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Article ; Online: Mitochondrial DNA Release in Innate Immune Signaling.

Newman, Laura E / Shadel, Gerald S

2023 Volume 92, Page(s) 299–332

Abstract: According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is the present-day mitochondrial DNA (mtDNA). ... ...

Abstract	According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is the present-day mitochondrial DNA (mtDNA). The ability of mtDNA to escape mitochondria and integrate into the nuclear genome was discovered in budding yeast, along with genes that regulate this process. Mitochondria have emerged as key regulators of innate immunity, and it is now recognized that mtDNA released into the cytoplasm, outside of the cell, or into circulation activates multiple innate immune signaling pathways. Here, we first review the mechanisms through which mtDNA is released into the cytoplasm, including several inducible mitochondrial pores and defective mitophagy or autophagy. Next, we cover how the different forms of released mtDNA activate specific innate immune nucleic acid sensors and inflammasomes. Finally, we discuss how intracellular and extracellular mtDNA release, including circulating cell-free mtDNA that promotes systemic inflammation, are implicated in human diseases, bacterial and viral infections, senescence and aging.
MeSH term(s)	Animals ; Humans ; DNA, Mitochondrial/genetics ; DNA, Mitochondrial/metabolism ; Mitochondria/genetics ; Mitochondria/metabolism ; Immunity, Innate/genetics ; Aging/genetics ; Cell Nucleus/genetics ; Cell Nucleus/metabolism ; Mammals/genetics
Chemical Substances	DNA, Mitochondrial
Language	English
Publishing date	2023-03-31
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	207924-0
ISSN	1545-4509 ; 0066-4154
ISSN (online)	1545-4509
ISSN	0066-4154
DOI	10.1146/annurev-biochem-032620-104401
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Article ; Online: The Psychosocial Treadmill: the Road to Improving High-risk Behavior in Advanced Therapy Candidates.

Newman, Laura

Current heart failure reports

2018 Volume 15, Issue 2, Page(s) 70–74

Abstract: Purpose of review: The purpose of this review is to explore the evaluation and identification of psychosocial risk factors during the heart transplant evaluation process with the goal of improving psychosocial candidacy prior to transplant listing. ... ...

Abstract	Purpose of review: The purpose of this review is to explore the evaluation and identification of psychosocial risk factors during the heart transplant evaluation process with the goal of improving psychosocial candidacy prior to transplant listing. Subsequently, more patients will be able to receive life-saving heart transplant and experience success after transplant. Recent findings: Evaluating and identifying psychosocial risk factors is an essential component of the transplant evaluation process. Less research exists demonstrating how patients may be able to reduce psychosocial risk factors over time to improve their candidacy for transplant. This review will describe a program developed for patients undergoing heart transplant evaluation at The Ohio State University Wexner Medical Center to improve their psychosocial risk. By implementing a comprehensive, multidisciplinary intervention to address psychosocial risk factors pre-transplant, patients can improve their psychosocial candidacy and go on to be listed for heart transplant.
MeSH term(s)	Heart Failure/psychology ; Heart Failure/surgery ; Heart Transplantation/psychology ; Humans ; Patient Selection ; Personality Assessment ; Waiting Lists
Language	English
Publishing date	2018-02-07
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2151202-4
ISSN	1546-9549 ; 1546-9530
ISSN (online)	1546-9549
ISSN	1546-9530
DOI	10.1007/s11897-018-0380-1
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Zs.A 5936: Show issues

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Article: An exploratory study of exercise behaviours and barriers to participation in people with Charcot-Marie-Tooth disease: a focus on resistance training.

Newman, Laura / Fornusek, Che / Hackett, Daniel

Journal of exercise rehabilitation

2023 Volume 19, Issue 1, Page(s) 35–44

Abstract: The aim of this study was to explore and describe the exercise behaviours and barriers in people with Charcot-Marie-Tooth disease (CMT), with a particular focus on resistance training (RT). Ninety-four Australian adults with a diagnosis of CMT completed ... ...

