bims-drumid 2024-10-27 papers

bims-drumid

Biomed News

on Drugs for mitochondrial diseases

Issue of 2024‒10‒27
ten papers selected by
Volkmar Weissig, Midwestern University

Novel Emerging Targets Identification in Reducing Risk of Alzheimer's Disease.
Omnidirectional improvement of mitochondrial health in Alzheimer's disease by multi-targeting engineered activated neutrophil exosomes.
Mitochondrial Stress as a Central Player in the Pathogenesis of Hypoxia-Related Myocardial Dysfunction: New Insights.
The Acute and Chronic influence of Exercise on Mitochondrial Dynamics in Skeletal Muscle.
Mitochondrial destabilization in tendinopathy and potential therapeutic strategies.
A narrative review of mitochondrial dysfunction and male infertility.
Surface engineered nano architectonics: An evolving paradigm for tackling Alzheimer's disease.
Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions.
Mitochondrial Maintenance in Skeletal Muscle.
Mitochondrial quality control in alcohol-associated liver disease.

Cent Nerv Syst Agents Med Chem. 2024 Oct 21.

Novel Emerging Targets Identification in Reducing Risk of Alzheimer's Disease.

Saurabh Sharma, Kalpana Rahate, Rahul Kumar.

  The accumulation of tau-containing neurofibrillary tangles and beta-amyloid deposits has been identified as the hallmark of Alzheimer's disease. Alzheimer's disease (AD) is a hereditary and neurological condition that can result in non-amnestic cognitive decline in less common forms and amnestic memory loss in its classic form. While Alzheimer's disease is the most prevalent cause of memory loss in middle-aged and older adults, other neurodegenerative and cerebrovascular disorders can have an impact on the disease's clinical course. Designing multi-target-directed ligands (MTDLs) is a very promising modern approach. This methodology was designed specifically for treating disorders with complex pathological mechanisms. Among these disorders is Alzheimer's disease (AD), which is currently the most prevalent multifactorial neurodegenerative illness. Increased amounts of the amyloid βpeptide (Aβ) and hyperphosphorylated tau protein, together with the loss of neurons and synapses, are linked to Alzheimer's disease (AD). Additionally, there is evidence that the pathophysiology of this condition is influenced by oxidative stress, metal ion dysregulation, inflammation, and failure of the cell cycle regulatory system. Since Alzheimer's disease (AD) is a multi-factor illness, there are many attractive targets for the development of anti-AD medications. These molecules can be useful in treating AD since they are multi-target-directed. This review focuses on the discovery of dual and multi-acting anti-AD drug candidates, especially hybrids made by combining chemically active moieties that function against distinct targets. The first group of substances consists of cholinesterase inhibitors with extra properties or those that function as multiple binding site inhibitors. Natural products also provide numerous options for slowing the progression and symptoms of many diseases, including Alzheimer's Meanwhile, Natural chemical structures with the following characteristics: alkaloids, sterols, triterpenes, tannins, flavonoids, polyphenols, and antioxidants as well as anti-inflammatory and anti-amyloidogenic properties. We provide an overview of Alzheimer's disease pathophysiology and therapy targets in this study. We also show several isolated chemicals and medicinal plants that are used to treat and prevent the symptoms of Alzheimer's disease.

Keywords:  AChE; Alzheimer’s disease; GSK-3β inhibitors; Natural products.; cholinesterase inhibitors; multi-target-directed ligands

DOI:  https://doi.org/10.2174/0118715249333381241012073557
J Control Release. 2024 Oct 23. pii: S0168-3659(24)00706-5. [Epub ahead of print]376 470-487

Omnidirectional improvement of mitochondrial health in Alzheimer's disease by multi-targeting engineered activated neutrophil exosomes.

Lei Zhang, Jiaquan Lin, Kai Xiang, Tianshu Shi, Baosheng Guo.

