Zhang.

  Photothermal therapy (PTT) is minimally invasive, precisely controlled, and therapeutically effective treatment method. However, its efficacy is limited by the overexpression of heat shock proteins (HSP), which leads to cellular thermal blockade. Targeting mitochondria with PTT can enhance anticancer efficacy, as mitochondria encode genes related to HSP and provide energy for their production. Nevertheless, mitochondrial dynamics confer resistance to damage from external stimuli. Therefore, disrupting the balance of mitochondrial dynamics is essential to impede HSP production. Herein, we synthesized degradable Cu3BiS3 (CBS) nanosheets (NSs) with one face modified by carboxylated triphenylphosphonium (TPP) to target mitochondria. This modification increases the production of exogenous reactive oxygen species (ROS) and induces the overexpression of dynamin-related protein 1 (Drp1), disrupting mitochondrial dynamic homeostasis. The other face was modified with carboxylated β-cyclodextrin (CD) to load the glycolysis inhibitor (2-deoxyglucose, 2DG), thereby reducing adenosine triphosphate (ATP) production in the extra-mitochondrial space, as glycolysis also occurs in the cytoplasm. The resulting TPP-CBS-2DG Janus NSs (JNSs) not only disrupt mitochondrial energy production, leading to cell starvation, but also inhibit HSP production. Consequently, TPP-CBS-2DG JNSs can enhance tumor thermal sensitivity in PTT, improving its efficacy. This work holds great promise for overcoming tumor heat resistance in PTT and provides a feasible method for fabricating selectively modified multifunctional NSs.

Keywords:  Degradation; Energy metabolism; Janus nanosheets; Mitochondrial dynamics; Sensitized photothermal therapy; Targeting mitochondria

DOI:  https://doi.org/10.1016/j.jcis.2024.10.180
Free Radic Biol Med. 2024 Nov 13. pii: S0891-5849(24)01053-0. [Epub ahead of print]

Safeguarding the brain from oxidative damage.

Kyung Hee Lee, Un Jeng Kim, Bae Hwan Lee, Myeounghoon Cha.

  Oxidative stress imposes a substantial cellular burden on the brain and contributes to diverse neurodegenerative diseases. Various antioxidant signaling pathways have been implicated in oxidative stress and have a protective effect on brain cells by increasing the release of numerous enzymes and through anti-inflammatory responses to oxidative damage caused by abnormal levels of reactive oxygen species (ROS). Although many molecules evaluated as antioxidants have shown therapeutic potentials in preclinical studies, the results of clinical trials have been less than satisfactory. This review focuses on several signaling pathways involved in oxidative stress that are associated with antioxidants. These pathways have a protective effect against stressors by increasing the release of various enzymes and also exert anti-inflammatory responses against oxidative damage. There is no doubt that oxidative stress is a crucial therapeutic target in the treatment of neurological diseases. Therefore, it is essential to understand the discovery of multiple routes that can efficiently repair the damage caused by ROS and prevent neurodegenerative disorders. This paper aims to provide a concise and objective review of the oxidative and antioxidant pathways and their potential therapeutic applications in treating oxidative injury in the brain.

Keywords:  Antioxidant; Neurodegenerative disease; Nrf2; Oxidative stress; Redox system

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.019
Ageing Res Rev. 2024 Nov 10. pii: S1568-1637(24)00395-7. [Epub ahead of print]102 102577

Mitochondrial dysfunction as a therapeutic strategy for neurodegenerative diseases: Current insights and future directions.

Ying-Ying Gu, Xin-Ru Zhao, Nan Zhang, Yuan Yang, Ying Yi, Qian-Hang Shao, Ming-Xuan Liu, Xiao-Ling Zhang.

  Neurodegenerative diseases, as common diseases in the elderly, tend to become younger due to environmental changes, social development and other factors. They are mainly characterized by progressive loss or dysfunction of neurons in the central or peripheral nervous system, and common diseases include Parkinson's disease, Alzheimer's disease, Huntington's disease and so on. Mitochondria are important organelles for adenosine triphosphate (ATP) production in the brain. In recent years, a large amount of evidence has shown that mitochondrial dysfunction plays a direct role in neurodegenerative diseases, which is expected to provide new ideas for the treatment of related diseases. This review will summarize the main mechanisms of mitochondrial dysfunction in neurodegenerative diseases, as well as collating recent advances in the study of mitochondrial disorders and new therapies.

