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Article ; Online: Oxidized mitochondrial DNA: a protective signal gone awry.

Xian, Hongxu / Karin, Michael

2023 Volume 44, Issue 3, Page(s) 188–200

Abstract: Despite the emergence of mitochondria as key regulators of innate immunity, the mechanisms underlying the generation and release of immunostimulatory alarmins by stressed mitochondria remains nebulous. We propose that the major mitochondrial alarmin in ... ...

Abstract	Despite the emergence of mitochondria as key regulators of innate immunity, the mechanisms underlying the generation and release of immunostimulatory alarmins by stressed mitochondria remains nebulous. We propose that the major mitochondrial alarmin in myeloid cells is oxidized mitochondrial DNA (Ox-mtDNA). Fragmented Ox-mtDNA enters the cytosol where it activates the NLRP3 inflammasome and generates IL-1β, IL-18, and cGAS-STING to induce type I interferons and interferon-stimulated genes. Inflammasome activation further enables the circulatory release of Ox-mtDNA by opening gasdermin D pores. We summarize new data showing that, in addition to being an autoimmune disease biomarker, Ox-mtDNA converts beneficial transient inflammation into long-lasting immunopathology. We discuss how Ox-mtDNA induces short- and long-term immune activation, and highlight its homeostatic and immunopathogenic functions.
MeSH term(s)	Humans ; DNA, Mitochondrial ; Inflammasomes ; Signal Transduction/physiology ; Mitochondria ; Immunity, Innate
Chemical Substances	DNA, Mitochondrial ; Inflammasomes
Language	English
Publishing date	2023-02-02
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2036831-8
ISSN	1471-4981 ; 1471-4906
ISSN (online)	1471-4981
ISSN	1471-4906
DOI	10.1016/j.it.2023.01.006
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Article ; Online: IRF1 regulates self-renewal and stress responsiveness to support hematopoietic stem cell maintenance.

Rundberg Nilsson, Alexandra J S / Xian, Hongxu / Shalapour, Shabnam / Cammenga, Jörg / Karin, Michael

Science advances

2023 Volume 9, Issue 43, Page(s) eadg5391

Abstract: Hematopoietic stem cells (HSCs) are tightly controlled to maintain a balance between blood cell production and self-renewal. While inflammation-related signaling is a critical regulator of HSC activity, the underlying mechanisms and the precise functions ...

Abstract	Hematopoietic stem cells (HSCs) are tightly controlled to maintain a balance between blood cell production and self-renewal. While inflammation-related signaling is a critical regulator of HSC activity, the underlying mechanisms and the precise functions of specific factors under steady-state and stress conditions remain incompletely understood. We investigated the role of interferon regulatory factor 1 (IRF1), a transcription factor that is affected by multiple inflammatory stimuli, in HSC regulation. Our findings demonstrate that the loss of IRF1 from mouse HSCs significantly impairs self-renewal, increases stress-induced proliferation, and confers resistance to apoptosis. In addition, given the frequent abnormal expression of
MeSH term(s)	Mice ; Humans ; Animals ; Interferon Regulatory Factor-1/genetics ; Interferon Regulatory Factor-1/metabolism ; Gene Expression Regulation ; Signal Transduction ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Hematopoietic Stem Cells/metabolism ; Cell Differentiation ; Cell Proliferation
Chemical Substances	Interferon Regulatory Factor-1 ; IRF1 protein, human
Language	English
Publishing date	2023-10-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adg5391
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Article: IRF1 regulates self-renewal and stress-responsiveness to support hematopoietic stem cell maintenance.

Rundberg Nilsson, Alexandra / Xian, Hongxu / Shalapour, Shabnam / Cammenga, Jörg / Karin, Michael

bioRxiv : the preprint server for biology

2023

Abstract: Inflammatory mediators induce emergency myelopoiesis and cycling of adult hematopoietic stem cells (HSCs) through incompletely understood mechanisms. To suppress the unwanted effects of inflammation and preserve its beneficial outcomes, the mechanisms by ...