Abstract	The aim of this study was to explore and describe the exercise behaviours and barriers in people with Charcot-Marie-Tooth disease (CMT), with a particular focus on resistance training (RT). Ninety-four Australian adults with a diagnosis of CMT completed an online survey. Fifty-seven percent of respondents reported performing some form of RT each week. Those performing RT engaged in more aerobic activity (
Language	English
Publishing date	2023-02-23
Publishing country	Korea (South)
Document type	Journal Article
ZDB-ID	2756291-8
ISSN	2288-1778 ; 2288-176X
ISSN (online)	2288-1778
ISSN	2288-176X
DOI	10.12965/jer.2346020.010
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Article ; Online: How do infant feeding method, sleeping location, and postpartum depression interact with maternal sleep quality?

Newman, Laura / Thorne, Hannah / Gupta, Charlotte C / Sprajcer, Madeline

Sleep medicine

2023 Volume 110, Page(s) 183–189

Abstract: New mothers generally experience poor and/or disrupted sleep. A range of infant care and mental health factors may impact new mothers' sleep quality. A cross-sectional online survey was completed by a sample of 101 Australian new mothers with children ... ...

Abstract	New mothers generally experience poor and/or disrupted sleep. A range of infant care and mental health factors may impact new mothers' sleep quality. A cross-sectional online survey was completed by a sample of 101 Australian new mothers with children under 12 months (M = 5.52 months, SD = 3.29 months) to examine the relationship between infant feeding method, infant sleeping location, and postpartum depression with maternal sleep quality. Subjective maternal sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI), and postpartum depression was measured using the Edinburgh Postpartum Depression Scale (EPDS). Overall, new mothers experienced poor subjective sleep quality, with high average PSQI scores, above the cut-off of 5 (M = 9.63, SD = 4.07). The majority of new mothers did not experience postpartum depression, with an average EPDS score below the cut-off of 11 (8.66, SD = 5.20). Mothers who breastfed their infants experienced significantly better subjective sleep quality than mothers who bottle-fed, with a medium effect size (ηp2 = 0.458). Subjective maternal sleep quality did not differ based on infant sleeping location. Poor subjective maternal sleep quality was a significant predictor of postpartum depression. While poor sleep was common in this sample of Australian new mothers, this study demonstrated that new mothers who breastfeed may experience slightly better subjective sleep quality than other feeding methods. Further research into, and better services for the education and advocation of, new mothers' sleep quality will be beneficial to both new mothers and clinicians.
MeSH term(s)	Female ; Child ; Infant ; Humans ; Depression, Postpartum ; Sleep Quality ; Cross-Sectional Studies ; Australia ; Sleep ; Breast Feeding ; Mothers/psychology ; Sleep Initiation and Maintenance Disorders
Language	English
Publishing date	2023-08-19
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2012041-2
ISSN	1878-5506 ; 1389-9457
ISSN (online)	1878-5506
ISSN	1389-9457
DOI	10.1016/j.sleep.2023.08.017
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Zs.A 5315: 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: Pink1/Parkin link inflammation, mitochondrial stress, and neurodegeneration.

Newman, Laura E / Shadel, Gerald S

The Journal of cell biology

2018 Volume 217, Issue 10, Page(s) 3327–3329

Abstract: What causes inflammation in age-related neurodegenerative diseases remains a mystery. Sliter et al. (2018. ...

Abstract	What causes inflammation in age-related neurodegenerative diseases remains a mystery. Sliter et al. (2018.
MeSH term(s)	Humans ; Inflammation ; Mitochondria ; Mitophagy ; Protein Kinases ; Ubiquitin-Protein Ligases
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2018-08-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.201808118
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Article ; Online: Lessons Learned from Public Health and State Prison Collaborations during COVID-19 Pandemic and Multifacility Tuberculosis Outbreak, Washington, USA.

Gurrey, Sixtine O / Strick, Lara B / Dov, Lana K / Miller, James S / Pecha, Monica / Stalter, Randy M / Miller, David L / Marshall, Brandon / Salazar, Alonso Pezo / Newman, Laura P

Emerging infectious diseases

2024 Volume 30, Issue 13, Page(s) S17–S20

Abstract: The large COVID-19 outbreaks in prisons in the Washington (USA) State Department of Corrections (WADOC) system during 2020 highlighted the need for a new public health approach to prevent and control COVID-19 transmission in the system's 12 facilities. ... ...

