bims-drumid 2024-10-20 papers

bims-drumid

Biomed News

on Drugs for mitochondrial diseases

Issue of 2024–10–20
28 papers selected by
Volkmar Weissig, Midwestern University

Oxidative Stress in Alzheimer's Disease: The Shortcomings of Antioxidant Therapies.
Amyloid-Directed Antibodies: Past, Present, and Future.
Melatonin in Alzheimer's Disease: Literature Review and Therapeutic Trials.
Immunotherapy in Alzheimer's Disease: Current Status and Future Directions.
A Comprehensive Review on Repurposing the Nanocarriers for the Treatment of Parkinson's Disease: An Updated Patent and Clinical Trials.
Treating Alzheimer's Disease: Focusing on Neurodegenerative Consequences.
Non-coding RNAs as therapeutic targets in Parkinson's Disease: A focus on dopamine.
Neuroprotective Effect of 2-(Benzyloxy)arylureas Is Not Related to CypD Inhibition nor Suppression of mPTP Opening.
NRIP1 is a downstream target of YY1 in promoting OGD/R-induced H9c2 cardiomyocyte injury and mitochondrial dysfunction.
Non-pathogenic Trojan horse Nissle1917 triggers mitophagy through PINK1/Parkin pathway to discourage colon cancer.
Ultraviolet radiation inhibits mitochondrial bioenergetics activity.
Drug Repurposing for Effective Alzheimer's Disease Medicines: Existing Methods and Novel Pharmacoepidemiological Approaches.
Exploring nanoparticular platform in delivery of repurposed drug for Alzheimer's disease: current approaches and future perspectives.
CT1812, a Small Molecule Sigma-2 Receptor Antagonist for Alzheimer's Disease Treatment: A Systematic Review of Available Clinical Data.
Metformin as a Potential Prevention Strategy for Alzheimer's Disease and Alzheimer's Disease Related Dementias.
Advances and Challenges in Gene Therapy for Alzheimer's Disease.
Mitochondrial transfer in the progression and treatment of cardiac disease.
The role of PI3K signaling pathway in Alzheimer's disease.
The Role of Sirtuin 1 in Ageing and Neurodegenerative Disease: A Molecular Perspective.
Supplementation with NAD+ Precursors for Treating Alzheimer's Disease: A Metabolic Approach.
Apoptosis-induced translocation of nesprin-2 from the nuclear envelope to mitochondria is associated with mitochondrial dysfunction.
Mitochondrial transplantation: a promising strategy for treating degenerative joint diseases.
BACE Inhibitor Clinical Trials for Alzheimer's Disease.
Mitochondrial Dysfunction Associated with mtDNA Mutation: Mitochondrial Genome Editing in Atherosclerosis Research.
Hormone Replacement Therapy and Alzheimer's Disease: Current State of Knowledge and Implications for Clinical Use.
TOMM40-APOE chimera linking Alzheimer's highest risk genes: a new pathway for mitochondria regulation and APOE4 pathogenesis.
Prospective Intervention Strategies Between Skeletal Muscle Health and Mitochondrial Changes During Aging.
MICUs protect the heart by regulating mitochondrial calcium.

J Alzheimers Dis. 2024 ;101(s1): S155-S178

Oxidative Stress in Alzheimer's Disease: The Shortcomings of Antioxidant Therapies.

Miguel A Pappolla, Ralph N Martins, Burkhard Poeggeler, Rawhi A Omar, George Perry.

  Alzheimer's disease (AD) is a neurodegenerative disorder characterized by gradual and progressive cognitive decline leading to dementia. At its core, the neuropathological features of AD include hallmark accumulations of amyloid-β and hyperphosphorylated tau proteins. Other harmful processes, such as oxidative stress and inflammation, contribute to the disease's neuropathological progression. This review evaluates the role of oxidative stress in AD, placing a spotlight on the disappointing outcomes of various antioxidant clinical trials. Several hypotheses are discussed that might elucidate the failures of these therapies in AD. Specifically: 1) The paradoxical and overlooked harmful implications of prooxidant intermediates, particularly stemming from conventional antioxidants like vitamins E and C; 2) The challenges and failure to appreciate the issue of bioavailability-epitomized by the dictum "no on-site protection, no protection"-and the preeminent, yet often ignored, role played by endogenous antioxidant enzymes in combating oxidative stress; 3) The influence of unrecognized etiologies, such as latent infectious agents and others, as foundational drivers of oxidative stress in AD; 4) The underestimation of the complexity of oxidative mechanisms and the necessity of multi-targeted therapeutic approaches, such as those provided by various diets; and 5) The limitations of clinical trial designs in fully capturing the effects of antioxidants on AD progression. This article also examines the outcomes of select clinical trials while highlighting the challenges and barriers these therapies pose, offering insights into potential mechanisms to overcome their marginal success.

Keywords:  Alzheimer’s disease; DASH diet; MIND diet; Mediterranean diet; clinical trials; melatonin; oxidative stress; resveratrol; vitamin C; vitamin E

DOI:  https://doi.org/10.3233/JAD-240659
J Alzheimers Dis. 2024 ;101(s1): S3-S22

Amyloid-Directed Antibodies: Past, Present, and Future.

Keith Noorda, Kevin Noorda, Marwan N Sabbagh, John Bertelson, Jonathan Singer, Boris Decourt.

   Background: Alzheimer's disease (AD) is the most common neurodegenerative disorder in patient demographics over 65 years old causing debilitating cognitive impairment. Most commonly, AD is diagnosed clinically as "probable AD", and definitive diagnosis is confirmed through postmortem brain autopsies to detect extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau tangles. The exact mechanism causing AD is still unknown, but treatments for AD have been actively investigated. Currently, immunotherapies have shown substantial promise in reducing the pathologic and clinical signs of AD.
Objective: This review aims to evaluate passive immunotherapies deemed to have promise for further development and use in the treatment of AD.
Methods: Immunotherapies were selected via a narrative review of medications that have potential clinical effectiveness with a status of FDA accepted, FDA fast-track, FDA status pending, or emerging therapies poised to pursue FDA approval.
Results: This review has yielded two anti-Aβ monoclonal antibodies (mAb) that are currently fully FDA approved, one mAb granted FDA fast-track status, two therapies on hold, three discontinued medications, and three promising emerging therapies.
Conclusions: We conclude that, in the near future, passive immunotherapies will be the preferred and evidence-based method of treatment for AD with the presence of brain Aβ deposits for both symptom management and potential slowing of disease progression. Specifically, lecanemab and donanemab will require further clinical studies to optimize patient selection based on safety profiles. Despite some key limitations, these two drugs are paving the way for disease-modifying treatments in patients displaying early signs of amyloid pathology.

