Interactions of amyloidogenic proteins with mitochondrial protein import machinery in aging-related neurodegenerative diseases

Frontiers in Physiology, Год журнала: 2023, Номер 14

Опубликована: Ноя. 2, 2023

Most mitochondrial proteins are targeted to the organelle by N-terminal targeting sequences (MTSs, or “presequences”) that recognized import machinery and subsequently cleaved yield mature protein. MTSs do not have conserved amino acid compositions, but share common physicochemical properties, including ability form amphipathic α-helical structures enriched with basic hydrophobic residues on alternating faces. The lack of strict sequence conservation implies some polypeptides can be mistargeted mitochondria, especially under cellular stress. pathogenic accumulation within mitochondria is implicated in many aging-related neurodegenerative diseases, Alzheimer’s, Parkinson’s, Huntington’s diseases. Mechanistically, these diseases may originate part from interactions amyloid-β precursor protein (APP) its cleavage product (Aβ), α-synuclein (α-syn), mutant forms huntingtin (mHtt), respectively, mediated through their associations machinery. Emerging evidence suggests amyloidogenic present cryptic signals act as MTS mimetics receptors transported into different compartments. Accumulation could overwhelm associated quality control mechanisms, thereby contributing neurological disease progression. Alternatively, uptake a mechanism for clearance cytotoxic proteins. Here we review pathomechanisms they relate effects function, what features APP/Aβ, α-syn mHtt make them suitable substrates machinery, how this information leveraged development therapeutic interventions.

Язык: Английский

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Cultured Rat Hippocampal Neurons Exposed to the Mitochondrial Uncoupler Carbonyl Cyanide Chlorophenylhydrazone Undergo a Rapid, Presenilin-Dependent Change in Neuronal Properties

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(1), С. 578 - 578

Опубликована: Янв. 1, 2024

Presenilin 1 (PS1) is a transmembrane proteolytic subunit of γ-secretase that cleaves amyloid precursor proteins. Mutations in PS1 (mPS1) are associated with early-onset familial Alzheimer’s disease (AD). The link between mutated PS1, mitochondrial calcium regulation, and AD has been studied extensively different test systems. Despite the wide-ranging role mPS1 AD, there paucity information on neuronal cell death, hallmark AD. In present study, we employed selective uncoupler carbonyl cyanide chlorophenylhydrazone (CCCP) compared reactivity mPS1-transfected cultured rat hippocampal neurons control situation impaired functions. CCCP causes slow rise cytosolic all three groups neurons, demonstrating faster rise. Consequently, were depolarized by measured TMRM, voltage indicator, more than other two groups. Morphologically, produced filopodia groups, which similarly affected drug. Finally, transfected tended to die from prolonged exposure sooner indicating an increase vulnerability lower ability regulate excess calcium.

Язык: Английский

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Emerging and Novel Therapeutic Treatments Targeting Mitochondrial-Endoplasmic Reticulum Contact Sites in Metabolic and Vascular Disorders

International Journal of Drug Discovery and Pharmacology, Год журнала: 2024, Номер unknown, С. 100008 - 100008

Опубликована: Июнь 6, 2024

Review Emerging and Novel Therapeutic Treatments Targeting Mitochondrial-Endoplasmic Reticulum Contact Sites in Metabolic Vascular Disorders Richard M. Monaghan The British Heart Foundation Centre of Research Excellence Manchester, Division Cardiovascular Sciences, Faculty Biology, Medicine, Health, University AV Hill Building, Oxford Road, M13 9PN, UK;[email protected] Received: 10 April 2024; Revised: 5 May Accepted: 7 Published: 6 June 2024 Abstract: Subcellular organellar contact sites, particularly those between mitochondria the endoplasmic reticulum (MERCSs), play crucial roles maintaining health. These specialized partitions facilitate vital communication organelles, regulating processes essential for cell function, including calcium balance, lipid biogenesis transport, mitochondrial dynamics, programmed death. Growing evidence shows that perturbation MERCSs contributes significantly to various diseases, neurodegenerative disorders like Alzheimer’s Parkinson’s, metabolic issues, such as type 2 diabetes, heart conditions, cancer. This review dives into this expanding field, exploring potential therapeutic targets. It provides a detailed overview proteins form maintain MERCSs, highlighting how their disruption can lead cellular dysfunction disease. Additionally, it examines recent exciting breakthroughs developing drugs strategies manipulate clinical benefits. While challenges remain, emphasises MERCS-based therapies outlines critical research needed move these treatments from lab clinic.

Язык: Английский

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Calcium Balance through Mutual Orchestrated Inter-organelle Communication: A Pleiotropic Target for Combating Alzheimer's Disease

Neurochemistry International, Год журнала: 2024, Номер unknown, С. 105905 - 105905

Опубликована: Ноя. 1, 2024

Dysfunctional intraneuronal organelles in Alzheimer's Disease (AD) propel aberrant calcium handling, triggering molecular miscommunication within such as mitochondria, endoplasmic reticulum, and lysosomes. This disruption organelle function not only impairs cellular homeostasis but also exacerbates neurodegenerative processes involving the accumulation of amyloid-β (Aβ) hyperphosphorylated tau, amplifying disease's vicious cycle. In this review, concept Mutual Orchestrated Inter-organelle Communication (MOIC) proposes potential therapeutic avenues for restoring Ca

Язык: Английский

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Mitochondria-targeting by small molecules against Alzheimer's disease: A mechanistic perspective

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2024, Номер 1871(3), С. 167617 - 167617

Опубликована: Дек. 8, 2024

Язык: Английский

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AD-specific brain amyloid interactome: Neural-network analysis of intra-aggregate crosslinking identifies novel drug targets

iScience, Год журнала: 2023, Номер 27(1), С. 108745 - 108745

Опубликована: Дек. 19, 2023

Alzheimer's disease (AD) is characterized by peri-neuronal amyloid plaque and intra-neuronal neurofibrillary tangles. These aggregates are identified the immunodetection of "seed" proteins (Aβ

Язык: Английский

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