Abstract	Inflammatory mediators induce emergency myelopoiesis and cycling of adult hematopoietic stem cells (HSCs) through incompletely understood mechanisms. To suppress the unwanted effects of inflammation and preserve its beneficial outcomes, the mechanisms by which inflammation affects hematopoiesis need to be fully elucidated. Rather than focusing on specific inflammatory stimuli, we here investigated the role of transcription factor Interferon (IFN) regulatory factor 1 (IRF1), which receives input from several inflammatory signaling pathways. We identify IRF1 as a master HSC regulator. IRF1 loss impairs HSC self-renewal, increases stress-induced cell cycle activation, and confers apoptosis resistance. Transcriptomic analysis revealed an aged, inflammatory signature devoid of IFN signaling with reduced megakaryocytic/erythroid priming and antigen presentation in IRF1-deficient HSCs. Finally, we conducted IRF1-based AML patient stratification to identify groups with distinct proliferative, survival and differentiation features, overlapping with our murine HSC results. Our findings position IRF1 as a pivotal regulator of HSC preservation and stress-induced responses.
Language	English
Publishing date	2023-03-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.24.525321
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Article ; Online: Functions of outer mitochondrial membrane proteins: mediating the crosstalk between mitochondrial dynamics and mitophagy.

Xian, Hongxu / Liou, Yih-Cherng

Cell death and differentiation

2020 Volume 28, Issue 3, Page(s) 827–842

Abstract: Most cellular stress responses converge on the mitochondria. Consequently, the mitochondria must rapidly respond to maintain cellular homeostasis and physiological demands by fine-tuning a plethora of mitochondria-associated processes. The outer ... ...

Abstract	Most cellular stress responses converge on the mitochondria. Consequently, the mitochondria must rapidly respond to maintain cellular homeostasis and physiological demands by fine-tuning a plethora of mitochondria-associated processes. The outer mitochondrial membrane (OMM) proteins are central to mediating mitochondrial dynamics, coupled with continuous fission and fusion. These OMM proteins also have vital roles in controlling mitochondrial quality and serving as mitophagic receptors for autophagosome enclosure during mitophagy. Mitochondrial fission segregates impaired mitochondria in smaller sizes from the mother mitochondria and may favor mitophagy for eliminating damaged mitochondria. Conversely, mitochondrial fusion mixes dysfunctional mitochondria with healthy ones to repair the damage by diluting the impaired components and consequently prevents mitochondrial clearance via mitophagy. Despite extensive research efforts into deciphering the interplay between fission-fusion and mitophagy, it is still not clear whether mitochondrial fission essentially precedes mitophagy. In this review, we summarize recent breakthroughs concerning OMM research, and dissect the functions of these proteins in mitophagy from their traditional roles in fission-fusion dynamics, in response to distinct context, at the intersection of the OMM platform. These insights into the OMM proteins in mechanistic researches would lead to new aspects of mitochondrial quality control and better understanding of mitochondrial homeostasis intimately tied to pathological impacts.
MeSH term(s)	Animals ; Autophagosomes/metabolism ; Cell Physiological Phenomena ; Homeostasis ; Humans ; Membrane Proteins/metabolism ; Mitochondria/metabolism ; Mitochondria/pathology ; Mitochondrial Dynamics/physiology ; Mitochondrial Proteins/metabolism ; Mitophagy/physiology
Chemical Substances	Membrane Proteins ; Mitochondrial Proteins
Language	English
Publishing date	2020-11-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1225672-9
ISSN	1476-5403 ; 1350-9047
ISSN (online)	1476-5403
ISSN	1350-9047
DOI	10.1038/s41418-020-00657-z
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Zs.A 4230: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Author Correction: STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism.

Xian, Hongxu / Yang, Qiaoyun / Xiao, Lin / Shen, Han-Ming / Liou, Yih-Cherng

Nature communications

2021 Volume 12, Issue 1, Page(s) 6782

Language	English
Publishing date	2021-11-16
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-26559-3
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Article ; Online: Loss of MIEF1/MiD51 confers susceptibility to BAX-mediated cell death and PINK1-PRKN-dependent mitophagy.

Xian, Hongxu / Liou, Yih-Cherng

Autophagy

2019 Volume 15, Issue 12, Page(s) 2107–2125

Abstract: Mitochondrial dynamics is highly implicated in a plethora of cellular processes including apoptosis and mitophagy. However, little is known about the scope and precise functions of mitochondrial dynamics proteins for mitochondrial quality control and ... ...