Keywords:  Alzheimer’s disease; FDA approval; amyloid plaques; clinical trials; passive immunotherapy

DOI:  https://doi.org/10.3233/JAD-240189
J Alzheimers Dis. 2024 ;101(s1): S193-S204

Melatonin in Alzheimer's Disease: Literature Review and Therapeutic Trials.

Marilyn J Steinbach, Natalie L Denburg.

  There are currently no effective treatments to prevent, halt, or reverse Alzheimer's disease (AD), the most common cause of dementia in older adults. Melatonin, a relatively harmless over-the-counter supplement, may offer some benefits to patients with AD. Melatonin is known for its sleep-enhancing properties, but research shows that it may provide other advantages as well, such as antioxidant and anti-amyloidogenic properties. Clinical trials for melatonin use in AD have mixed results but, overall, show modest benefits. However, it is difficult to interpret clinical research in this area as there is little standardization to guide the administration and study of melatonin. This review covers basic biology and clinical research on melatonin in AD focusing on prominent hypotheses of pathophysiology of neurodegeneration and cognitive decline in AD (i.e., amyloid and tau hypotheses, antioxidant and anti-inflammation, insulin resistance and glucose homeostasis, the cholinergic hypothesis, sleep regulation, and the hypothalamic-pituitary-adrenal axis and cortisol). This is followed by a discussion on pending clinical trials, considerations for future research protocols, and open questions in the field.

Keywords:  Aging; Alzheimer’s disease; circadian rhythm; clinical trials; dementia; melatonin; sleep

DOI:  https://doi.org/10.3233/JAD-230760
J Alzheimers Dis. 2024 ;101(s1): S23-S39

Immunotherapy in Alzheimer's Disease: Current Status and Future Directions.

Kshitij Vashisth, Shivani Sharma, Shampa Ghosh, M Arockia Babu, Soumya Ghosh, Danish Iqbal, Mehnaz Kamal, Abdulmajeed G Almutary, Saurabh Kumar Jha, Shreesh Ojha, Rakesh Bhaskar, Niraj Kumar Jha, Jitendra Kumar Sinha.

  Alzheimer's disease (AD) is a progressive neurological disorder characterized by memory loss, cognitive decline, and behavioral changes. Immunotherapy aims to harness the immune system to target the underlying pathology of AD and has shown promise as a disease-modifying treatment for AD. By focusing on the underlying disease pathogenesis and encouraging the removal of abnormal protein aggregates in the brain, immunotherapy shows promise as a potential treatment for AD. The development of immunotherapy for AD began with early attempts to use antibodies to target beta-amyloid. The amyloid hypothesis which suggests that the accumulation of beta-amyloid in the brain triggers the pathological cascade that leads to AD has been a driving force behind the development of immunotherapy for AD. However, recent clinical trials of monoclonal antibodies targeting amyloid-β have shown mixed results, highlighting the need for further research into alternative immunotherapy approaches. Additionally, the safety and efficacy of immunotherapy for AD remain an area of active investigation. Some immunotherapeutic approaches have shown promise, while others have been associated with significant side effects, including inflammation of the brain. Sleep has a significant impact on various physiological processes, including the immune system, and has been linked to the pathogenesis of AD. Thus, improving sleep quality and duration may benefit the immune system and potentially enhance the effectiveness of immunotherapeutic approaches for AD. In this review, we discussed the promises of immunotherapy as a disease-modifying treatment for AD as well as possible methods to improve the efficacy and safety of immunotherapy to achieve better therapeutic outcomes.

Keywords:  Alzheimer’s disease; amyloid-β; dementia; immunotherapy; personalized medicine; sleep-immune interactions

DOI:  https://doi.org/10.3233/JAD-230603
CNS Neurol Disord Drug Targets. 2024 Oct 11.

A Comprehensive Review on Repurposing the Nanocarriers for the Treatment of Parkinson's Disease: An Updated Patent and Clinical Trials.

Sara Khan, Md Faheem Haider.

  Parkinson's Disease (PD) is a progressive neurodegenerative disorder marked by the deterioration of dopamine-producing neurons, resulting in motor impairments like tremors and rigidity. While the precise cause remains elusive, genetic and environmental factors are implicated. Mitochondrial dysfunction, oxidative stress, and protein misfolding contribute to the disease's pathology. Current therapeutics primarily aim at symptom alleviation, employing dopamine replacement and deep brain stimulation. However, the quest for disease-modifying treatments persists. Ongoing clinical trials explore novel approaches, such as neuroprotective agents and gene therapies, reflecting the evolving PD research landscape. This review provides a comprehensive overview of PD, covering its basics, causal factors, major pathways, existing treatments, and a nuanced exploration of ongoing clinical trials. As the scientific community strives to unravel PD's complexities, this review offers insights into the multifaceted strategies pursued for a better understanding and enhanced management of this debilitating condition.

Keywords:  Neurodegenerative; clinical trials; dopamine; nanocarriers; patent

DOI:  https://doi.org/10.2174/0118715273323074241001071645
J Alzheimers Dis. 2024 ;101(s1): S263-S274

Treating Alzheimer's Disease: Focusing on Neurodegenerative Consequences.

Miao-Kun Sun, Daniel L Alkon.

  Neurodegenerative disorders involve progressive dysfunction and loss of synapses and neurons and brain atrophy, slowly declining memories and cognitive skills, throughout a long process. Alzheimer's disease (AD), the leading neurodegenerative disorder, suffers from a lack of effective therapeutic drugs. Decades of efforts targeting its pathologic hallmarks, amyloid plaques and neurofibrillary tangles, in clinical trials have produced therapeutics with marginal benefits that lack meaningful clinical improvements in cognition. Delivering meaningful clinical therapeutics to treat or prevent neurodegenerative disorders thus remains a great challenge to scientists and clinicians. Emerging evidence, however, suggests that dysfunction of various synaptogenic signaling pathways participates in the neurodegenerative progression, resulting in deterioration of operation/structure of the synaptic networks involved in cognition. These derailed endogenous signaling pathways and disease processes are potential pharmacological targets for the therapies. Therapeutics with meaningful clinical benefit in cognition may depend on the effectiveness of arresting and reversing the neurodegenerative process through these targets. In essence, promoting neuro-regeneration may represent the only option to recover degenerated synapses and neurons. These potential directions in clinical trials for AD therapeutics with meaningful clinical benefit in cognitive function are summarized and discussed.

