Bax, Bak and beyond — mitochondrial performance in apoptosis

Peña‐Blanco, Aida; García‐Sáez, Ana J.

doi:10.1111/febs.14186

Cited by 648 publications

(425 citation statements)

References 134 publications

Supporting

Mentioning

353

Contrasting

Unclassified

Order By: Relevance

“…Taken together, these results suggest that Aβ 42  H 2 O 2 activates a cascade of events leading to the JNK> c-JUN, p53 > PUMA pathway. Although PUMA has been shown to cooperate with direct activator proteins (e.g., BAX) to promote mitochondrial outer membrane permeabilization (MOMP) and apoptosis [64], the exact mechanism by which MOMP occurs is not fully understood [65]. Interestingly, PSEN1…”

Section: Discussionmentioning

confidence: 99%

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

Soto-Mercado

Mendivil-Perez

Vélez-Pardo

et al. 2019

Preprint

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive disturbance as a consequence of the loss of cholinergic neurons in the brain, neuritic plaques and hyperphosphorylation of TAU protein. Although the underlying mechanisms leading to these events are unclear, mutations in presenilin 1 (PSEN1), e.g., E280A (PSEN1 E280A), are causative factors for autosomal dominant early-onset familial AD (FAD). Despite advances in the understanding of the physiopathology of AD, there are no efficient therapies to date. Limitations in culturing brain-derived live neurons might explain the limited effectiveness of AD research. Here, we show that mesenchymal stromal (stem) cells (MSCs) can be used to model FAD, providing novel opportunities to study cellular mechanisms and to establish therapeutic strategies.Indeed, we cultured MSCs with the FAD mutation PSEN1 E280A and wild-type (WT) PSEN1 from umbilical cords and characterized the transdifferentiation of these cells into cholinergic-like neurons (ChLNs). PSEN1 E280A ChLNs but not WT PSEN1 ChLNs exhibited increased intra-and extracellular A42 peptide and TAU phosphorylation (at residues Ser202/Thr205), recapitulating the molecular pathogenesis of FAD caused by mutant PSEN1. Furthermore, PSEN1 E280A ChLNs presented oxidative stress (OS) as evidenced by the oxidation of DJ-1Cys106-SH into DJ-1Cys106-SO3 and the detection of DCF-positive cells and apoptosis markers such as activated pro-apoptosis proteins p53, c-JUN, PUMA and CASPASE-3 and the concomitant loss of the mitochondrial membrane potential and DNA fragmentation. Additionally, mutant ChLNs displayed Ca2+ flux dysregulation and deficient acetylcholinesterase (AChE) activity compared to control ChLNs. Interestingly, the inhibitor JNK SP600125 almost completely blocked TAU phosphorylation. Our findings demonstrate that FAD MSC-derived cholinergic neurons with the PSEN1 E280A mutation are a valid model of AD and provide important clues for the identification of targetable pathological molecules.

show abstract

Section: Discussionmentioning

confidence: 99%

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

Soto-Mercado

Mendivil-Perez

Vélez-Pardo

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition, the upregulation of Bax and the downregulation of Bcl-2 induced by glucose in H9C2 cells were reversed by miR-1 silencing. Bcl-2 binds to Bax and inhibits its activation (38,39). …”

Section: Discussionmentioning

confidence: 99%

Downregulation of microRNA‑1 attenuates glucose‑induced apoptosis by regulating the liver X receptor α in cardiomyocytes

et al. 2018

View full text Add to dashboard Cite

Diabetic cardiomyopathy (DCM) is characterized by abnormal myocardial structure or performance. It has been suggested that microRNA-1 (miR-1) may be abnormally expressed in the hearts of patients with diabetes. In the present study, the role of miR-1 in glucose-induced apoptosis and its underlying mechanism of action was investigated in rat cardiomyocyte H9C2 cells. Cells were transfected with anti-miR-1 or miR-1-overexpression plasmids and the expression of miR-1 and liver X receptor α (LXRα) were determined by reverse transcription-quantitative polymerase chain reaction analysis. The proportion of apoptotic cells was determined using an Annexin-V-FITC apoptosis detection kit and the mitochondrial membrane potential (ΔΨ) was measured following staining with rhodamine 123. In addition, the expression of apoptosis-associated proteins was measured by western blot analysis. The results demonstrated that expression of miR-1 was significantly increased, whereas the expression of LXRα was significantly decreased in H9C2 cells following treatment with glucose. miR-1 knockdown significantly inhibited apoptosis, increased the ΔΨ and suppressed the cleavage of poly (adenosine diphosphate-ribose) polymerase, caspase-3 and caspase-9. It also significantly downregulated the expression of Bcl-2 and upregulated the expression of Bax. In addition, it was demonstrated that miR-1 regulates LXRα; transfection with anti-miR-1 significantly increased the expression of LXRα. Furthermore, treatment of cells with the LXR agonist GW3965 inhibited apoptosis in glucose-induced anti-miR-1 cells. These results suggest a novel function of miR-1: The regulation of cardiomyocyte apoptosis via LXRα, and provide novel insights into regarding the complex mechanisms involved in DCM.

show abstract

“…Cell autophagy is a benign form of cell death, 48 that minimizes the release of proinflammatory molecules into extracellular matrix, avoiding extracellular tissue damage. 49 The pathway is initiated by protein p53, leading to an imbalance of proapoptotic protein Bax and antiapoptotic protein Bcl-2, which triggers cytochrome c leakage and apoptosome formation, leading to apoptosis. 48 Mitochondria are closely associated with apoptosis, that is, programmed cell death through the mitochondrial apoptotic pathway, which is also known as the intrinsic pathway.…”

Section: Mitochondria In Depressionmentioning

confidence: 99%

Mitochondria could be a potential key mediator linking the intestinal microbiota to depression

Chen¹,

Vitetta

2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

The intestinal microbiota has been reported to affect depression, a common mental condition with severe health‐related consequences. However, what mediates the effect of the intestinal microbiota on depression has not been well elucidated. We summarize the roles of the mitochondria in eliciting beneficial effects on the gut microbiota to ameliorate symptoms of depression. It is well known that mitochondria play a key role in depression. An important pathogenic factor, namely inflammatory response, may adversely impact mitochondrial functionality to maintain cellular homeostasis. Dysfunction of mitochondria not only affects neuronal function but also reduces neuron cell numbers. We posit that the intestinal microbiota could affect neuronal mitochondrial function through short‐chain fatty acids such as butyrate. Brain inflammatory processes could also be affected through the modulation of gut permeability and blood lipopolysaccharide levels. Aberrant mitochondria functionality coupled to adverse cellular homeostasis could be a key mediator for the effect of the intestinal microbiota on the progression of depression.

show abstract

Bax, Bak and beyond — mitochondrial performance in apoptosis

Cited by 648 publications

References 134 publications

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

Downregulation of microRNA‑1 attenuates glucose‑induced apoptosis by regulating the liver X receptor α in cardiomyocytes

Mitochondria could be a potential key mediator linking the intestinal microbiota to depression

Contact Info

Product

Resources

About