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Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE248639 | GEO | 2024/06/01

REPOSITORIES: GEO

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Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening （human_HSC_RNA_Seq)

Project description:Mitochondria have recently been identified as a critical regulator for the homeostasis of hematopoietic stem cells (HSCs). However, the mechanism underlying HSC regulation still needs to be clarified. Here, we identify transcription factor Nynrin as a novel regulator of HSC maintenance through modulation of mitochondrial function. We demonstrate that Nynrin is highly expressed in HSC under steady and stress state. Nynrin knockout leads to significantly decreased long-term HSC frequency, markedly reduced HSC dormancy, and self-renewal capacity in steady-state and stress hematopoiesis. We observed abnormal mitochondrial metabolism and mitochondrial permeability transition pore (mPTP) opening in Nynrin-deficient HSCs. Notably, Nynrin-deficient HSCs are more compromised in tolerance of irradiation- and 5-fluorouracil-induced stresses and exhibit typical phenotypes of necrosis. In contrast, overexpression of Nynrin in HSC is resistant to the radiation. Mechanistically, Nynrin deletion induces transactivation of Ppif. Overexpression of cyclophilin D (CypD), the protein encoded by the Ppif gene, causes mPTP opening, mitochondrial swelling, ROS overinduction, and cell necrosis. Both blocking the function of CypD by using cyclosporin A (CsA) or reducing the expression of Ppif could inhibit Nynrin deficiency-induced mitochondrial metabolism enhancement and ROS overproduction, thereby evidently rescuing the impairment of HSCs in Nynrin mutant mice. Collectively, our data, for the first time, characterize Nynrin as a critical regulator of HSC function acting through the Ppif/mPTP mitochondria axis and highlight the importance of Nynrin in HSC maintenance. These data provide new insights into the mechanisms for controlling HSC fate.

2024-06-01 | GSE248636 | GEO

Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening (ChIP_Seq)

2024-06-01 | GSE248635 | GEO

Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening (scRNA-Seq)

2024-06-01 | GSE248638 | GEO

Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening (RNA-Seq for Nynrin cko HSC)

2024-06-01 | GSE248637 | GEO

Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening.

Project description:Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening.

| PRJNA1045290 | ENA

Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening (ChIP_Seq)

Project description:Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening (ChIP_Seq)

| PRJNA1045291 | ENA

Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening （human_HSC_RNA_Seq)

Project description:Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening （human_HSC_RNA_Seq)

| PRJNA1045293 | ENA

Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening (scRNA-Seq)

Project description:Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening (scRNA-Seq)

| PRJNA1045295 | ENA

Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening (RNA-Seq for Nynrin cko HSC)

Project description:Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening (RNA-Seq for Nynrin cko HSC)

| PRJNA1045292 | ENA

Dual dynamics of mitochondrial permeability transition pore opening.

Project description:Mitochondria play an essential role in bioenergetics and cellular Ca[Formula: see text] handling. The mitochondrial permeability transition pore (mPTP) is a non-specific channel located in the inner mitochondrial membrane. Long-lasting openings of the pore allow the rapid passage of ions and large molecules, which can result in cell death. The mPTP also exhibits transient, low conductance openings that contribute to Ca[Formula: see text] homeostasis. Although many regulators of the pore have been identified, none of them uniquely governs the passage between the two operating modes, which thus probably relies on a still unidentified network of interactions. By developing a core computational model for mPTP opening under the control of mitochondrial voltage and Ca[Formula: see text], we uncovered the existence of a positive feedback loop leading to bistability. The characteristics of the two stable steady-states correspond to those of the two opening states. When inserted in a full model of Ca[Formula: see text] handling by mitochondria, our description of the pore reproduces observations in mitochondrial suspensions. Moreover, the model predicted the occurrence of hysteresis in the switching between the two modes, upon addition and removal of free Ca[Formula: see text] in the extra-mitochondrial medium. Stochastic simulations then confirmed that the pore can undergo transient openings resembling those observed in intact cells.

| S-EPMC7054270 | biostudies-literature

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