Keywords:  Alzheimer’s disease; brain-derived neurotrophic factor; cognitive therapy; meaningful clinical benefit; neuroinflammation; neuropharmacology; protein kinase Cɛ

DOI:  https://doi.org/10.3233/JAD-240479
Pathol Res Pract. 2024 Oct 03. pii: S0344-0338(24)00552-1. [Epub ahead of print]263 155641

Non-coding RNAs as therapeutic targets in Parkinson's Disease: A focus on dopamine.

Khalid Saad Alharbi.

  Parkinson's Disease is a highly complicated neurological disorder, with a key manifestation of loss of dopaminergic neurons. Despite the plethora of medicines that alleviate the symptoms, there is an urgent need for new treatments acting on the fundamental pathology of PD. Non-coding RNAs are becoming increasingly important in gene regulation and various cellular processes and are found to play a role in PD pathophysiology. This review analyzes the cross-talk of distinct ncRNAs with dopamine signaling. We attempt to constrain the various ncRNA networks that can activate dopamine production. First, we describe the deregulation of miRNAs that target dopamine receptors and have been implicated in PD. Next, we turn to the functions of lncRNAs in dopaminergic neurons and the connections to susceptibility genes for PD. Finally, we will analyze the novel circRNAs, such as ciRS-7, which may modulate dopamine-linked processes and serve as possible PD biomarkers. In this review, we describe recent progress in dopamine neuron revival to treat PD and the therapeutic potential of ncRNA. This review critically evaluates the available data, and we predict the role of some ncRNAs, such as PTBP1, to become candidate treatment targets in the future. Thus, this review aims to summarize the molecular causes for the deficit in dopamine signaling in PD and point to novel ncRNAs-linked therapeutic directions in neuroscience.

Keywords:  Dopamine signaling; Dopaminergic neurons; NcRNAs; Parkinson’s disease; Pathology; Therapeutic candidate

DOI:  https://doi.org/10.1016/j.prp.2024.155641
ACS Med Chem Lett. 2024 Oct 10. 15(10): 1756-1763

Neuroprotective Effect of 2-(Benzyloxy)arylureas Is Not Related to CypD Inhibition nor Suppression of mPTP Opening.

Annamaria Haleckova, Veronika Syrova, Andrea Joklova, Tereza Vernerova, Jan Hurdalek, Rene Endlicher, Katerina Salamonova, Petra Bubelova, Haka Fajriana Febda Kurnia, Monika Schmidt, Kamil Musilek, Lucie Zemanova, Ondrej Benek.

Cyclophilin D (CypD) is a mitochondrial enzyme widely accepted as a regulator of the mitochondrial permeability transition pore (mPTP). Excessive opening of mPTP is associated with mitochondrial dysfunction and the development of various diseases; thus, suppression of mPTP opening through CypD inhibition presents a promising therapeutic approach. However, only a limited number of selective CypD inhibitors are currently available. In this study, 10 derivatives of 2-(benzyloxy)arylurea similar or identical to previously published CypD/mPTP inhibitors were synthesized. Unlike the original reports that assessed the opening of mPTP at the cellular level, the compounds were tested directly on the purified CypD enzyme to validate their putative mechanism of action. Additionally, the effect of the selected compounds was tested on isolated mitochondria. The obtained results show that the compounds are only weak inhibitors of CypD and mPTP opening, which is in contrast to previous conclusions drawn from the unspecific cellular JC-1 assay.

DOI: https://doi.org/10.1021/acsmedchemlett.4c00353
Histol Histopathol. 2024 Sep 24. 18820

NRIP1 is a downstream target of YY1 in promoting OGD/R-induced H9c2 cardiomyocyte injury and mitochondrial dysfunction.

Wanliu Zhang, Jingqian Zhang, Jingqian Lu, Yan Gao, Qianhong Song, Shihua Luo, Yi Li.

BACKGROUND AND OBJECTIVE: From a clinical standpoint, myocardial ischemia/reperfusion injury (MIRI) has always been an enormous challenge for the treatment of acute myocardial infarction (AMI). Molecular targeting therapy may help overcome this challenge. The present work aimed to elucidate the possible involvement of Yin-Yang 1 (YY1)/nuclear receptor-interacting protein 1 (NRIP1) and discover the molecular mechanism of MIRI.
METHODS: Herein, a cardiomyocyte ischemia/reperfusion (I/R) model was established via oxygen-glucose deprivation/re-oxygenation (OGD/R) damage in H9c2 cardiomyocytes. Reverse transcription-quantitative PCR and western blotting were conducted to measure the levels of YY1 and NRIP1 at the RNA and protein levels, respectively. H9c2 cell viability and apoptosis were assayed using the Cell Counting Kit-8, flow cytometry, and western blotting. In addition, superoxide dismutase, glutathione peroxidase, and malondialdehyde levels were analyzed as markers of oxidative stress. Additionally, mitochondrial membrane potential, which was measured via JC-1 staining, ATP content, Complex I activity, mitochondrial DNA copy number, and mitochondrial permeability transition pore (mPTP) opening rate were analyzed to evaluate mitochondrial activity. Moreover, luciferase reporter and chromatin immunoprecipitation assays experimentally validated the predicted affinity of YY1 with the NRIP1 promoter according to the HumanTFDB online tool.
RESULTS: YY1/NRIP1 were both highly expressed in OGD/R-injured H9c2 cardiomyocytes. Downregulation of NRIP1 improved cell viability, whereas it inhibited cell apoptosis and oxidative stress, and suppressed mitochondrial dysfunction in OGD/R-injured H9c2 cardiomyocytes. Importantly, it was verified that YY1 could bind to the NRIP1 promoter to positively regulate NRIP1 expression. The protective effects of NRIP1 knockdown against cardiomyocyte damage and mitochondrial dysfunction in OGD/R-injured H9c2 cardiomyocytes were partly abolished through overexpression of YY1.
CONCLUSION: NRIP1 emerged as a downstream target of YY1 in promoting OGD/R-induced H9c2 cardiomyocyte injury and mitochondrial dysfunction, providing novel ideas for targeted treatments to alleviate MIRI.