Abstract	The large COVID-19 outbreaks in prisons in the Washington (USA) State Department of Corrections (WADOC) system during 2020 highlighted the need for a new public health approach to prevent and control COVID-19 transmission in the system's 12 facilities. WADOC and the Washington State Department of Health (WADOH) responded by strengthening partnerships through dedicated corrections-focused public health staff, improving cross-agency outbreak response coordination, implementing and developing corrections-specific public health guidance, and establishing collaborative data systems. The preexisting partnerships and trust between WADOC and WADOH, strengthened during the COVID-19 response, laid the foundation for a collaborative response during late 2021 to the largest tuberculosis outbreak in Washington State in the past 20 years. We describe challenges of a multiagency collaboration during 2 outbreak responses, as well as approaches to address those challenges, and share lessons learned for future communicable disease outbreak responses in correctional settings.
MeSH term(s)	Humans ; COVID-19/epidemiology ; COVID-19/prevention & control ; Public Health ; Prisons ; Washington/epidemiology ; Pandemics/prevention & control ; Disease Outbreaks/prevention & control ; Tuberculosis/epidemiology ; Tuberculosis/prevention & control
Language	English
Publishing date	2024-04-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1380686-5
ISSN	1080-6059 ; 1080-6040
ISSN (online)	1080-6059
ISSN	1080-6040
DOI	10.3201/eid3013.230777
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Zs.A 4778: Show issues

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Article ; Online: COVID-19 Outbreak Among Farmworkers - Okanogan County, Washington, May-August 2020.

Miller, James S / Holshue, Michelle / Dostal, Tia K H / Newman, Laura P / Lindquist, Scott

MMWR. Morbidity and mortality weekly report

2021 Volume 70, Issue 17, Page(s) 617–621

Abstract: Okanogan County, Washington, experienced increased community transmission of SARS-CoV-2, the virus that causes COVID-19, during summer 2020 (1). Multiple COVID-19 outbreaks occurred in agricultural settings, including a large outbreak among employees of ... ...

Abstract	Okanogan County, Washington, experienced increased community transmission of SARS-CoV-2, the virus that causes COVID-19, during summer 2020 (1). Multiple COVID-19 outbreaks occurred in agricultural settings, including a large outbreak among employees of a fruit grower during May-August. Because of this outbreak, Okanogan County Public Health and the Washington State Department of Health initiated one-time, on-site screening testing (2) of all orchard and warehouse employees in August 2020 and assessed risk factors for SARS-CoV-2 infection. Among 3,708 known orchard employees, a valid SARS-CoV-2 test result or information on COVID-19-like symptoms in the absence of a test was available for 3,013 (81%). Cumulative incidence of SARS-CoV-2 infection during approximately 3 months among tested orchard employees was 6%. Cumulative incidence was 12% in employees residing in the community, compared with 4% in employees residing in farmworker housing (p<0.001); point prevalence during the single screening testing event was 1% in both groups. Among 1,247 known warehouse employees, a valid result was available for 726 (58%). Cumulative incidence over approximately 3 months among tested warehouse employees was 23%, with substantial variation across job roles. Positive test results were received by 28% of employees who worked packing and sorting fruit, 24% of those in other roles in the packing and sorting area, 10% of forklift operators, 7% of employees in other warehouse roles, and 6% of office employees. Point prevalence among all warehouse workers was 1% at the screening testing event. Collaboration among employers, community groups, and public health authorities can reveal risk factors and help decrease farmworkers' risk for SARS-CoV-2 infection in the community and the workplace. Creation of a COVID-19 assessment and control plan by agricultural employers, with particular focus on indoor workers whose jobs limit physical distancing, could reduce workplace transmission.
MeSH term(s)	COVID-19/epidemiology ; COVID-19/prevention & control ; COVID-19/transmission ; COVID-19 Testing/statistics & numerical data ; Disease Outbreaks ; Farmers/statistics & numerical data ; Humans ; Incidence ; Occupational Diseases/epidemiology ; Physical Distancing ; Risk Factors ; Washington/epidemiology
Language	English
Publishing date	2021-04-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	412775-4
ISSN	1545-861X ; 0149-2195
ISSN (online)	1545-861X
ISSN	0149-2195
DOI	10.15585/mmwr.mm7017a3
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Article ; Online: Activation of the cGAS-STING innate immune response in cells with deficient mitochondrial topoisomerase TOP1MT.