Abstract	Mitochondrial dynamics is highly implicated in a plethora of cellular processes including apoptosis and mitophagy. However, little is known about the scope and precise functions of mitochondrial dynamics proteins for mitochondrial quality control and cellular homeostasis. Whether mitochondrial dynamics proteins serve in cellular processes reliant on mitochondrial fission-fusion is still not fully explored. MIEF1/MiD51 (mitochondrial elongation factor 1) is known to promote mitochondrial fission via the recruitment of GTPase protein DNM1L/DRP1 (dynamin 1 like), but the fundamental understandings of MIEF1 for mitochondrial-dependent cellular processes are largely elusive. Here, we report novel roles of MIEF1 in responding to apoptotic stimuli and mitochondrial damage. Given our result that staurosporine (STS) treatment induced the degradation of MIEF1 via the ubiquitin-proteasome system (UPS), we are motivated to explore the role of MIEF1 in apoptosis. MIEF1 loss triggered the imbalance of BCL2 family members on the mitochondria, consequently initiating the translocation of BAX onto the mitochondria, catalyzing the decrease of mitochondrial membrane potential and promoting the release of DIABLO/SMAC (diablo IAP-binding mitochondrial protein) and CYCS (cytochrome c, somatic). We further demonstrate that MIEF1 deficiency impaired mitochondrial respiration and induced mitochondrial oxidative stress, sensitizing cells to PINK1-PRKN-mediated mitophagy. The recruitment of PRKN to depolarized mitochondria modulated the UPS-dependent degradation of MFN2 (mitofusin 2) and FIS1 (fission, mitochondrial 1) specifically, to further promote mitophagy. Our findings uncover a bridging role of MIEF1 integrating cell death and mitophagy, unlikely dependent on mitochondrial dynamics, implying new insights to mechanisms determining cellular fate.
MeSH term(s)	Apoptosis/drug effects ; Apoptosis/genetics ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Dynamins/genetics ; Dynamins/metabolism ; GTP Phosphohydrolases/genetics ; GTP Phosphohydrolases/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Membrane Potential, Mitochondrial/genetics ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondria/pathology ; Mitochondrial Dynamics/drug effects ; Mitochondrial Dynamics/genetics ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Mitophagy/drug effects ; Mitophagy/genetics ; Peptide Elongation Factors/genetics ; Peptide Elongation Factors/metabolism ; Proteasome Endopeptidase Complex/drug effects ; Proteasome Endopeptidase Complex/genetics ; Proteasome Endopeptidase Complex/metabolism ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Staurosporine/pharmacology ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination/drug effects ; Ubiquitination/genetics ; bcl-2-Associated X Protein/genetics ; bcl-2-Associated X Protein/metabolism ; bcl-X Protein/genetics ; bcl-X Protein/metabolism
Chemical Substances	Apoptosis Regulatory Proteins ; BAX protein, human ; BCL2L1 protein, human ; DIABLO protein, human ; FIS1 protein, human ; MIEF1 protein, human ; Membrane Proteins ; MiD51 protein, mouse ; Mitochondrial Proteins ; Peptide Elongation Factors ; Reactive Oxygen Species ; Receptors, Cytoplasmic and Nuclear ; bcl-2-Associated X Protein ; bcl-X Protein ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; parkin protein (EC 2.3.2.27) ; Protein Kinases (EC 2.7.-) ; PTEN-induced putative kinase (EC 2.7.11.1) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; GTP Phosphohydrolases (EC 3.6.1.-) ; MFN2 protein, human (EC 3.6.1.-) ; DNM1L protein, human (EC 3.6.5.5) ; Dynamins (EC 3.6.5.5) ; Staurosporine (H88EPA0A3N)
Language	English
Publishing date	2019-03-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2019.1596494
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Article ; Online: Author Correction

Hongxu Xian / Qiaoyun Yang / Lin Xiao / Han-Ming Shen / Yih-Cherng Liou

Nature Communications, Vol 12, Iss 1, Pp 1-

STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism

2021 Volume 1

Keywords	Science ; Q
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Differences in the Correlation between the Built Environment and Walking, Moderate, and Vigorous Physical Activity among the Elderly in Low- and High-Income Areas.

Zang, Peng / Xian, Fei / Qiu, Hualong / Ma, Shifa / Guo, Hongxu / Wang, Mengrui / Yang, Linchuan

International journal of environmental research and public health

2022 Volume 19, Issue 3

Abstract: Studies have proved that activity and fitness behaviors are closely related to the quality of life and health status of the elderly. However, different intensities of physical activity (PA)-walking, moderate PA, and vigorous PA-have different ... ...