DOI: https://doi.org/10.14670/HH-18-820
Mater Today Bio. 2024 Dec;29 101273

Non-pathogenic Trojan horse Nissle1917 triggers mitophagy through PINK1/Parkin pathway to discourage colon cancer.

Yang Wang, Yao Liu, Xiaomin Su, Lili Niu, Nannan Li, Ce Xu, Zanya Sun, Huishu Guo, Shun Shen, Minghua Yu.

  Bacteria-mediated antitumor therapy has gained widespread attention for its innate tumor-targeting capability and excellent immune activation properties. Nevertheless, the clinical approval of bacterial therapies remains elusive primarily due to the formidable challenge of balancing safety with enhancing in vivo efficacy. In this study, leveraging the probiotic Escherichia coli Nissle1917 (EcN) emerges as a promising approach for colon cancer therapy, offering a high level of safety attributed to its lack of virulence factors and its tumor-targeting potential owing to its obligate anaerobic nature. Specifically, we delineate the erythrocyte (RBC) membrane-camouflaged EcN, termed as Trojan horse EcN@RBC, which triggers apoptosis in tumor cells by mitigating mitochondrial membrane potential (MMP) and subsequently activating the PINK1/Parkin pathway associated with mitophagy. Concurrently, the decline in MMP induced by mitophagy disrupts the mitochondrial permeability transition pore (MPTP), leading to the release of Cytochrome C and subsequent apoptosis induction. Moreover, synergistic effects were observed through the combination of the autophagy activator rapamycin, bolstering the antitumor efficacy in vivo. These findings offer novel insights into probiotic-mediated antitumor mechanisms and underscore the therapeutic potential of EcN@RBC for colon cancer patients.

Keywords:  Apoptosis; EcN@RBC; Mitophagy; RBC membrane

DOI:  https://doi.org/10.1016/j.mtbio.2024.101273
Photochem Photobiol. 2024 Oct 16.

Ultraviolet radiation inhibits mitochondrial bioenergetics activity.

Aline S Perez, Natalia M Inada, Natasha F Mezzacappo, Jose D Vollet-Filho, Vanderlei S Bagnato.

  Mitochondria play an important role in cellular function, not only as a major site of adenosine triphosphate (ATP) production but also by regulating energy expenditure, apoptosis signaling, control of the cell cycle, cellular growth, cell differentiation, transportation of metabolites, and production of reactive oxygen species. Interaction with electromagnetic waves can lead to dysregulation or alterations in the patterns of energy activities in the mitochondria. Ultraviolet light (UV) can be found in sunlight and artificial sources, such as lamps. UV radiation can cause damage to DNA, proteins, and lipids. Besides that, UV radiation is largely used in microorganism disinfection. To establish possible alterations in mitochondrial bioenergetics, this study proposes to investigate the UV (at two distinct intervals) effects on isolated mitochondria from mice liver to obtain direct responses and selective permeability of the internal membrane information. UVA-371 and UVC-255 nm lamps were used to irradiate, at different doses varying from 22.5 to 756 mJ/cm2, isolated mitochondria samples. Mitochondrial respiration pathways were investigated by high-resolution respirometry, and possible mitochondrial membrane damages were evaluated by mitochondrial swelling by spectrophotometer analysis. UVC irradiation results (in the higher dose) indicate decrease in 75% of mitochondrial bioenergetics capacity, such as limitation of oxidative phosphorylation in 60% and increased energy dissipation in 30%. Mitochondrial swelling experiments (spectrophotometer) indicated inner membrane damage, and consequently a loss of selective permeability. Direct correlation between irradiation and effect responses was observed, mitochondrial bioenergetics is severely affected by UVC radiation, but (UVA) radiation did not present bioenergetic alterations. These alterations can contribute to improving the knowledge behind the cell death mechanism in disinfection UV light and UV therapy such as phototherapy.

Keywords:  bioenergetics; electromagnetic radiation; isolated mitochondria; ultraviolet radiation

DOI:  https://doi.org/10.1111/php.14034
J Alzheimers Dis. 2024 ;101(s1): S299-S315

Drug Repurposing for Effective Alzheimer's Disease Medicines: Existing Methods and Novel Pharmacoepidemiological Approaches.

Jackson A Roberts, Vijay R Varma, Attila Jones, Madhav Thambisetty.

  Drug repurposing is a methodology used to identify new clinical indications for existing drugs developed for other indications and has been successfully applied in the treatment of numerous conditions. Alzheimer's disease (AD) may be particularly well-suited to the application of drug repurposing methods given the absence of effective therapies and abundance of multi-omic data that has been generated in AD patients recently that may facilitate discovery of candidate AD drugs. A recent focus of drug repurposing has been in the application of pharmacoepidemiologic approaches to drug evaluation. Here, real-world clinical datasets with large numbers of patients are leveraged to establish observational efficacy of candidate drugs for further evaluation in disease models and clinical trials. In this review, we provide a selected overview of methods for drug repurposing, including signature matching, network analysis, molecular docking, phenotypic screening, semantic network, and pharmacoepidemiological analyses. Numerous methods have also been applied specifically to AD with the aim of nominating novel drug candidates for evaluation. These approaches, however, are prone to numerous limitations and potential biases that we have sought to address in the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study, a multi-step framework for selection and validation of potential drug candidates that has demonstrated the promise of STAT3 inhibitors and re-evaluated evidence for other drug candidates, such as phosphodiesterase inhibitors. Taken together, drug repurposing holds significant promise for development of novel AD therapeutics, particularly as the pace of data generation and development of analytical methods continue to accelerate.

Keywords:  Alzheimer’s disease; clinical trials; drug repositioning; drug repurposing; metabolomics; pharmacoepidemiology; proteomics

DOI:  https://doi.org/10.3233/JAD-240680
Expert Opin Drug Deliv. 2024 Oct 13. 1-22

Exploring nanoparticular platform in delivery of repurposed drug for Alzheimer's disease: current approaches and future perspectives.