  Alzheimer's disease (AD) is one kind of devasting neurodegenerative disorders affecting over 50 million people worldwide. Multi-targeted therapy has emerged as a new treatment for diagnosing and alleviating the pathogenesis process of AD; however, the current strategy is limited by its unsatisfactory efficiency. In our study, engineered activated neutrophil-derived exosomes (MP@Cur-MExo) were developed to improve the mitochondrial function in neurons by targeting and alleviating Aβ-induced neurotoxicity. MP@Cur-MExo are exosomes derived from IL-8-stimulated neutrophils decorated with mitochondria targeting ligand and Aβ targeted ligand modified SPION. Engineered exosomes can be cleaved by matrix metallopeptidase-2, which is overexpressed in the AD brain. Consequently, the released SPION and Curcumin-loaded engineered exosomes collaboratively protected neuron cells against Aβ-induced mitochondrial deficiency. In addition, MP@Cur-MExo effectively accumulated in the inflamed region of AD brain at an early stage, allowing early diagnosis of AD through bimodal (MRI/IVIS) imaging. Importantly, in a mouse model at an early stage of AD, intravenously injected MP@Cur-MExo restored mitochondrial function and reduced Aβ-induced mitochondrial damage, thereby attenuating AD progression. In conclusion, our designed engineered exosomes demonstrated that omnidirectional improvement of mitochondrial function can serve as a novel and practical approach for the diagnosis and treatment of neurodegenerative diseases. This study also reveals a promising therapeutic agent for impeding AD progression for future clinical applications.

Keywords:  AD treatments; Engineered activated neutrophil exosomes; Mitochondrial health; Mitophagy; Multi-target therapy

DOI:  https://doi.org/10.1016/j.jconrel.2024.10.033
Int J Med Sci. 2024 ;21(13): 2502-2509

Mitochondrial Stress as a Central Player in the Pathogenesis of Hypoxia-Related Myocardial Dysfunction: New Insights.

Zhijiang Guo, Yingjie Tian, Nanyang Liu, Ye Chen, Xiaohan Chen, Guoxing Yuan, An Chang, Xing Chang, Jie Wu, Hao Zhou.

  Hypoxic injury is a critical pathological factor in the development of various cardiovascular diseases, such as congenital heart disease, myocardial infarction, and heart failure. Mitochondrial quality control is essential for protecting cardiomyocytes from hypoxic damage. Under hypoxic conditions, disruptions in mitochondrial homeostasis result in excessive reactive oxygen species (ROS) production, imbalances in mitochondrial dynamics, and initiate pathological processes including oxidative stress, inflammatory responses, and apoptosis. Targeted interventions to enhance mitochondrial quality control, such as coenzyme Q10 and statins, have shown promise in mitigating hypoxia-induced mitochondrial dysfunction. These treatments offer potential therapeutic strategies for hypoxia-related cardiovascular diseases by regulating mitochondrial fission and fusion, restoring mitochondrial biogenesis, reducing ROS production, and promoting mitophagy.

Keywords:  Hypoxia; Mitochondrial Homeostasis; Myocardial Injury

DOI:  https://doi.org/10.7150/ijms.99359
Am J Physiol Endocrinol Metab. 2024 Oct 23.

The Acute and Chronic influence of Exercise on Mitochondrial Dynamics in Skeletal Muscle.

Elya Janis Ritenis, Camila S Padilha, Matthew B Cooke, Christos George Stathis, Andrew Philp, Donny M Camera.

  Exercise and nutritional modulation are potent stimuli for eliciting increases in mitochondrial mass and function. Collectively, these beneficial adaptations are increasingly recognized to coincide with improvements to skeletal muscle health. Mitochondrial dynamics of fission and fusion are increasingly implicated as having a central role in mediating aspects of key organelle adaptions that are seen with exercise. Exercise-induced mitochondrial adaptations that dynamics have been implicated in are: 1) Increases to mitochondrial turnover, resulting from elevated rates of mitochondrial synthesis (biogenesis) and degradative (mitophagy) processes. 2) Morphological changes to the 3D tubular network, known as the mitochondrial reticulum, that mitochondria form in skeletal muscle. Notably, mitochondrial fission has also been implicated in coordinating increases in mitophagy, following acute exercise. Further, increased fusion following exercise training promotes increased connectivity of the mitochondrial reticulum and is associated with improved metabolism and mitochondrial function. However, the molecular basis and fashion in which exercise infers beneficial mitochondrial adaptations through mitochondrial dynamics remains poorly understood. This review attempts to highlight recent developments investigating the effects of exercise on mitochondrial dynamics, while attempting to offer a perspective of the methodological refinements and potential variables, such as substrate/glycogen availability, which should be considered going forward.

