Mitochondria-associated endoplasmic reticulum membranes (MAMs) involve in the regulation of mitochondrial dysfunction and heart failure

Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity.

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Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

APOPTOSIS ◽

10.1007/s10495-021-01668-y ◽

2021 ◽

Author(s):

Michela Raimondi ◽

Fabrizio Fontana ◽

Monica Marzagalli ◽

Matteo Audano ◽

Giangiacomo Beretta ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Mitochondrial Dysfunction ◽

Atp Synthesis ◽

Melanoma Cells ◽

Human Melanoma ◽

Ros Generation ◽

Therapy Outcomes ◽

Human Melanoma Cells ◽

Oxphos Complex

Abstract Melanoma is an aggressive tumor with still poor therapy outcomes. δ-tocotrienol (δ-TT) is a vitamin E derivative displaying potent anti-cancer properties. Previously, we demonstrated that δ-TT triggers apoptosis in human melanoma cells. Here, we investigated whether it might also activate paraptosis, a non-canonical programmed cell death. In accordance with the main paraptotic features, δ-TT was shown to promote cytoplasmic vacuolization, associated with endoplasmic reticulum/mitochondrial dilation and protein synthesis, as well as MAPK activation in A375 and BLM cell lines. Moreover, treated cells exhibited a significant reduced expression of OXPHOS complex I and a marked decrease in oxygen consumption and mitochondrial membrane potential, culminating in decreased ATP synthesis and AMPK phosphorylation. This mitochondrial dysfunction resulted in ROS overproduction, found to be responsible for paraptosis induction. Additionally, δ-TT caused Ca2+ homeostasis disruption, with endoplasmic reticulum-derived ions accumulating in mitochondria and activating the paraptotic signaling. Interestingly, by using both IP3R and VDAC inhibitors, a close cause-effect relationship between mitochondrial Ca2+ overload and ROS generation was evidenced. Collectively, these results provide novel insights into δ-TT anti-melanoma activity, highlighting its ability to induce mitochondrial dysfunction-mediated paraptosis. Graphic Abstract δ-tocotrienol induces paraptotic cell death in human melanoma cells, causing endoplasmic reticulum dilation and mitochondrial swelling. These alterations induce an impairment of mitochondrial function, ROS production and calcium overload.

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Catechin-7-O-xyloside induces apoptosis via endoplasmic reticulum stress and mitochondrial dysfunction in human non-small cell lung carcinoma H1299 cells

Oncology Reports ◽

10.3892/or.2013.2840 ◽

2013 ◽

Vol 31 (1) ◽

pp. 314-320 ◽

Cited By ~ 3

Author(s):

JANG WON YOON ◽

JONG SUK LEE ◽

BYEONG MO KIM ◽

JOUNGJWA AHN ◽

KYUNG MI YANG

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Mitochondrial Dysfunction ◽

Lung Carcinoma ◽

Small Cell Lung Carcinoma ◽

Small Cell ◽

Small Cell Lung ◽

Cell Lung Carcinoma

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The impact of obesity on oocytes: evidence for lipotoxicity mechanisms

Reproduction Fertility and Development ◽

10.1071/rd11904 ◽

2012 ◽

Vol 24 (1) ◽

pp. 29 ◽

Cited By ~ 31

Author(s):

Linda L.-Y. Wu ◽

Robert J. Norman ◽

Rebecca L. Robker

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Mitochondrial Dysfunction ◽

Intracytoplasmic Sperm Injection ◽

Oocyte Quality ◽

Early Embryo ◽

Pregnancy Rates ◽

Clinical Literature ◽

The Impact

Obesity can have detrimental effects on pregnancy rates in natural conceptions and also in women undergoing IVF or intracytoplasmic sperm injection (ICSI). This review summarises the most recent clinical literature investigating whether obesity impacts oocyte quality and early embryo growth. In other tissues, obesity leads to lipotoxicity responses including endoplasmic reticulum stress, mitochondrial dysfunction and apoptosis. Recent reports indicate that lipotoxicity is a mechanism by which obesity may impact oocyte quality.

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Abstract P233: Diabetic Cardiomyopathy is Reversed by Increased Mitochondrial Bioenergetics Due to PGC-1α Activation by EET Treatment of Obese Mice

Hypertension ◽

10.1161/hyp.68.suppl_1.p233 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Jian Cao ◽

John A McClung ◽

Shailendra P Singh ◽

Lars Bellner ◽

Maayan Waldman ◽

...

Keyword(s):