Snigdha Chakraborty, Sukriti Vishwas, Vancha Harish, Gaurav Gupta, Keshav Raj Paudel, Muralikrishnan Dhanasekaran, Bey Hing Goh, Flavia Zacconi, Terezinha de Jesus Andreoli Pinto, Popat Kumbhar, John Disouza, Kamal Dua, Sachin Kumar Singh.

   INTRODUCTION: Alzheimer's disease (AD) stands as significant challenge in realm of neurodegenerative disorder. It is characterized by gradual decline in cognitive function and memory loss. It has already expanded its prevalence to 55 million people worldwide and is expected to rise significantly. Unfortunately, there exists a limited therapeutic option that would mitigate its progression. Repurposing existing drugs and employing nanoparticle as delivery agent presents a potential solution to address the intricate pathology of AD.
AREAS COVERED: In this review, we delve into utilization of nanoparticular platforms to enhance the delivery of repurposed drugs for treatment of AD. Firstly, the review begins with the elucidation of intricate pathology underpinning AD, subsequently followed by rationale behind drug repurposing in AD. Covered are explorations of nanoparticle-based repurposing of drugs in AD, highlighting their clinical implication. Further, the associated challenges and probable future perspective are delineated.
EXPERT OPINION: The article has highlighted that extensive research has been carried out on the delivery of repurposed nanomedicines against AD. However, there is a need for advanced and long-term research including clinical trials required to shed light upon their safety and toxicity profile. Furthermore, their scalability in pharmaceutical set-up should also be validated.

Keywords:  Alzheimer’s disease; Pre-clinical study; drug repurposing; non-anti-Alzheimer’s drugs; novel drug delivery system

DOI:  https://doi.org/10.1080/17425247.2024.2414768
J Alzheimers Dis. 2024 ;101(s1): S115-S128

CT1812, a Small Molecule Sigma-2 Receptor Antagonist for Alzheimer's Disease Treatment: A Systematic Review of Available Clinical Data.

Premrutai Thitilertdecha, James Michael Brimson.

   Background: Alzheimer's disease (AD) is of growing concern worldwide as the demographic changes to a more aged population. Amyloid-β (Aβ deposition is thought to be a key target for treating AD. However, Aβ antibodies have had mixed results, and there is concern over their safety. Studies have shown that the sigma-2 receptor (σ-2R)/TMEM97 is a binding site for Aβ oligomers. Therefore, targeting the receptor may be beneficial in displacing Aβ oligomers from the brain. CT1812 is a σ-2R/TMEM97 antagonist that is effective in preclinical studies of AD and has been entered into clinical trials.
Objective: The objective of this study was to systematically review the safety and efficacy of CT1812 for the treatment of AD.
Methods: Between June and August 2023, we searched the primary literature (PubMed, Scopus, Google Scholar, etc.) and clinical trials databases (http://www.clinicaltrails.gov). The extracted data is evaluated within this manuscript.
Results: CT1812 is relatively safe, with only mild adverse events reported at doses up to 840 mg. CT1812 can displace Aβ in the clinical studies, in line with the preclinical data. Studies have investigated brain connectivity and function in response to CT1812. However, the cognitive data is still lacking, with only one study including cognitive data as a secondary outcome.
Conclusions: CT1812 safely works to displace Aβ however, whether this is enough to prevent/slow the cognitive decline seen in AD remains to be seen. Longer clinical trials are needed to assess the efficacy of CT1812; several trials of this nature are currently ongoing.

Keywords:  Alzheimer’s disease; Elayta; Sigma receptors; Sigma-2 receptor; Sigma-2 receptor antagonist; TMEM97; amyloid oligomer displacement; clinical data; dementia

DOI:  https://doi.org/10.3233/JAD-230994
J Alzheimers Dis. 2024 ;101(s1): S345-S356

Metformin as a Potential Prevention Strategy for Alzheimer's Disease and Alzheimer's Disease Related Dementias.

Mouna Tahmi, Richard Benitez, José A Luchsinger.

   Background: Metformin is a safe and effective medication for type 2 diabetes (T2D) that has been proposed to decrease the risk of aging related disorders including Alzheimer's disease (AD) and Alzheimer's disease related disorders(ADRD).
Objective: This review seeks to summarize findings from studies examining the association of metformin with AD/ADRD related outcomes.
Methods: This is a narrative review of human studies, including observational studies and clinical trials, examining the association of metformin with cognitive and brain outcomes. We used PubMed as the main database for our literature search with a focus on English language human studies including observational studies and clinical trials. We prioritized studies published from 2013 until February 15, 2024.
Results: Observational human studies are conflicting, but those with better study designs suggest that metformin use in persons with T2D is associated with a lower risk of dementia. However, these observational studies are limited by the use of administrative data to ascertain metformin use and/or cognitive outcomes. There are few clinical trials in persons without T2D that have small sample sizes and short durations but suggest that metformin could prevent AD/ADRD. There are ongoing studies including large clinical trials with long duration that are testing the effect of metformin on AD/ADRD outcomes in persons without T2D at risk for dementia.
Conclusions: Clinical trial results are needed to establish the effect of metformin on the risk of AD and ADRD.

Keywords:  Alzheimer’s disease; dementia; diabetes; metformin

DOI:  https://doi.org/10.3233/JAD-240495
J Alzheimers Dis. 2024 ;101(s1): S417-S431

Advances and Challenges in Gene Therapy for Alzheimer's Disease.

Fabiana Morroni, Antonella Caccamo.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral impairments. Despite extensive research efforts, effective treatment options for AD remain limited. Recently, gene therapy has emerged as a promising avenue for targeted intervention in the pathogenesis of AD. This review will provide an overview of clinical and preclinical studies where gene therapy techniques have been utilized in the context of AD, highlighting their potential as novel therapeutic strategies. While challenges remain, ongoing research and technological advancement continue to enhance the potential of gene therapy as a targeted and personalized therapeutic approach for AD.

Keywords:  Adeno associated virus; Alzheimer’s disease; amyloid-β; neurotrophins; tau

DOI:  https://doi.org/10.3233/JAD-230783
Life Sci. 2024 Oct 10. pii: S0024-3205(24)00709-4. [Epub ahead of print]358 123119

Mitochondrial transfer in the progression and treatment of cardiac disease.