Al Khatib, Iman / Deng, Jingti / Lei, Yuanjiu / Torres-Odio, Sylvia / Rojas, Gladys R / Newman, Laura E / Chung, Brian K / Symes, Andrew / Zhang, Hongliang / Huang, Shar-Yin N / Pommier, Yves / Khan, Aneal / Shadel, Gerald S / West, Andrew Phillip / Gibson, William T / Shutt, Timothy E

Human molecular genetics

2024 Volume 32, Issue 15, Page(s) 2422–2440

Abstract: The recognition that cytosolic mitochondrial DNA (mtDNA) activates cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) innate immune signaling has unlocked novel disease mechanisms. Here, an uncharacterized variant predicted to affect ... ...

Abstract	The recognition that cytosolic mitochondrial DNA (mtDNA) activates cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) innate immune signaling has unlocked novel disease mechanisms. Here, an uncharacterized variant predicted to affect TOP1MT function, P193L, was discovered in a family with multiple early onset autoimmune diseases, including Systemic Lupus Erythematosus (SLE). Although there was no previous genetic association between TOP1MT and autoimmune disease, the role of TOP1MT as a regulator of mtDNA led us to investigate whether TOP1MT could mediate the release of mtDNA to the cytosol, where it could then activate the cGAS-STING innate immune pathway known to be activated in SLE and other autoimmune diseases. Through analysis of cells with reduced TOP1MT expression, we show that loss of TOP1MT results in release of mtDNA to the cytosol, which activates the cGAS-STING pathway. We also characterized the P193L variant for its ability to rescue several TOP1MT functions when expressed in TOP1MT knockout cells. We show that the P193L variant is not fully functional, as its re-expression at high levels was unable to rescue mitochondrial respiration deficits, and only showed partial rescue for other functions, including repletion of mtDNA replication following depletion, nucleoid size, steady state mtDNA transcripts levels and mitochondrial morphology. Additionally, expression of P193L at endogenous levels was unable to rescue mtDNA release-mediated cGAS-STING signaling. Overall, we report a link between TOP1MT and mtDNA release leading to cGAS-STING activation. Moreover, we show that the P193L variant has partial loss of function that may contribute to autoimmune disease susceptibility via cGAS-STING mediated activation of the innate immune system.
MeSH term(s)	Humans ; Autoimmune Diseases ; DNA, Mitochondrial/genetics ; Immunity, Innate/genetics ; Interferons ; Lupus Erythematosus, Systemic ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism
Chemical Substances	DNA, Mitochondrial ; Interferons (9008-11-1) ; Nucleotidyltransferases (EC 2.7.7.-) ; TOP1MT protein, human (EC 5.99.1.2) ; Top1mt protein, mouse (EC 5.99.1.2) ; cGAS protein, human (EC 2.7.7.-) ; cGAS protein, mouse (EC 2.7.7.-) ; STING1 protein, human ; Sting1 protein, mouse
Language	English
Publishing date	2024-01-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddad062
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Zs.A 3469: Show issues

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Article ; Online: Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.

Newman, Laura E / Weiser Novak, Sammy / Rojas, Gladys R / Tadepalle, Nimesha / Schiavon, Cara R / Grotjahn, Danielle A / Towers, Christina G / Tremblay, Marie-Ève / Donnelly, Matthew P / Ghosh, Sagnika / Medina, Michaela / Rocha, Sienna / Rodriguez-Enriquez, Ricardo / Chevez, Joshua A / Lemersal, Ian / Manor, Uri / Shadel, Gerald S

Nature cell biology

2024 Volume 26, Issue 2, Page(s) 194–206

Abstract: Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into ... ...