Keywords:  Exercise; Mitochondrial Dynamics; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpendo.00311.2024
J Orthop Translat. 2024 Nov;49 49-61

Mitochondrial destabilization in tendinopathy and potential therapeutic strategies.

Linxiang Cheng, Qiangqiang Zheng, Kaijie Qiu, Dai Fei Elmer Ker, Xiao Chen, Zi Yin.

  Tendinopathy is a prevalent aging-related disorder characterized by pain, swelling, and impaired function, often resulting from micro-scarring and degeneration caused by overuse or trauma. Current interventions for tendinopathy have limited efficacy, highlighting the need for innovative therapies. Mitochondria play an underappreciated and yet crucial role in tenocytes function, including energy production, redox homeostasis, autophagy, and calcium regulation. Abnormalities in mitochondrial function may lead to cellular senescence. Within this context, this review provides an overview of the physiological functions of mitochondria in tendons and presents current insights into mitochondrial dysfunction in tendinopathy. It also proposes potential therapeutic strategies that focus on targeting mitochondrial health in tenocytes. These strategies include: (1) utilizing reactive oxygen species (ROS) scavengers to mitigate the detrimental effects of aberrant mitochondria, (2) employing mitochondria-protecting agents to reduce the production of dysfunctional mitochondria, and (3) supplementing with exogenous normal mitochondria. In conclusion, mitochondria-targeted therapies hold great promise for restoring mitochondrial function and improving outcomes in patients with tendinopathy. The translational potential of this article: Tendinopathy is challenging to treat effectively due to its poorly understood pathogenesis. This review thoroughly analyzes the role of mitochondria in tenocytes and proposes potential strategies for the mitochondrial treatment of tendinopathy. These findings establish a theoretical basis for future research and the clinical translation of mitochondrial therapy for tendinopathy.

Keywords:  Aging; Mitochondria; Stem cells; Tendinopathy; Therapeutic strategies

DOI:  https://doi.org/10.1016/j.jot.2024.09.003
Transl Androl Urol. 2024 Sep 30. 13(9): 2134-2145

A narrative review of mitochondrial dysfunction and male infertility.

Zihang Mai, Di Yang, Dan Wang, Jingyi Zhang, Qi Zhou, Baoquan Han, Zhongyi Sun.

  Background and Objective: Recent investigations have highlighted mitochondrial dysfunction as a major component in reduced sperm function and male infertility. The creation of energy, control of reactive oxygen species (ROS), apoptosis, and sperm motility are all critically dependent on mitochondria. The health of the male reproductive system may be significantly impacted by any alteration of mitochondrial structure, function, or integrity. This review intends to open the door to better diagnostic methods, novel therapy strategies, and improved reproductive outcomes for infertile couples by clarifying the crucial function of mitochondria.Methods: We searched PubMed, Google Scholar, and others for articles related to male infertility and mitochondrial dysfunction from 2014 to 2023. The articles related to the theme were preliminarily screened by abstract, and then the selected literature was read and summarized. In this essay, we examine the research on male infertility and mitochondrial malfunction. We investigate the intricate connection between sperm quality, deoxyribonucleic acid damage, oxidative stress (OS), and mitochondrial bioenergetics. We discuss about how spermatogenesis and sperm function are affected by mitochondrial mutations, deletions, and single nucleotide polymorphisms. We also explore the impact of age-related changes, lifestyle choices, and environmental factors on mitochondrial function and male fertility. This review also clarifies the mechanisms by which mitochondrial dysfunction impacts the viability, morphology, and capacitation of sperm, among other aspects of male reproductive health. Furthermore, we go over the recently developed field of mitochondrial treatments and possible therapeutic approaches that target mitochondrial malfunction to enhance male fertility.
Key Content and Findings: Mitochondria are important for sperm: The control of sperm motility, capacitation, and general quality is largely dependent on mitochondria. Deterioration of sperm motility and male infertility may result from disruption of the structure, function, or integrity of the mitochondria. Future studies should focus on figuring out the processes underlying mitochondrial dysfunction as fertility and reproductive health are significantly impacted by it.
Conclusions: We discuss the evaluation of infertile men mitochondrial function defects and difficulties, and make recommendations for further study in this area. This article provides a thorough resource for clinicians, researchers, and reproductive biologists to understand the underlying mechanisms of male infertility and explore potential therapeutic interventions.