Abstract	Studies have proved that activity and fitness behaviors are closely related to the quality of life and health status of the elderly. However, different intensities of physical activity (PA)-walking, moderate PA, and vigorous PA-have different correlations with the built environment (BE). This study combines the high and low socioeconomic status (SES) of Guangzhou to establish two types of BE models. The physical activity time of 600 elderly people was collected from questionnaires. Through ArcGIS software, 300 m, 500 m, 800 m, and 1000 m buffer zones were identified, and the land use diversity, street design, population density, distance to destination, distance to public transportation-the five Ds of the BE-were measured. SPSS software was adopted to analyze the correlation between the BE and PA. Results: The PA of people living in low-SES areas was more dependent on the BE, whereas the correlation may be limited in high SES areas. Moreover, in low SES areas, walking was negatively correlated with street connectivity; moderate PA was positively correlated with street connectivity and the shortest distance to the subway station, but negatively correlated with the density of entertainment points of interest (POIs). Studying the relevant factors of the environment can propose better strategies to improve the initiative of the elderly to engage in PA.
MeSH term(s)	Aged ; Built Environment ; Cross-Sectional Studies ; Environment Design ; Exercise ; Humans ; Quality of Life ; Residence Characteristics ; Walking
Language	English
Publishing date	2022-02-08
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2175195-X
ISSN	1660-4601 ; 1661-7827
ISSN (online)	1660-4601
ISSN	1661-7827
DOI	10.3390/ijerph19031894
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Article ; Online: Nonlinear Effects of the Built Environment on Light Physical Activity among Older Adults: The Case of Lanzhou, China.

Zang, Peng / Qiu, Hualong / Xian, Fei / Yang, Linchuan / Qiu, Yanan / Guo, Hongxu

International journal of environmental research and public health

2022 Volume 19, Issue 14

Abstract: The aging of the population is increasing the load on the healthcare system, and enhancing light physical activity among older adults can alleviate this problem. This study used medical examination data from 1773 older adults in Lanzhou city (China) and ... ...

Abstract	The aging of the population is increasing the load on the healthcare system, and enhancing light physical activity among older adults can alleviate this problem. This study used medical examination data from 1773 older adults in Lanzhou city (China) and adopted the random forest model to investigate the effect of the built environment on the duration of light physical activity of older adults. The results showed that streetscape greenery has the most significant impact on older adults' light physical activity; greenery can be assessed in a hierarchy of areas; population density and land-use mix only have a positive effect on older adults' light physical activity up to a certain point but a negative effect beyond that point; and a greater distance to the park within 1 km is associated with a longer time spent on light physical activity. Therefore, we conclude that the built environment's impact is only positive within a specific range. Changes in the intervention of environmental variables can be observed visually by calculating the relative importance of the nonlinearity of built environment elements with partial dependency plots. These results provide a reasonable reference indicator for age-friendly community planning.
MeSH term(s)	Built Environment ; China ; Cross-Sectional Studies ; Environment Design ; Exercise ; Residence Characteristics ; Walking
Language	English
Publishing date	2022-07-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2175195-X
ISSN	1660-4601 ; 1661-7827
ISSN (online)	1660-4601
ISSN	1661-7827
DOI	10.3390/ijerph19148848
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Article ; Online: Differences in the Correlation between the Built Environment and Walking, Moderate, and Vigorous Physical Activity among the Elderly in Low- and High-Income Areas

Peng Zang / Fei Xian / Hualong Qiu / Shifa Ma / Hongxu Guo / Mengrui Wang / Linchuan Yang

International Journal of Environmental Research and Public Health, Vol 19, Iss 1894, p

2022 Volume 1894

Abstract: Studies have proved that activity and fitness behaviors are closely related to the quality of life and health status of the elderly. However, different intensities of physical activity (PA)—walking, moderate PA, and vigorous PA—have different ... ...

Abstract	Studies have proved that activity and fitness behaviors are closely related to the quality of life and health status of the elderly. However, different intensities of physical activity (PA)—walking, moderate PA, and vigorous PA—have different correlations with the built environment (BE). This study combines the high and low socioeconomic status (SES) of Guangzhou to establish two types of BE models. The physical activity time of 600 elderly people was collected from questionnaires. Through ArcGIS software, 300 m, 500 m, 800 m, and 1000 m buffer zones were identified, and the land use diversity, street design, population density, distance to destination, distance to public transportation—the five Ds of the BE—were measured. SPSS software was adopted to analyze the correlation between the BE and PA. Results: The PA of people living in low-SES areas was more dependent on the BE, whereas the correlation may be limited in high SES areas. Moreover, in low SES areas, walking was negatively correlated with street connectivity; moderate PA was positively correlated with street connectivity and the shortest distance to the subway station, but negatively correlated with the density of entertainment points of interest (POIs). Studying the relevant factors of the environment can propose better strategies to improve the initiative of the elderly to engage in PA.
Keywords	physical activity ; built environment ; physical environment ; the elderly ; Guangzhou ; Medicine ; R
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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