Keywords:  Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Neurodegenerative diseases; Oxidative stress

DOI:  https://doi.org/10.1016/j.arr.2024.102577
Nutrition. 2024 Oct 23. pii: S0899-9007(24)00259-4. [Epub ahead of print]130 112610

Plant-derived compounds as potential neuroprotective agents in Parkinson's disease.

Chengu Niu, Yu Zou, Miaoxian Dong, Yingcai Niu.

   OBJECTIVES: Current Parkinson's disease (PD) medications treat symptoms; none can slow down or arrest the disease progression. Disease-modifying therapies for PD remain an urgent unmet clinical need. This review was designed to summarize recent findings regarding to the efficacy of phytochemicals in the treatment of PD and their underlying mechanisms.
METHODS: A literature search was performed using PubMed databases from inception until January 2024.
RESULTS: We first review the role of oxidative stress in PD and phytochemical-based antioxidant therapy. We then summarize recent work on neuroinflammation in the pathogenesis of PD, as well as preclinical data supporting anti-inflammatory efficacy in treating or preventing the disease. We last evaluate evidence for brain mitochondrial dysfunction in PD, together with the phytochemicals that protect mitochondrial function in preclinical model of PD. Furthermore, we discussed possible reasons for failures of preclinical-to-clinical translation for neuroprotective therapeutics.
CONCLUSIONS: There is now extensive evidence from preclinical studies that neuroprotective phytochemicals as promising candidate drugs for PD are needed to translate from the laboratory to the clinic.

Keywords:  Mitochondrial dysfunction; Neuroinflammation; Oxidative stress; Parkinson's disease; Phytochemicals

DOI:  https://doi.org/10.1016/j.nut.2024.112610
Int J Mol Sci. 2024 Oct 31. pii: 11720. [Epub ahead of print]25(21):

From Plaques to Pathways in Alzheimer's Disease: The Mitochondrial-Neurovascular-Metabolic Hypothesis.

Sarah Kazemeini, Ahmed Nadeem-Tariq, Ryan Shih, John Rafanan, Nabih Ghani, Thomas A Vida.

  Alzheimer's disease (AD) presents a public health challenge due to its progressive neurodegeneration, cognitive decline, and memory loss. The amyloid cascade hypothesis, which postulates that the accumulation of amyloid-beta (Aβ) peptides initiates a cascade leading to AD, has dominated research and therapeutic strategies. The failure of recent Aβ-targeted therapies to yield conclusive benefits necessitates further exploration of AD pathology. This review proposes the Mitochondrial-Neurovascular-Metabolic (MNM) hypothesis, which integrates mitochondrial dysfunction, impaired neurovascular regulation, and systemic metabolic disturbances as interrelated contributors to AD pathogenesis. Mitochondrial dysfunction, a hallmark of AD, leads to oxidative stress and bioenergetic failure. Concurrently, the breakdown of the blood-brain barrier (BBB) and impaired cerebral blood flow, which characterize neurovascular dysregulation, accelerate neurodegeneration. Metabolic disturbances such as glucose hypometabolism and insulin resistance further impair neuronal function and survival. This hypothesis highlights the interconnectedness of these pathways and suggests that therapeutic strategies targeting mitochondrial health, neurovascular integrity, and metabolic regulation may offer more effective interventions. The MNM hypothesis addresses these multifaceted aspects of AD, providing a comprehensive framework for understanding disease progression and developing novel therapeutic approaches. This approach paves the way for developing innovative therapeutic strategies that could significantly improve outcomes for millions affected worldwide.

Keywords:  Alzheimer’s disease; amyloid-beta peptide; blood–brain barrier; metabolic disturbances; mitochondrial dysfunction; neurodegeneration; neurovascular regulation; oxidative stress

DOI:  https://doi.org/10.3390/ijms252111720
Anal Bioanal Chem. 2024 Nov 13.

Revealing mitochondrial microenvironmental changes triggered by ferroptosis regulation.

Lili Cong, Yanting Shen, Jiaqi Wang, Fanxiang Meng, Weiqing Xu, Weixia Sun, Shuping Xu.

