Genetics of Constant and Severe Pain in the NAPS2 Cohort of Recurrent Acute and Chronic Pancreatitis Patients DOI Creative Commons

Ellyn Dunbar,

Phil J. Greer, Jami L. Saloman

et al.

Journal of Pain, Journal Year: 2024, Volume and Issue: unknown, P. 104754 - 104754

Published: Dec. 1, 2024

Recurrent acute and chronic pancreatitis (RAP, CP) are complex, progressive inflammatory diseases with variable pain experiences impacting patient function quality of life. The genetic variants pathways in patients contributing to most severe unknown. We used previously genotyped individuals RAP/CP from the North American Pancreatitis Study II (NAPS2) European Ancestry for nested genome-wide associated study (GWAS) pain-severity, chronicity, or both. Lead GWAS were determined using FUMA. Loci p<1e-5 identified post-hoc candidate identification. Transcriptome-wide association studies (TWAS) loci cis trans lead variants. Serum phenotyped CP PROspective Evaluation Chronic EpidEmiologic Translational StuDies (PROCEED) was assessed BDNF levels Meso Scale Discovery Immunoassay. four systems defined by genes: 1) Pancreas-associated injury/stress mitigation genes include: REG gene cluster, CTRC, NEURL3 HSF22. 2) Neural development axon guidance tracing SNPO, RGMA, MAML1 DOK6 (part RET complex). 3) Genes linked psychiatric stress disorders include TMEM65, RBFOX1, ZNF385D. 4) dorsal horn pain-modulating BDNF/neuropathic pathway included SYNPR, NTF3 RBFOX1. In an independent cohort significantly elevated constant-severe pain. Extension expansion this exploratory may identify pathway- mechanism-dependent targets individualized treatments patients. PERSPECTIVE: Pain is distressing debilitating feature pancreatitis. Yet many have little no includes over 1250 all stages clinical phenotypic characteristics carefully recorded. did not correlate well disease stage, inflammation, fibrosis other features. Here we spit into groups and/or syndromes compared them genetically reporting mild minimal Although some expressed cells (1) pancreas, nervous system (2) neural (as needed descending inhibition pathway), (3) disorders, (4) regulating sensory nerves neuropathic Similar overlapping 2 -4 also seen form organs. implications treating pancreatic great that can longer focus on just pancreas. Furthermore, new designed tissues be effective Further research replicate extend these observations so new, genetics-guided rational developed delivered.

Language: Английский

The roles of mitochondria in global and local intracellular calcium signalling DOI
Benjamín Cartes-Saavedra, Arijita Ghosh, György Hajnóczky

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Language: Английский

Citations

4
Mitochondrial Calcium Regulation of Cardiac Metabolism in Health and Disease DOI
Enrique Balderas, Sandra Lee, Neeraj Kumar Vasistha

et al.

Physiology, Journal Year: 2024, Volume and Issue: 39(5), P. 247 - 268

Published: May 7, 2024

Oxidative phosphorylation is regulated by mitochondrial calcium (Ca2+) in health and disease. In physiological states, Ca2+ enters via the uniporter rapidly enhances NADH ATP production. However, maintaining homeostasis critical: insufficient impairs stress adaptation, overload can trigger cell death. this review, we delve into recent insights further defining relationship between dynamics oxidative phosphorylation. Our focus on how such regulation affects cardiac function disease, including heart failure, ischemia-reperfusion, arrhythmias, catecholaminergic polymorphic ventricular tachycardia, cardiomyopathies, Barth syndrome, Friedreich's ataxia. Several themes emerge from data. First, critical for fuel substrate selection, metabolite import, matching of supply to demand. Second, regulates both production response reactive oxygen species (ROS), balance its pro- antioxidant effects key it contributes pathological states. Third, exerts localized electron transport chain (ETC), not through traditional allosteric mechanisms but rather indirectly. These hinge specific transporters, as or Na+/Ca2+ exchanger, may be noticeable acutely, contributing differently phenotypes depending whether transporters are acutely chronically modified. Perturbations these novel relationships during disease states either serve compensatory exacerbate impairments Consequently, targeting holds promise a therapeutic strategy variety diseases characterized contractile failure arrhythmias.