Yaqing Huang, Wanling Li, Hongyu Sun, Xin Guo, Yue Zhou, Jun Liu, Feila Liu, Yonghong Fan.

  Mitochondria are the primary site for energy production and play a crucial role in supporting normal physiological functions of the human body. In cardiomyocytes (CMs), mitochondria can occupy up to 30 % of the cell volume, providing sufficient energy for CMs contraction and relaxation. However, some pathological conditions such as ischemia, hypoxia, infection, and the side effect of drugs, can cause mitochondrial dysfunction in CMs, leading to various myocardial injury-related diseases including myocardial infarction (MI), myocardial hypertrophy, and heart failure. Self-control of mitochondria quality and conversion of metabolism pathway in energy production can serve as the self-rescue measure to avoid autologous mitochondrial damage. Particularly, mitochondrial transfer from the neighboring or extraneous cells enables to mitigate mitochondrial dysfunction and restore their biological functions in CMs. Here, we described the homeostatic control strategies and related mechanisms of mitochondria in injured CMs, including autologous mitochondrial quality control, mitochondrial energy conversion, and especially the exogenetic mitochondrial donation. Additionally, this review emphasizes on the therapeutic effects and potential application of utilizing mitochondrial transfer in reducing myocardial injury. We hope that this review can provide theoretical clues for the developing of advanced therapeutics to treat cardiac diseases.

Keywords:  Cardiac diseases; Cardiomyocyte; Mitochondrial quality control; Mitochondrial therapy; Mitochondrial transfer

DOI:  https://doi.org/10.1016/j.lfs.2024.123119
Front Aging Neurosci. 2024 ;16 1459025

The role of PI3K signaling pathway in Alzheimer's disease.

Jingying Pan, Qi Yao, Yankai Wang, Suyan Chang, Chenlong Li, Yongjiang Wu, Jianhong Shen, Riyun Yang.

  Alzheimer's disease (AD) is a debilitating progressively neurodegenerative disease. The best-characterized hallmark of AD, which is marked by behavioral alterations and cognitive deficits, is the aggregation of deposition of amyloid-beta (Aβ) and hyper-phosphorylated microtubule-associated protein Tau. Despite decades of experimental progress, the control rate of AD remains poor, and more precise deciphering is needed for potential therapeutic targets and signaling pathways involved. In recent years, phosphoinositide 3-kinase (PI3K) and Akt have been recognized for their role in the neuroprotective effect of various agents, and glycogen synthase kinase 3 (GSK3), a downstream enzyme, is also crucial in the tau phosphorylation and Aβ deposition. An overview of the function of PI3K/Akt pathway in the pathophysiology of AD is provided in this review, along with a discussion of recent developments in the pharmaceuticals and herbal remedies that target the PI3K/Akt signaling pathway. In conclusion, despite the challenges and hurdles, cumulative findings of novel targets and agents in the PI3K/Akt signaling axis are expected to hold promise for advancing AD prevention and treatment.

Keywords:  Akt; Alzheimer’s disease; GSK3; PI3K; amyloid-β; tau protein

DOI:  https://doi.org/10.3389/fnagi.2024.1459025
Ageing Res Rev. 2024 Oct 16. pii: S1568-1637(24)00363-5. [Epub ahead of print] 102545

The Role of Sirtuin 1 in Ageing and Neurodegenerative Disease: A Molecular Perspective.

Riya Thapa, Ehssan Moglad, Muhammad Afzal, Gaurav Kumar, Asif Ahmad Bhat, Waleed Hassan Almalki, Imran Kazmi, Sami I Alzarea, Kumud Pant, Thakur Gurjeet Singh, Sachin Kumar Singh, Haider Ali.

  Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, has emerged as a key regulator of cellular processes linked to ageing and neurodegeneration. SIRT1 modulates various signalling pathways, including those involved in autophagy, oxidative stress, and mitochondrial function, which are critical in the pathogenesis of neurodegenerative diseases. This review explores the therapeutic potential of SIRT1 in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Preclinical studies have demonstrated that SIRT1 activators, such as resveratrol, SRT1720, and SRT2104, can alleviate disease symptoms by reducing oxidative stress, enhancing autophagic flux, and promoting neuronal survival. Ongoing clinical trials are evaluating the efficacy of these SIRT1 activators, providing hope for future therapeutic strategies targeting SIRT1 in neurodegenerative diseases. This review explores the role of SIRT1 in ageing and neurodegenerative diseases, with a particular focus on its molecular mechanisms, therapeutic potential, and clinical applications.

Keywords:  Alzheimer's Disease; Cellular Homeostasis; Huntington's Disease; Neurodegenerative Diseases; Parkinson's Disease; Sirtuin 1

DOI:  https://doi.org/10.1016/j.arr.2024.102545
J Alzheimers Dis. 2024 ;101(s1): S467-S477

Supplementation with NAD+ Precursors for Treating Alzheimer's Disease: A Metabolic Approach.

Mohammed Alghamdi, Nady Braidy.

   Background: Alzheimer's disease (AD) is a progressive neurocognitive disorder. There is no cure for AD. Maintenance on intracellular levels of nicotinamide adenine dinucleotide (NAD+) has been reported to be a promising therapeutic strategy for the treatment of AD. NAD+ precursors that represent candidate targets include nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR).
Objective: This systematic review provides insights into the potential therapeutic value of NAD+ precursors including NMN and NR, for the treatment of AD using preclinical and clinical studies published in the last 5 years.
Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol was followed to systematically search the literature using two databases.
Results: We found 3 studies that used NMN to treat AD in preclinical murine models. However, human clinical trials using NMN as a therapeutic intervention in AD was not available in the current literature. We also found 4 studies that investigated the potential benefits of NR for the treatment of AD in preclinical models. We also found 2 human clinical trials that showed marked improvements in plasma and neuroimaging biomarkers, and cognitive measures following supplementation with NR.
Conclusions: Results of preclinical and clinical studies confirm the potential benefits of NAD+ precursors for the treatment of AD. However, further clinical studies are required to confirm the increasingly important value of NAD+ precursors as effective pharmacological interventions in the clinic.

Keywords:  Alzheimer’s disease; NAD+; amyloid; dementia; nicotinamide; sirtuins

DOI:  https://doi.org/10.3233/JAD-231277
Nucleus. 2024 Dec;15(1): 2413501

Apoptosis-induced translocation of nesprin-2 from the nuclear envelope to mitochondria is associated with mitochondrial dysfunction.