Keywords:  Mitochondrial dysfunction; male infertility; mitochondrial genetics; oxidative stress (OS)

DOI:  https://doi.org/10.21037/tau-24-262
Life Sci. 2024 Oct 19. pii: S0024-3205(24)00745-8. [Epub ahead of print]358 123155

Surface engineered nano architectonics: An evolving paradigm for tackling Alzheimer's disease.

Mansi Negi, Etikala Amulya, Vivek Phatale, Noella Abraham, Aachal Hedaoo, Dadi A Srinivasarao, Saurabh Srivastava.

  As per the World Health Organization (WHO) estimation, Alzheimer's disease (AD) will affect 100 million population across the globe by 2050. AD is an incurable neurodegenerative disease that remains a mystery for neurologists owing to its complex pathophysiology. Currently, available therapeutic regimens will only cause symptomatic relief by improving the cognitive and behavioral functions of AD. However, the major pitfalls in managing AD include tight junctions in the endothelial cells of the blood-brain barrier (BBB), diminished neuronal bioavailability, enzymatic degradation and reduced stability of the therapeutic moiety. In an effort to surmount the drawbacks mentioned above, researchers shifted their focus toward nanocarriers (NCs). Nevertheless, non-specific targeting of NCs imparts toxicity to the peripheral organs, thereby reducing the bioavailability of therapeutic moiety at the target site. To unravel this unmet clinical need, scientists came up with the idea of a novel intriguing strategy of surface engineering by targeting ligands. Surface-decorated NCs provide targeted drug delivery, controlled drug release, enhanced penetration and bioavailability. In this state-of-the-art review, we have highlighted in detail various molecular signalling pathways involved in AD pathogenesis. The significance of surface functionalization and its application in AD management have been deliberated. We have elaborated on the regulatory bottlenecks and clinical hurdles faced during lab-to-industrial scale translation along with possible solutions.

Keywords:  Alzheimer's disease; Amyloid-β; Clinical translation; Nanocarriers; Surface functionalization

DOI:  https://doi.org/10.1016/j.lfs.2024.123155
Ageing Res Rev. 2024 Oct 19. pii: S1568-1637(24)00367-2. [Epub ahead of print]102 102549

Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions.

Luigi Ferrucci, Flora Guerra, Cecilia Bucci, Emanuele Marzetti, Anna Picca.

  Mitophagy is the intracellular recycling system that disposes damaged/inefficient mitochondria and allows biogenesis of new organelles to ensure mitochondrial quality is optimized. Dysfunctional mitophagy has been implicated in human aging and diseases. Multiple evolutionarily selected, redundant mechanisms of mitophagy have been identified, but their specific roles in human health and their potential exploitation as therapeutic targets are unclear. Recently, the characterization of the endosomal-lysosomal system has revealed additional mechanisms of mitophagy and mitochondrial quality control that operate via the production of mitochondria-derived vesicles (MDVs). Circulating MDVs can be isolated and characterized to provide an unprecedented opportunity to study this type of mitochondrial recycling in vivo and to relate it to human physiology and pathology. Defining the role of MDVs in human physiology, pathology, and aging is hampered by the lack of standardized methods to isolate, validate, and characterize these vesicles. Hence, some basic questions about MDVs remain unanswered. While MDVs are generated directly through the extrusion of mitochondrial membranes within the cell, a set of circulating extracellular vesicles leaking from the endosomal-lysosomal system and containing mitochondrial portions have also been identified and warrant investigation. Preliminary research indicates that MDV generation serves multiple biological roles and contributes to restoring cell homeostasis. However, studies have shown that MDVs may also be involved in pathological conditions. Therefore, further research is warranted to establish when/whether MDVs are supporting disease progression and/or are extracting damaged mitochondrial components to alleviate cellular oxidative burden and restore redox homeoastasis. This information will be relevant for exploiting these vesicles for therapeutic purpose. Herein, we provide an overview of preclinical and clinical studies on MDVs in aging and associated conditions and discuss the interplay between MDVs and some of the hallmarks of aging (mitophagy, inflammation, and proteostasis). We also outline open questions on MDV research that should be prioritized by future investigations.