Heart Failure ◽

Insulin Resistance ◽

Oxidative Phosphorylation ◽

Mitochondrial Dysfunction ◽

Diabetic Cardiomyopathy ◽

Cardiac Fibrosis ◽

Systolic Function ◽

Control Group ◽

Protein Markers ◽

Obesity And Diabetes

Introduction: Obesity and diabetes are associated with progressive cardiac fibrosis that, sequentially, results in diastolic dysfunction, reduced contractility, and ultimately heart failure. Contributing factors include hyperglycemia, insulin resistance, mitochondrial dysfunction, and a reduction in AMPK signaling. PGC-1α activates mitochondrial biogenesis and oxidative phosphorylation and is decreased in patients with diabetes mellitus (DM). We hypothesize that an epoxyeicosatrienoic acids (EETs) agonist (EET-A) will increase PGC-1α levels in a db mouse model of DM attenuate cardiomyopathy, and prevent heart failure. Methods: Db mice (4-wks), were allowed to acclimatize for 16-wks and were then divided into 3 treatment groups for an additional 16 wks: A) control, B) EET-A 1.5mg/100g BW 2 weeks and C) EET-A-Ln-PGC-1α shRNA. Ln-PGC-1α shRNA suppressed PGC-1α protein in heart tissue by 40-50%. Oxygen consumption (VO 2 ), and blood glucose was determined. Heart tissues were harvested to measure PGC-1α, HO-1, pAMPK, PGC-1α, echocardiographic fractional shortening, mitochondrial oxidative phosphorylation (OXPHOS) and mitofusion protein markers. Results: All mice developed heart failure by the end of 16 weeks and were characterized by a decrease in myocardial contractility, an increase in insulin resistance and blood pressure, decreased VO 2 , the appearance of mitochondria dysfunction and a decrease in AMPK and downstream PGC-1α signaling. Mice treated with EET-A demonstrated an increase in PGC-1α levels, improved mitochondrial function and oxidative phosphorylation (p<0.01 vs control), increased NO bioavailability (p<0.05 vs control), and normalization of glucose metabolism, insulin levels, VO 2 and LV systolic function (p<0.05 vs control). All of these findings were suppressed by PGC-1α inhibition which was accompanied by the onset of even more severe LV dysfunction than in the control group. Conclusion: Increased EET levels result in activation of PGC-1α-HO-1 which reverses diabetes induced insulin resistance, mitochondrial dysfunction, and cardiomyopathy. EET may have potential as a powerful agent for therapeutic application in the treatment of diabetic cardiomyopathy.

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Mitochondrial Dysfunction and Mitochondrial Therapies in Heart Failure

Pharmacological Research ◽

10.1016/j.phrs.2021.106038 ◽

2021 ◽

pp. 106038

Author(s):

Chennan Wu ◽

Zhen Zhang ◽

Weidong Zhang ◽

Xia Liu

Keyword(s):

Heart Failure ◽

Mitochondrial Dysfunction

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Myeloid-Derived Growth Factor Protects Against Pressure Overload-Induced Heart Failure by Preserving Sarco/Endoplasmic Reticulum Ca 2+ -ATPase Expression in Cardiomyocytes

Circulation ◽

10.1161/circulationaha.120.053365 ◽

2021 ◽

Author(s):

Mortimer Korf-Klingebiel ◽

Marc R. Reboll ◽

Felix Polten ◽

Natalie Weber ◽

Felix Jäckle ◽

...

Keyword(s):

Heart Failure ◽

Bone Marrow ◽

Endoplasmic Reticulum ◽

Growth Factor ◽

Plasma Concentrations ◽

Pressure Overload ◽

Inflammatory Cells ◽

Left Ventricular ◽

Neonatal Rat ◽

Wild Type

Background: Inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation's potential benefits. Inflammatory cells secrete myeloid-derived growth factor (MYDGF) to promote tissue repair after acute myocardial infarction. We hypothesized that MYDGF has a role in cardiac adaptation to persistent pressure overload. Methods: We defined the cellular sources and function of MYDGF in wild-type, Mydgf -deficient ( Mydgf -/- ), and Mydgf bone marrow-chimeric or bone marrow-conditional transgenic mice with pressure overload-induced heart failure after transverse aortic constriction surgery. We measured MYDGF plasma concentrations by targeted liquid chromatography-mass spectrometry. We identified MYDGF signaling targets by phosphoproteomics and substrate-based kinase activity inference. We recorded Ca 2+ transients and sarcomere contractions in isolated cardiomyocytes. Additionally, we explored the therapeutic potential of recombinant MYDGF. Results: MYDGF protein abundance increased in the left ventricular (LV) myocardium and in blood plasma of pressure-overloaded mice. Patients with severe aortic stenosis also had elevated MYDGF plasma concentrations, which declined after transcatheter aortic valve implantation. Monocytes and macrophages emerged as the main MYDGF sources in the pressure-overloaded murine heart. While Mydgf -/- mice had no apparent phenotype at baseline, they developed more severe LV hypertrophy and contractile dysfunction during pressure overload than wild-type mice. Conversely, conditional transgenic overexpression of MYDGF in bone marrow-derived inflammatory cells attenuated pressure overload-induced hypertrophy and dysfunction. Mechanistically, MYDGF inhibited G protein coupled receptor agonist-induced hypertrophy and augmented sarco/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a) expression in cultured neonatal rat cardiomyocytes by enhancing PIM1 serine/threonine kinase expression and activity. Along this line, cardiomyocytes from pressure-overloaded Mydgf -/- mice displayed reduced PIM1 and SERCA2a expression, greater hypertrophy, and impaired Ca 2+ cycling and sarcomere function compared to cardiomyocytes from pressure-overloaded wild-type mice. Transplanting Mydgf -/- mice with wild-type bone marrow cells augmented cardiac PIM1 and SERCA2a levels and ameliorated pressure overload-induced hypertrophy and dysfunction. Pressure-overloaded Mydgf -/- mice were similarly rescued by adenoviral Serca2a gene transfer. Treating pressure-overloaded wild-type mice subcutaneously with recombinant MYDGF enhanced SERCA2a expression, attenuated LV hypertrophy and dysfunction, and improved survival. Conclusions: These findings establish a MYDGF-based adaptive crosstalk between inflammatory cells and cardiomyocytes that protects against pressure overload-induced heart failure.

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