Hila Zohar, Liora Lindenboim, Oren Gozlan, Gregg G Gundersen, Howard J Worman, Reuven Stein.

  Accumulating evidence suggests that the nuclear envelope (NE) is not just a target, but also a mediator of apoptosis. We showed recently that the NE protein nesprin-2 has pro-apoptotic activity, which involves its subcellular redistribution and Bcl-2 proteins. Here we further characterize the pro-apoptotic activity of nesprin-2 focusing on its redistribution. We assessed the redistribution kinetics of endogenous nesprin-2 tagged with GFP relative to apoptosis-associated mitochondrial dysfunction. The results show apoptosis-induced GFP-nesprin-2G redistribution occurred by two different modes - complete and partial, both lead to appearance of nesprin-2G near the mitochondria. Moreover, GFP-nesprin-2 redistribution is associated with reduction in mitochondrial membrane potential and mitochondrial outer membrane permeabilization and precedes the appearance of morphological features of apoptosis. Our results show that nesprin-2G redistribution and translocation near mitochondria is an early apoptotic effect associated with mitochondrial dysfunction, which may be responsible for the pro-apoptotic function of nesprin-2.

Keywords:  Apoptosis; LINC complex; mitochondria; nesprin-2; nuclear envelope; nucleus

DOI:  https://doi.org/10.1080/19491034.2024.2413501
J Transl Med. 2024 Oct 15. 22(1): 941

Mitochondrial transplantation: a promising strategy for treating degenerative joint diseases.

Hong Luo, Yue Lai, Weili Tang, Guoyou Wang, Jianlin Shen, Huan Liu.

  The prevalence of age-related degenerative joint diseases, particularly intervertebral disc degeneration and osteoarthritis, is increasing, thereby posing significant challenges for the elderly population. Mitochondrial dysfunction is a critical factor in the etiology and progression of these disorders. Therapeutic interventions that incorporate mitochondrial transplantation exhibit considerable promise by increasing mitochondrial numbers and improving their functionality. Existing evidence suggests that exogenous mitochondrial therapy improves clinical outcomes for patients with degenerative joint diseases. This review elucidates the mitochondrial abnormalities associated with degenerative joint diseases and examines the mechanisms of mitochondrial intercellular transfer and artificial mitochondrial transplantation. Furthermore, therapeutic strategies for mitochondrial transplantation in degenerative joint diseases are synthesized, and the concept of engineered mitochondrial transplantation is proposed.

Keywords:  Degenerative joint diseases; Engineered mitochondria; Intervertebral disc degeneration; Mitochondrial transplantation; Osteoarthritis

DOI:  https://doi.org/10.1186/s12967-024-05752-0
J Alzheimers Dis. 2024 ;101(s1): S41-S52

BACE Inhibitor Clinical Trials for Alzheimer's Disease.

Elyse A Watkins, Robert Vassar.

  The amyloid hypothesis posits that the amyloid-β aggregates in the brain initiate a cascade of events that eventually lead to neuron loss and Alzheimer's disease. Recent clinical trials of passive immunotherapy with anti-amyloid-β antibodies support this hypothesis, because clearing plaques led to better cognitive outcomes. Orally available small molecule BACE1 inhibitors are another approach to slowing the buildup of plaques and thereby cognitive worsening by preventing the cleavage of amyloid-β protein precursor (AβPP) into amyloid-β peptide, the major component of plaques. This approach is particularly attractive because of their ease of use, low cost, and advanced clinical stage. However, although effective in preventing amyloid-β production in late-stage clinical trials, BACE inhibitors have been associated with early, non-progressive, likely reversible, cognitive decline. The clinical trials tested high levels of BACE inhibition, greater than 50%, whereas genetics suggest that even a 30% inhibition may be sufficient to protect from Alzheimer's disease. Aside from AβPP, BACE1 cleaves many other substrates in the brain that may be contributing to the cognitive worsening. It is important to know what the cause of cognitive worsening is, and if a lower level of inhibition would sufficiently slow the progress of pathology while preventing these unwanted side effects. Should these side effects be mitigated, BACE inhibitors could rapidly move forward in clinical trials either as a primary prevention strategy in individuals that are at risk or biomarker positive, or as a maintenance therapy following amyloid clearance with an anti-amyloid antibody.

Keywords:  Alzheimer’s disease; amyloid-β protein precursor; beta-secretase; clinical trial

DOI:  https://doi.org/10.3233/JAD-231258
Curr Med Chem. 2024 Oct 11.

Mitochondrial Dysfunction Associated with mtDNA Mutation: Mitochondrial Genome Editing in Atherosclerosis Research.

Victoria A Khotina, Andrey Y Vinokurov, Vasily V Sinyov, Alexander D Zhuravlev, Daniil Y Popov, Vasily N Sukhorukov, Igor A Sobenin, Alexander N Orekhov.

   BACKGROUND: Atherosclerosis is a complex cardiovascular disease often associated with mitochondrial dysfunction, which can lead to various cellular and metabolic abnormalities. Within the mitochondrial genome, specific mutations have been implicated in contributing to mitochondrial dysfunction. Atherosclerosis-associated m.15059G>A mutation has been of particular interest due to its potential role in altering mitochondrial function and cellular health.
OBJECTIVE: This study aims to investigate the role of the atherosclerosis-associated m.15059G>A mutation in the development of mitochondrial dysfunction in monocyte-- like cells.
METHODS: Monocyte-like cytoplasmic hybrid cell line TC-HSMAM1, which contains the m.15059G>A mutation in mtDNA, was used. The MitoCas9 vector was utilized to eliminate mtDNA copies carrying the m.15059G>A mutation from TC-HSMAM1 cybrids. Mitochondrial membrane potential, generation of reactive oxygen species, and lipid peroxidation levels were assessed using flow cytometry. Cellular reduced glutathione levels were assessed using the confocal microscopy. The oxygen consumption rate was measured using polarographic oxygen respirometry.
RESULTS: The elimination of the m.15059G>A mutation resulted in a significant increase in mitochondrial membrane potential and improved mitochondrial efficiency while also causing a decrease in the generation of reactive oxygen species, lipid peroxidation, as well as cellular bioenergetic parameters, such as proton leak and non-mitochondrial oxygen consumption. At the same time, no changes were found in the intracellular antioxidant system after the mitochondrial genome editing.
CONCLUSIONS: The presence of the m.15059G>A mutation contributes to mitochondrial dysfunction by reducing mitochondrial membrane potential, increasing the generation of reactive oxygen species and lipid peroxidation, and altering mitochondrial bioenergetics. Elimination of the mtDNA containing atherogenic mutation leads to an improvement in mitochondrial function.