Language: Английский

Citations

11
Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models DOI Creative Commons
Madeleine J. Twyning, Roberta Tufi,

Thomas P. Gleeson

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(2), P. 113681 - 113681

Published: Jan. 21, 2024

Mitochondrial calcium (Ca2+) uptake augments metabolic processes and buffers cytosolic Ca2+ levels; however, excessive mitochondrial can cause cell death. Disrupted function homeostasis are linked to numerous neurodegenerative diseases (NDs), but the impact of disruption is not well understood. Here, we show that Drosophila models multiple NDs (Parkinson's, Huntington's, Alzheimer's, frontotemporal dementia) reveal a consistent increase in neuronal levels, as reduced buffering capacity, associated with increased mitochondria-endoplasmic reticulum contact sites (MERCs). Importantly, loss channel MCU or overexpression efflux NCLX robustly suppresses key pathological phenotypes across these ND models. Thus, imbalance common feature diverse vivo an important contributor disease pathogenesis. The broad beneficial effects from partial presents common, druggable target for therapeutic intervention.

Language: Английский

Citations

8
MCU-independent Ca2+ uptake mediates mitochondrial Ca2+ overload and necrotic cell death in a mouse model of Duchenne muscular dystrophy DOI Creative Commons
Michael J. Bround, Eaman Abay, Jiuzhou Huo

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: March 21, 2024

Mitochondrial Ca2+ overload can mediate mitochondria-dependent cell death, a major contributor to several human diseases. Indeed, Duchenne muscular dystrophy (MD) is driven by dysfunctional influx across the sarcolemma that causes mitochondrial overload, organelle rupture, and muscle necrosis. The uniporter (MCU) complex primary characterized mechanism for acute uptake. One strategy preventing deletion of Mcu gene, pore forming subunit MCU-complex. Conversely, enhanced MCU-complex uptake achieved deleting inhibitory Mcub gene. Here we show myofiber-specific was not protective in mouse model MD. Specifically, gene did reduce histopathology, improve function, prevent overload. Moreover, myofiber specific augment MD pathology. Interestingly, observed MCU-independent dystrophic mitochondria sufficient drive permeability transition (MPTP) activation skeletal necrosis, this same type activity heart, liver, brain mitochondria. These results demonstrate possess an uncharacterized MPTP-dependent necrosis vivo.

Language: Английский

Citations

6
Mitochondrial redox state, bioenergetics, and calcium transport in caloric restriction: A metabolic nexus DOI
Eloisa Aparecida Vilas‐Boas, Alicia J. Kowaltowski

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: 219, P. 195 - 214

Published: April 25, 2024

Language: Английский

Citations

4
Calcium Signals as Regulators of Ferroptosis in Cancer DOI Creative Commons
Ioana Stejerean‐Todoran, Christine S. Gibhardt, Ivan Bogeski

et al.

Cell Calcium, Journal Year: 2024, Volume and Issue: 124, P. 102966 - 102966

Published: Oct. 30, 2024

Language: Английский

Citations

4
Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB DOI Creative Commons
Donato D’Angelo, Víctor Hugo Sánchez-Vázquez, Benjamín Cartes-Saavedra

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 21, 2025

Cells utilize protein disaggregases to avoid abnormal aggregation that causes many diseases. Among these, caseinolytic peptidase B homolog (CLPB) is localized in the mitochondrial intermembrane space and linked human disease. Upon CLPB loss, MICU1 MICU2, regulators of calcium uniporter complex (mtCU), OPA1, a main mediator fusion, become insoluble but functional outcome remains unclear. In this work we demonstrate required maintain signalling fusion dynamics. loss results altered mtCU composition, interfering with uptake independently cytosolic membrane potential. Additionally, OPA1 decreases, occurs, accompanied by fragmentation. Disease-associated mutations gene present skin fibroblasts from patients also display structural changes. Thus, activity are dependent on CLPB, their impairments might contribute disease caused variants. disaggregase has been Here, authors show different models chronic or acute disaggregase, Ca2+ handling dynamics impaired, revealing dependence CLPB.

