Mitochondria-associated endoplasmic reticulum membrane (MAM): a dark horse for diabetic cardiomyopathy treatment

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Март 20, 2024

Abstract Diabetic cardiomyopathy (DCM), an important complication of diabetes mellitus (DM), is one the most serious chronic heart diseases and has become a major cause failure worldwide. At present, pathogenesis DCM unclear, there still lack effective therapeutics. Previous studies have shown that homeostasis mitochondria endoplasmic reticulum (ER) play core role in maintaining cardiovascular function, structural functional abnormalities these organelles seriously impact occurrence development various diseases, including DCM. The interplay between ER mediated by mitochondria-associated membrane (MAM), which participates regulating energy metabolism, calcium homeostasis, mitochondrial dynamics, autophagy, stress, inflammation, other cellular processes. Recent proven MAM closely related to initiation progression In this study, we aim summarize recent research progress on MAM, elaborate key DCM, discuss potential as therapeutic target for thereby providing theoretical reference basic clinical treatment.

Язык: Английский

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So close, yet so far away: the relationship between MAM and cardiac disease

Frontiers in Cardiovascular Medicine, Год журнала: 2024, Номер 11

Опубликована: Фев. 5, 2024

Mitochondria-associated membrane (MAM) serve as crucial contact sites between mitochondria and the endoplasmic reticulum (ER). Recent research has highlighted significance of MAM, which a platform for various protein molecules, in processes such calcium signaling, ATP production, mitochondrial structure function, autophagy. Cardiac diseases caused by any reason can lead to changes myocardial significantly impacting human health. Notably, MAM exhibits regulatory effects maintain cellular balance several cardiac conditions, obesity, diabetes mellitus, cardiotoxicity. proteins independently or interact with their counterparts, forming essential tethers ER cardiomyocytes. This review provides an overview key regulators, detailing functions. Additionally, it explores connection injuries, suggesting that precise genetic, pharmacological, physical regulation may be promising strategy preventing treating heart failure.

Язык: Английский

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Towards a Unitary Hypothesis of Alzheimer’s Disease Pathogenesis

Journal of Alzheimer s Disease, Год журнала: 2024, Номер 98(4), С. 1243 - 1275

Опубликована: Апрель 5, 2024

The "amyloid cascade" hypothesis of Alzheimer's disease (AD) pathogenesis invokes the accumulation in brain plaques (containing amyloid-β protein precursor [AβPP] cleavage product [Aβ]) and tangles hyperphosphorylated tau) as drivers pathogenesis. However, poor track record clinical trials based on this suggests that these peptides is not only cause AD. Here, an alternative proposed which AβPP C99, Aβ, main culprit, via its role a regulator cholesterol metabolism. sensor, promotes formation mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), cholesterol-rich lipid raft-like subdomain ER communicates, both physically biochemically, with mitochondria. We propose early-onset AD (EOAD), MAM-localized C99 elevated above normal levels, resulting increased transport from plasma membrane to intracellular organelles, such ER/endosomes, thereby upregulating MAM function driving pathology. By same token, late-onset (LOAD) triggered by any genetic variant increases that, turn, boosts levels again upregulates function. Thus, functional upregulated causes hallmark phenotypes, including tangles. Accordingly, two key interrelated elements, cholesterol, converge at drive From perspective, is, bottom, disorder.

Язык: Английский

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Mitochondria-associated endoplasmic reticulum membranes as a therapeutic target for cardiovascular diseases

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Апрель 17, 2024

Cardiovascular diseases (CVDs) are currently the leading cause of death worldwide. In 2022, CVDs contributed to 19.8 million deaths globally, accounting for one-third all global deaths. With an aging population and changing lifestyles, pose a major threat human health. Mitochondria-associated endoplasmic reticulum membranes (MAMs) communication platforms between cellular organelles regulate physiological functions, including apoptosis, autophagy, programmed necrosis. Further research has shown that MAMs play critical role in pathogenesis CVDs, myocardial ischemia reperfusion injury, heart failure, pulmonary hypertension, coronary atherosclerosis. This suggests could be important therapeutic target managing CVDs. The goal this study is summarize protein complex MAMs, discuss its pathological mechanisms terms functions such as Ca

Язык: Английский

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Not So Rare: Diseases Based on Mutant Proteins Controlling Endoplasmic Reticulum-Mitochondria Contact (MERC) Tethering

