Understanding MCL1: From Cellular Function and Regulation to Pharmacological Inhibition

Abstract The mammalian target of rapamycin (mTOR) signaling pathway efficiently regulates the energy state of cells and maintains tissue homeostasis. Dysregulation of the mTOR pathway has been implicated in several human diseases. Rapamycin is a specific inhibitor of mTOR and pharmacological inhibition of mTOR with rapamycin promote cardiac cell generation from the differentiation of mouse and human embryonic stem cells. These studies strongly implicate a role of sustained mTOR activity in the differentiating functions of embryonic stem cells; however, they do not directly address the required effect for sustained mTOR activity in human cardiac progenitor cells. In the present study, we evaluated the effect of mTOR inhibition by rapamycin on the cellular function of human cardiac progenitor cells and discovered that treatment with rapamycin markedly attenuated replicative cell senescence in human cardiac progenitor cells (hCPCs) and promoted their cellular functions. Furthermore, rapamycin not only inhibited mTOR signaling but also influenced signaling pathways, including STAT3 and PIM1, in hCPCs. Therefore, these data reveal a crucial function for rapamycin in senescent hCPCs and provide clinical strategies based on chronic mTOR activity.

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MEKK3-MEK5-ERK5 signaling promotes mitochondrial degradation

Cell Death Discovery ◽

10.1038/s41420-020-00342-7 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Jane E. Craig ◽

Joseph N. Miller ◽

Raju R. Rayavarapu ◽

Zhenya Hong ◽

Gamze B. Bulut ◽

...

Keyword(s):

Cell Death ◽

Mitochondrial Biogenesis ◽

Energy Homeostasis ◽

Cellular Function ◽

Mitochondrial Content ◽

Cellular Energy ◽

Pharmacological Inhibition ◽

Positive Regulator ◽

Kinase Cascade ◽

Mitochondrial Turnover

Abstract Mitochondria are vital organelles that coordinate cellular energy homeostasis and have important roles in cell death. Therefore, the removal of damaged or excessive mitochondria is critical for maintaining proper cellular function. The PINK1-Parkin pathway removes acutely damaged mitochondria through a well-characterized mitophagy pathway, but basal mitochondrial turnover occurs via distinct and less well-understood mechanisms. Here we report that the MEKK3-MEK5-ERK5 kinase cascade is required for mitochondrial degradation in the absence of exogenous damage. We demonstrate that genetic or pharmacological inhibition of the MEKK3-MEK5-ERK5 pathway increases mitochondrial content by reducing lysosome-mediated degradation of mitochondria under basal conditions. We show that the MEKK3-MEK5-ERK5 pathway plays a selective role in basal mitochondrial degradation but is not required for non-selective bulk autophagy, damage-induced mitophagy, or restraint of mitochondrial biogenesis. This illuminates the MEKK3-MEK5-ERK5 pathway as a positive regulator of mitochondrial degradation that acts independently of exogenous mitochondrial stressors.

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MEKK3-MEK5-ERK5 Signaling Promotes Mitochondrial Degradation

10.1101/2020.05.15.098442 ◽

2020 ◽

Author(s):

Jane E. Craig ◽

Joseph N. Miller ◽

Raju R. Rayavarapu ◽

Zhenya Hong ◽

Gamze B. Bulut ◽

...

Keyword(s):

Cell Death ◽

Mitochondrial Biogenesis ◽

Energy Homeostasis ◽

Cellular Function ◽

Mitochondrial Content ◽

Cellular Energy ◽

Pharmacological Inhibition ◽

Positive Regulator ◽

Kinase Cascade ◽

Mitochondrial Turnover

AbstractMitochondria are vital organelles that coordinate cellular energy homeostasis and have important roles in cell death. Therefore, the removal of damaged or excessive mitochondria is critical for maintaining proper cellular function. The PINK1-Parkin pathway removes acutely damaged mitochondria through a well-characterized mitophagy pathway, but basal mitochondrial turnover occurs via distinct and less well-understood mechanisms. Here we report that the MEKK3-MEK5-ERK5 kinase cascade is required for mitochondrial degradation in the absence of exogenous damage. We demonstrate that genetic or pharmacological inhibition of the MEKK3-MEK5-ERK5 pathway increases mitochondrial content by reducing lysosome-mediated degradation of mitochondria under basal conditions. We show that the MEKK3-MEK5-ERK5 pathway plays a selective role in basal mitochondrial degradation but is not required for non-selective bulk autophagy, damage-induced mitophagy, or restraint of mitochondrial biogenesis. This illuminates the MEKK3-MEK5-ERK5 pathway as a positive regulator of mitochondrial degradation that acts independently of exogenous mitochondrial stressors.

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Structure in Relation to Cellular Function

Gastroenterology ◽

10.1016/s0016-5085(50)80157-9 ◽

1950 ◽

Vol 15 (3) ◽

pp. 563

Keyword(s):

Cellular Function

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Review for "Pharmacological inhibition of RORC2 enhances human Th17‐Treg stability and function"

10.1002/eji.201948435/v1/review2 ◽

2019 ◽

Author(s):

Matthias Lochner

Keyword(s):

Pharmacological Inhibition ◽

And Function

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Decision letter for "Pharmacological inhibition of RORC2 enhances human Th17‐Treg stability and function"

10.1002/eji.201948435/v1/decision1 ◽

2019 ◽

Keyword(s):

Pharmacological Inhibition ◽

And Function

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Pharmacological inhibition of nicotinamide N-methyltransferase (NNMT) in adipocytes by romidepsin

Diabetologie und Stoffwechsel ◽

10.1055/s-0036-1580818 ◽

2016 ◽

Vol 11 (S 01) ◽

Author(s):

B Zapp ◽

B Rudolphi ◽

NA Kraus ◽

J Klein ◽

C Wanner ◽

...

Keyword(s):

Pharmacological Inhibition

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Demonstration and Quantitation of Pharmacological Inhibition of Pulmonary Uptake of N-lsopropyl-123l-p-lodoamphetamine by Propranolol

Nuklearmedizin ◽

10.1055/s-0038-1629478 ◽

1989 ◽

Vol 28 (03) ◽

pp. 100-104 ◽

Cited By ~ 1

Author(s):

S. F. Akber

Keyword(s):

Binding Sites ◽

Bolus Injection ◽

Cell Function ◽

Lung Pathology ◽

Lung Uptake ◽

Pharmacological Inhibition ◽

Sensitive Index ◽

Pulmonary Uptake ◽

First Pass

The first-pass pulmonary extraction values of N-lsopropyl-123l-p-lodoamphetamine (123I-IMP) in pretreated dogs decreases from 90 to 62% as the amount of propranolol increases from 0 to 20 mg. The first-pass pulmonary extraction values of 123I-IMP in dogs with a simultaneous bolus injection of propranolol decreases from 90 to 62% as the amount of propranolol increases from 0 to 10 mg. The pulmonary extraction of 123I-IMP with a simultaneous bolus injection of ketamine and 123I-IMP decreases from 90 to 64% as the ketamine dose increases from 0 to 100 mg. These results suggest that the pulmonary uptake of 123I-IMP may be at least partially mediated by receptors. They also indicate that endothelial metabolic cell function may be a useful index of early lung pathology. Furthermore, studies of the degree of lung uptake may be a sensitive index of pathologic states in which alterations of amine binding sites have occurred.

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