Language: Английский

Citations

0
Differential Control of Inhibitory and Excitatory Nerve Terminal Function by Mitochondria DOI Creative Commons
Kirsten Bredvik, Timothy A. Ryan

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 19, 2024

Abstract Inhibitory neurons shape the brain’s computational landscape and rely on different cellular architectures intrinsic properties than excitatory neurons. Maintenance of overall balance (E) versus inhibitory (I) drive is essential, as disruptions can lead to neuropathological conditions, including autism epilepsy. Metabolic perturbations are a common driver E/I imbalance but differential sensitivity these two neuron types metabolic lesions not well understood. Here, we characterized differences in presynaptic bioenergetic regulation between nerve terminals using genetically encoded indicators expressed primary dissociated neuronal cultures. Our experiments showed that sustain higher ATP levels arising from increased mitochondrial metabolism. Additionally, mitochondria play greater role buffering Ca 2+ handling differentially regulated by TMEM65-mediated acceleration extrusion following bursts activity. These thus identify reliance function across major types.

Language: Английский

Citations

2
How does mitochondrial Ca2+ change during ischemia and reperfusion? Implications for activation of the permeability transition pore DOI Open Access
Elizabeth Murphy, David Eisner

The Journal of General Physiology, Journal Year: 2024, Volume and Issue: 157(1)

Published: Dec. 19, 2024

Cardiac ischemia followed by reperfusion results in cardiac cell death, which has been attributed to an increase of mitochondrial Ca2+ concentration, resulting activation the permeability transition pore (PTP). Evaluating this hypothesis requires understanding mechanisms responsible for control physiological conditions and how they are altered during both reperfusion. influx is thought occur through uniporter (MCU). However, with deletion MCU, still occurs, suggesting alternative mechanism ischemia. There less certainty about efflux, contributions from Ca2+/H+ exchange a Na+-dependent efflux pathway. The molecular details not fully resolved. We discuss pathways accumulation further role PTP.

Language: Английский

Citations

1
Genetics of Constant and Severe Pain in the NAPS2 Cohort of Recurrent Acute and Chronic Pancreatitis Patients DOI Creative Commons

Ellyn Dunbar,

Phil J. Greer, Jami L. Saloman

et al.

Journal of Pain, Journal Year: 2024, Volume and Issue: unknown, P. 104754 - 104754

Published: Dec. 1, 2024

Recurrent acute and chronic pancreatitis (RAP, CP) are complex, progressive inflammatory diseases with variable pain experiences impacting patient function quality of life. The genetic variants pathways in patients contributing to most severe unknown. We used previously genotyped individuals RAP/CP from the North American Pancreatitis Study II (NAPS2) European Ancestry for nested genome-wide associated study (GWAS) pain-severity, chronicity, or both. Lead GWAS were determined using FUMA. Loci p<1e-5 identified post-hoc candidate identification. Transcriptome-wide association studies (TWAS) loci cis trans lead variants. Serum phenotyped CP PROspective Evaluation Chronic EpidEmiologic Translational StuDies (PROCEED) was assessed BDNF levels Meso Scale Discovery Immunoassay. four systems defined by genes: 1) Pancreas-associated injury/stress mitigation genes include: REG gene cluster, CTRC, NEURL3 HSF22. 2) Neural development axon guidance tracing SNPO, RGMA, MAML1 DOK6 (part RET complex). 3) Genes linked psychiatric stress disorders include TMEM65, RBFOX1, ZNF385D. 4) dorsal horn pain-modulating BDNF/neuropathic pathway included SYNPR, NTF3 RBFOX1. In an independent cohort significantly elevated constant-severe pain. Extension expansion this exploratory may identify pathway- mechanism-dependent targets individualized treatments patients. PERSPECTIVE: Pain is distressing debilitating feature pancreatitis. Yet many have little no includes over 1250 all stages clinical phenotypic characteristics carefully recorded. did not correlate well disease stage, inflammation, fibrosis other features. Here we spit into groups and/or syndromes compared them genetically reporting mild minimal Although some expressed cells (1) pancreas, nervous system (2) neural (as needed descending inhibition pathway), (3) disorders, (4) regulating sensory nerves neuropathic Similar overlapping 2 -4 also seen form organs. implications treating pancreatic great that can longer focus on just pancreas. Furthermore, new designed tissues be effective Further research replicate extend these observations so new, genetics-guided rational developed delivered.

Language: Английский

Citations

0