Abstract	Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, transcription factor A, mitochondrial (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA-protein complexes) and activation of cGAS-STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS-STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS-STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria-endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states.
MeSH term(s)	Humans ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; DNA, Mitochondrial/genetics ; DNA, Mitochondrial/metabolism ; DNA Replication ; Endosomes/metabolism ; Nucleotidyltransferases/genetics ; Inflammation/genetics ; Mitochondrial Proteins/metabolism
Chemical Substances	DNA-Binding Proteins ; DNA, Mitochondrial ; Nucleotidyltransferases (EC 2.7.7.-) ; Mitochondrial Proteins
Language	English
Publishing date	2024-02-08
Publishing country	England
Document type	Journal Article
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/s41556-023-01343-1
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Zs.A 5169: 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: ELMOD2 regulates mitochondrial fusion in a mitofusin-dependent manner, downstream of ARL2.

Schiavon, Cara R / Turn, Rachel E / Newman, Laura E / Kahn, Richard A

Molecular biology of the cell

2019 Volume 30, Issue 10, Page(s) 1198–1213

Abstract: Mitochondria are essential and dynamic organelles undergoing constant fission and fusion. The primary players in mitochondrial morphology (MFN1/2, OPA1, DRP1) have been identified, but their mechanism(s) of regulation are still being elucidated. ARL2 is ... ...

Abstract	Mitochondria are essential and dynamic organelles undergoing constant fission and fusion. The primary players in mitochondrial morphology (MFN1/2, OPA1, DRP1) have been identified, but their mechanism(s) of regulation are still being elucidated. ARL2 is a regulatory GTPase that has previously been shown to play a role in the regulation of mitochondrial morphology. Here we demonstrate that ELMOD2, an ARL2 GTPase-activating protein (GAP), is necessary for ARL2 to promote mitochondrial elongation. We show that loss of ELMOD2 causes mitochondrial fragmentation and a lower rate of mitochondrial fusion, while ELMOD2 overexpression promotes mitochondrial tubulation and increases the rate of fusion in a mitofusin-dependent manner. We also show that a mutant of ELMOD2 lacking GAP activity is capable of promoting fusion, suggesting that ELMOD2 does not need GAP activity to influence mitochondrial morphology. Finally, we show that ELMOD2, ARL2, Mitofusins 1 and 2, Miros 1 and 2, and mitochondrial phospholipase D (mitoPLD) all localize to discrete, regularly spaced puncta along mitochondria. These results suggest that ELMOD2 is functioning as an effector downstream of ARL2 and upstream of the mitofusins to promote mitochondrial fusion. Our data provide insights into the pathway by which mitochondrial fusion is regulated in the cell.
MeSH term(s)	Animals ; COS Cells ; Cell Line ; Cercopithecus aethiops ; Cytoskeletal Proteins/genetics ; Cytoskeletal Proteins/metabolism ; GTP Phosphohydrolases/metabolism ; GTP-Binding Proteins/genetics ; GTP-Binding Proteins/metabolism ; Gene Knockout Techniques/methods ; Humans ; Membrane Fusion/physiology ; Mice ; Microtubule-Associated Proteins/metabolism ; Mitochondria/metabolism ; Mitochondria/physiology ; Mitochondrial Dynamics/physiology ; Mitochondrial Membranes/metabolism ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Phospholipase D/genetics ; Phospholipase D/metabolism
Chemical Substances	Cytoskeletal Proteins ; ELMOD2 protein, human ; Microtubule-Associated Proteins ; Mitochondrial Proteins ; Phospholipase D (EC 3.1.4.4) ; mitoPLD protein, human (EC 3.1.4.4) ; ARL2 protein, human (EC 3.6.1.-) ; GTP Phosphohydrolases (EC 3.6.1.-) ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2019-03-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1098979-1
ISSN	1939-4586 ; 1059-1524
ISSN (online)	1939-4586
ISSN	1059-1524
DOI	10.1091/mbc.E18-12-0804
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Zs.MO 410: Show issues

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