  Ferroptosis is a unique form of iron-dependent cell death characterized by dramatic ultrastructural changes in mitochondria. Since mitochondria are intracellular energy factories and binding sites for producing reactive oxygen species, there is increasing evidence that mitochondria are closely related to ferroptosis and play a crucial role in the regulation and execution of ferroptosis. The pH of the mitochondrial microenvironment is an important parameter for cellular physiological activities. Its abnormal fluctuations are commonly thought to be associated with cancers and other diseases. Herein, a surface-enhanced Raman scattering (SERS)-based pH nanosensor with high sensitivity and targeting function was utilized to quantify and monitor mitochondrial pH value. This nanosensor was constructed by gold nanorods (AuNRs) functionalized with pH-responsive molecules (4-mercaptopyridine, MPy) and mitochondrion-targeting peptides (AMMT) that can precisely deliver AuNRs to mitochondria. Super-resolution fluorescence imaging was employed to evidence the mitochondrial targeting feature of this nanosensor. Ferroptosis regulation induces intracellular accumulation of lipid peroxide (LPO) and reactive oxygen species (ROS), which cause changes in the mitochondrial pH. This method reveals that ferroptosis leads to the gradual acidification of the mitochondrial internal environment. The conclusion deduced by this study will be helpful for the evaluation and diagnosis of diseases according to intracellular abnormal microenvironments.

Keywords:  Ferroptosis; Mitochondrial microenvironment; Nanosensor; Surface-enhanced Raman spectroscopy; pH-responsive

DOI:  https://doi.org/10.1007/s00216-024-05638-6
Methods Mol Biol. 2025 ;2878 273-291

Methodologies for Mitochondrial Omic Profiling During Spaceflight.

Joseph W Guarnieri, JangKeun Kim, Douglas C Wallace, Christopher E Mason, Masafumi Muratani, Afshin Beheshti.

  To be able to understand how spaceflight can affect human biology, there is a need for maximizing the amount of information that can be obtained from experiments flown to space. Recently there has been an influx of data obtained from astronauts through multi-omics approaches based on both governmental and commercial spaceflight missions. In addition to data from humans, mitochondrial specific data is gathered for other experiments from rodents and other organisms that are flown in space. This data has started to universally demonstrate that mitochondrial dysfunction is the key regulator associated with increasing health risks associated with spaceflight. This mitochondrial dysfunction can have influence downstream on immune suppression, inflammation, circadian rhythm issues, and more. Due to the space environment, standard methodologies have to be altered for performing mitochondrial specific analysis and in general sample collection for omics. To perform mitochondrial specific analysis and data collection from samples flown to space we will outline the current sample collection methods, processing of the samples, and specific analysis. Specifically we will highlight the different mitochondrial methodologies and challenges involved with research associated with spaceflight.

Keywords:  Astronauts; ImmunoblottingImmunoblotting; Mitochondria; Mitochondrial DNA; Multi-omics; Omics; PBMCs; RNA-sequence; Transcriptomics; mtDNA

DOI:  https://doi.org/10.1007/978-1-0716-4264-1_15
J Clin Pediatr Dent. 2024 Nov;48(6): 12-28

Clinical indications for the diagnosis and treatment of functional posterior crossbite in pediatric population: a narrative review with clinical description.

Antonino Lo Giudice, Alessandro Polizzi, Rosalia Leonardi, Gaetano Isola.

  The present manuscript aims to provide an updated overview of the clinical management of functional posterior crossbite (FPXB) in growing subjects which can be helpful for orthodontists and pediatric dentists in daily practice. Database searches were performed until December 2023 to evaluate the published literature on the topic. The most pertinent articles were chosen for the review from the retrieved articles. No restrictions regarding the year or language of publication were applied. Additional studies were included by manually searching the references of the included studies. The manuscript has been structured for a narrative purpose. Although there is evidence of spontaneous correction in the transition from deciduous to mixed dentition, the literature suggests initiating the treatment early to increase the success rate. Early treatment involves reducing the risk for potential temporomandibular disorders and adaptations at the level of skeletal, dental, and muscle components. Recent advancements in tridimensionali (3D) imaging systems can also help define the appropriate treatment time case-by-case. Considering the prevalence and the multiple etiological factors involved in the development of FPXB in the pediatric population, orthodontists and pediatric dentists should decide the treatment time for this condition with a careful evaluation of the risk/benefit ratio.

Keywords:  Functional posterior crossbite; Interceptive orthodontics; Mandibular shift; Maxillary expansion

DOI:  https://doi.org/10.22514/jocpd.2024.123