Contact, Год журнала: 2024, Номер 7

Опубликована: Янв. 1, 2024

Mitochondria-endoplasmic reticulum contacts (MERCs), also called endoplasmic (ER)-mitochondria contact sites (ERMCS), are the membrane domains, where these two organelles exchange lipids, Ca 2+ ions, and reactive oxygen species. This crosstalk is a major determinant of cell metabolism, since it allows ER to control mitochondrial oxidative phosphorylation Krebs cycle, while conversely, mitochondria provide sufficient ATP proteostasis. MERC metabolic signaling under tethers multitude regulatory proteins. Many proteins have recently been discovered give rise rare diseases if their genes mutated. Surprisingly, share important hallmarks cause neurological defects, sometimes paired with, or replaced by skeletal muscle deficiency. Typical symptoms include developmental delay, intellectual disability, facial dysmorphism ophthalmologic defects. Seizures, epilepsy, deafness, ataxia, peripheral neuropathy can occur upon mutation protein. Given that most secondary functions, some protein-based do not fit into this categorization. Typically, however, affected in those dominant functions unrelated roles MERCs tethering regulation. We discussing avenues pharmacologically target genetic leading based on our novel insight defects lead common characteristics diseases. These shared disorders raise hope they may allow for similar treatment options.

Язык: Английский

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Lipin1 ameliorates cognitive ability of diabetic encephalopathy via regulating Ca2+ transfer through mitochondria-associated endoplasmic reticulum membranes

International Immunopharmacology, Год журнала: 2025, Номер 150, С. 114266 - 114266

Опубликована: Фев. 16, 2025

Diabetic encephalopathy (DE) is a common central nervous system complication resulting from diabetes mellitus (DM). While the exact pathogenesis remains unclear, homeostatic imbalance of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) within neurons has been shown to be closely associated with dysfunctional cognitive pathology this condition. Our previous work revealed that phosphatidate phosphatase Lipin1 plays critical role in processes DE via regulating mitochondrial function. In study, we reported integrity neuronal MAMs was disrupted mice, which accompanied by decrease expression hippocampal Lipin1. With knock-down normal ER stress induced, structures were impaired and Ca2+ transfer suppressed. Such effects resulted dysfunction, synaptic plasticity impairments, finally dysfunctions. contrast, an up-regulation model partially alleviated these These results suggest may ameliorate dysfunctions transfers through MAMs. Therefore, targeting serve as therapeutic strategy for clinical treatment DE.

Язык: Английский

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Myo‐inositol trispyrophosphate prevents right ventricular failure and improves survival in monocrotaline‐induced pulmonary hypertension in the rat

British Journal of Pharmacology, Год журнала: 2024, Номер 181(20), С. 4050 - 4066

Опубликована: Июль 1, 2024

Abstract Background and Purpose Pulmonary hypertension (PH) results from pulmonary vasculopathy, initially leading to a compensatory right ventricular (RV) hypertrophy, eventually RV failure. Hypoxia can trigger both vasculopathy Therefore, we tested if myo‐inositol trispyrophosphate (ITPP), which facilitates oxygen dissociation haemoglobin, relieve hypoxia, prevent failure mortality in the rat model of monocrotaline‐induced PH. Experimental approach Rats were injected with monocrotaline or saline (control) received ITPP placebo for 5 weeks. Serial echocardiograms obtained monitor disease, pressure‐volume loops recorded evaluated, myocardial pO 2 was measured using fluorescent probe, histological molecular analyses conducted at conclusion experiment. Key Results Conclusions reduced PH‐related mortality. It had no effect on progressive increase vascular resistance, yet significantly relieved intramyocardial associated improvement function reduction wall stress. also tended increased hypoxia inducible factor‐1 α expression cardiac myocytes but did not affect capillary density. Implications Our study suggests that strategies aimed increasing delivery hypoxic PH could potentially be used as adjuncts other therapies target vessels, thus ability withstand afterload reducing may one such potential therapy.

Язык: Английский

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Targeting protein interaction networks in mitochondrial dynamics for neurodegenerative diseases

Journal of Proteins and Proteomics, Год журнала: 2024, Номер 15(3), С. 309 - 328

Опубликована: Июль 5, 2024

Язык: Английский

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