Keywords:  Atherosclerosis; mitochondrial DNA mutations; mitochondrial membrane potential; mitochondrial respiration; reactive oxygen species.

DOI:  https://doi.org/10.2174/0109298673323639240926095549
J Alzheimers Dis. 2024 ;101(s1): S235-S261

Hormone Replacement Therapy and Alzheimer's Disease: Current State of Knowledge and Implications for Clinical Use.

Jessica Sayfullaeva, John McLoughlin, Andrea Kwakowsky.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder responsible for over half of dementia cases, with two-thirds being women. Growing evidence from preclinical and clinical studies underscores the significance of sex-specific biological mechanisms in shaping AD risk. While older age is the greatest risk factor for AD, other distinct biological mechanisms increase the risk and progression of AD in women including sex hormones, brain structural differences, genetic background, immunomodulation and vascular disorders. Research indicates a correlation between declining estrogen levels during menopause and an increased risk of developing AD, highlighting a possible link with AD pathogenesis. The neuroprotective effects of estrogen vary with the age of treatment initiation, menopause stage, and type. This review assesses clinical and observational studies conducted in women, examining the influence of estrogen on cognitive function or addressing the ongoing question regarding the potential use of hormone replacement therapy (HRT) as a preventive or therapeutic option for AD. This review covers recent literature and discusses the working hypothesis, current use, controversies and challenges regarding HRT in preventing and treating age-related cognitive decline and AD. The available evidence indicates that estrogen plays a significant role in influencing dementia risk, with studies demonstrating both beneficial and detrimental effects of HRT. Recommendations regarding HRT usage should carefully consider the age when the hormonal supplementation is initiated, baseline characteristics such as genotype and cardiovascular health, and treatment duration until this approach can be more thoroughly investigated or progress in the development of alternative treatments can be made.

Keywords:  Alzheimer’s disease; cognition; dementia; estradiol; estrogen; hormone replacement therapy; hormone therapy; memory

DOI:  https://doi.org/10.3233/JAD-240899
bioRxiv. 2024 Oct 09. pii: 2024.10.09.617477. [Epub ahead of print]

TOMM40-APOE chimera linking Alzheimer's highest risk genes: a new pathway for mitochondria regulation and APOE4 pathogenesis.

Jinglei Xu, Jingqi Duan, Zhiqiang Cai, Chie Arai, Chao Di, Christopher C Venters, Jian Xu, Maura Jones, Byung-Ran So, Gideon Dreyfuss.

The patho-mechanism of apolipoprotein variant, APOE4, the strongest genetic risk for late-onset Alzheimer's disease (AD) and longevity, remains unclear. APOE's neighboring gene, TOMM40 (mitochondria protein transport channel), is associated with brain trauma outcome and aging-related cognitive decline, however its role in AD APOE4-independently is controversial. We report that TOMM40 is prone to transcription readthrough into APOE that can generate spliced TOMM40-APOE mRNA chimera (termed T9A2) detected in human neurons and other cells and tissues. T9A2 translation tethers APOE (normal APOE3 or APOE4) to near-full-length TOM40 that is targeted to mitochondria. Importantly, T9A2-APOE3 boosts mitochondrial bioenergetic capacity and decreases oxidative stress significantly more than T9A2-APOE4 and APOE3, and lacking in APOE4. We describe detailed interactomes of these actors that may inform about the activities and roles in pathogenesis. T9A2 uncovers a new candidate pathway for mitochondria regulation and oxidative stress-protection that are impaired in APOE4 genotypes and could initiate neurodegeneration.

DOI: https://doi.org/10.1101/2024.10.09.617477
Adv Biol (Weinh). 2024 Oct 16. e2400235

Prospective Intervention Strategies Between Skeletal Muscle Health and Mitochondrial Changes During Aging.

Xin Zhang, Suchan Liao, Lingling Huang, Jinhua Wang.

  Sarcopenia is a geriatric condition characterized by a decrease in skeletal muscle mass and function, significantly impacting both quality of life and overall health. Mitochondria are the main sites of energy production within the cell, and also produce reactive oxygen species (ROS), which maintain mitochondrial homeostasis-mitophagy (clearing damaged mitochondria); mitochondrial dynamics, which involve fusion and fission to regulate mitochondrial morphology; mitochondrial biogenesis, which ensures the functionality and homeostasis of mitochondria. Sarcopenia is linked to mitochondrial dysfunction, suggesting that muscle mitochondrial function therapy should be investigated. Extrinsic therapies are extensively examined to identify new treatments for muscular illnesses including sarcopenia. Changes in muscle physiology and lifestyle interventions, such as pharmacological treatments and exercise, can modulate mitochondrial activity in older adults. This PubMed review encompasses the most significant mitophagy and sarcopenia research from the past five years. Animal models, cellular models, and human samples are well covered. The review will inform the development of novel mitochondria-targeted therapies aimed at combating age-related muscle atrophy.

Keywords:  Aging; mechanism; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1002/adbi.202400235
Trends Pharmacol Sci. 2024 Oct 14. pii: S0165-6147(24)00209-8. [Epub ahead of print]

MICUs protect the heart by regulating mitochondrial calcium.

Ulas Ozkurede, Shanmugasundaram Pakkiriswami, Julia C Liu.

  Regulation of mitochondrial calcium uptake by the mitochondrial calcium uniporter (mtCU) complex is crucial for heart function. In a recent study, Hasan et al. demonstrated that mitochondrial calcium uptake (MICU)1 and MICU2, regulatory subunits of the complex, help maintain calcium homeostasis in cardiac mitochondria, providing potential targets for therapies aimed at improving mitochondrial function in heart disease.

Keywords:  EMRE; MCU; MICU1; MICU2; calcium; heart; mitochondria

DOI:  https://doi.org/10.1016/j.tips.2024.09.010