Keywords:  Exosomes; Extracellular vesicles; Inflammaging; Mitochondrial DNA; Mitochondrial quality control; Mitophagy

DOI:  https://doi.org/10.1016/j.arr.2024.102549
Cold Spring Harb Perspect Biol. 2024 Oct 21. pii: a041514. [Epub ahead of print]

Mitochondrial Maintenance in Skeletal Muscle.

Laura M de Smalen, Christoph Handschin.

Skeletal muscle is one of the tissues with the highest range of variability in metabolic rate, which, to a large extent, is critically dependent on tightly controlled and fine-tuned mitochondrial activity. Besides energy production, other mitochondrial processes, including calcium buffering, generation of heat, redox and reactive oxygen species homeostasis, intermediate metabolism, substrate biosynthesis, and anaplerosis, are essential for proper muscle contractility and performance. It is thus not surprising that adequate mitochondrial function is ensured by a plethora of mechanisms, aimed at balancing mitochondrial biogenesis, proteostasis, dynamics, and degradation. The fine-tuning of such maintenance mechanisms ranges from proper folding or degradation of individual proteins to the elimination of whole organelles, and in extremis, apoptosis of cells. In this review, the present knowledge on these processes in the context of skeletal muscle biology is summarized. Moreover, existing gaps in knowledge are highlighted, alluding to potential future studies and therapeutic implications.

DOI: https://doi.org/10.1101/cshperspect.a041514
Hepatol Commun. 2024 Nov 01. pii: e0534. [Epub ahead of print]8(11):

Mitochondrial quality control in alcohol-associated liver disease.

Themis Thoudam, Hui Gao, Yanchao Jiang, Nazmul Huda, Zhihong Yang, Jing Ma, Suthat Liangpunsakul.

Excessive alcohol consumption is a leading cause of alcohol-associated liver disease (ALD), a significant global health concern with limited therapeutic options. Understanding the key factors contributing to ALD pathogenesis is crucial for identifying potential therapeutic targets. Central to ALD pathogenesis is the intricate interplay between alcohol metabolism and cellular processes, particularly involving mitochondria. Mitochondria are essential organelles in the liver, critical for energy production and metabolic functions. However, they are particularly vulnerable to alcohol-induced damage due to their involvement in alcohol metabolism. Alcohol disrupts mitochondrial function, impairing ATP production and triggering oxidative stress, which leads to cellular damage and inflammation. Mitochondrial quality control mechanisms, including biogenesis, dynamics, and mitophagy, are crucial for maintaining optimal mitochondrial function. Chronic alcohol consumption disrupts mitochondrial quality control checkpoints, leading to mitochondrial dysfunction that impairs fatty acid oxidation and contributes to hepatic steatosis in ALD. Moreover, alcohol promotes the accumulation of damaged mitochondria and the release of proinflammatory components, exacerbating liver damage and inflammation. Preserving mitochondrial health presents a promising therapeutic approach to mitigate ALD progression. In this review, we provide a comprehensive overview of the effects of alcohol on mitochondrial function and quality control mechanisms, highlighting their role in ALD pathogenesis. Understanding these mechanisms may pave the way for the development of novel therapeutic interventions for ALD.

DOI: https://doi.org/10.1097/HC9.0000000000000534