Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 30, 2023

Abstract Mitochondria carry their own circular genome and disruption of the mitochondrial is associated with various aging-related diseases. Unlike nuclear genome, DNA (mtDNA) can be present at 1000 s to 10,000 copies in somatic cells variants may exist a state heteroplasmy, where only fraction molecules harbors particular variant. We quantify mtDNA heteroplasmy 194,871 participants UK Biobank find that 1.5-fold increased risk all-cause mortality. Additionally, we functionally characterize single nucleotide (SNVs) using constraint-based score, local constraint score sum (MSS) it mortality, prevalence incidence cancer cancer-related particularly leukemia. These results indicate mitochondria have functional role certain cancers, heteroplasmic SNVs serve as prognostic marker for cancer, especially

Language: Английский

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Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(21), P. 15788 - 15788

Published: Oct. 31, 2023

Due to their beneficial effects in an array of diseases, Mesenchymal Stromal Cells (MSCs) have been the focus intense preclinical research and clinical implementation for decades. MSCs multilineage differentiation capacity, support hematopoiesis, secrete pro-regenerative factors exert immunoregulatory functions promoting homeostasis resolution injury/inflammation. The main include modulation immune cells (macrophages, neutrophils, lymphocytes), secretion antimicrobial peptides, transfer mitochondria (Mt) injured cells. These actions can be enhanced by priming (i.e., licensing) prior exposure deleterious microenvironments. Preclinical evidence suggests that therapeutic a variety pathological states, including cardiac, respiratory, hepatic, renal, neurological diseases. One key emerging is improvement mitochondrial tissues enhancing quality control (MQC). Recent advances understanding cellular MQC, biogenesis, mitophagy, fission, fusion, helped uncover how enhance these processes. Specifically, suggested regulate peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)-dependent Parkin-dependent Mitofusins (Mfn1/2) or Dynamin Related Protein-1 (Drp1)-mediated fission/fusion. In addition, previous studies also verified from through tunneling nanotubes via microvesicular transport. Combined, improve functions, thereby contributing injury inflammation. Thus, uncovering affect MQC opens new avenues organ injury, transplantation MSC-derived might represent attractive approach.

Language: Английский

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Children born after assisted reproduction more commonly carry a mitochondrial genotype associating with low birthweight

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 9, 2024

Abstract Children conceived through assisted reproductive technologies (ART) have an elevated risk of lower birthweight, yet the underlying cause remains unclear. Our study explores mitochondrial DNA (mtDNA) variants as contributors to birthweight differences by impacting function during prenatal development. We deep-sequenced mtDNA 451 ART and spontaneously (SC) individuals, 157 mother-child pairs 113 individual oocytes from either natural menstrual cycles or after ovarian stimulation (OS) find that individuals carried a different genotype than SC with more de novo non-synonymous variants. These variants, along rRNA correlate percentiles, independent conception mode. Their higher occurrence in stems mutagenesis associated maternal aging OS-induced oocyte cohort size. Future research will establish long-term health consequences these changes how findings impact clinical practice patient counselling future.

Language: Английский

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A platform to map the mind–mitochondria connection and the hallmarks of psychobiology: the MiSBIE study

Trends in Endocrinology and Metabolism, Journal Year: 2024, Volume and Issue: 35(10), P. 884 - 901

Published: Oct. 1, 2024

Language: Английский

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Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases

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

Published: April 21, 2024

Abstract GDF15 (growth differentiation factor 15) is a marker of cellular energetic stress linked to physical-mental illness, aging, and mortality. However, questions remain about its dynamic properties measurability in human biofluids other than blood. Here, we examine the natural dynamics psychobiological regulation plasma saliva four studies representing 4,749 samples from 188 individuals. We show that protein detectable (8% concentration), likely produced by salivary glands secretory duct cells. Using brief laboratory socio-evaluative stressor paradigm, find psychosocial increases (+3.5-5.9%) (+43%) with distinct kinetics, within minutes. Moreover, exhibits robust awakening response, declining ∼40-89% 30-45 minutes peak level at time waking up. Clinically, individuals genetic mitochondrial OxPhos diseases elevated baseline GDF15, post-stress levels both correlate multi-system disease severity, exercise intolerance, subjective experience fatigue. Taken together, our data establish dynamic, sensitive psychological states, clinically relevant endocrine diseases. These findings also point shared pathway integrating metabolic mental stress.

Language: Английский

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Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance

World Journal of Methodology, Journal Year: 2025, Volume and Issue: 15(3)

Published: March 6, 2025

The mitochondrial DNA copy number (mtDNAcn) plays a vital role in cellular energy metabolism and health. As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylation, maintaining an appropriate mtDNAcn level is the overall function. Alterations have been linked to various diseases, including neurodegenerative disorders, metabolic conditions, cancers, making it important biomarker understanding disease pathogenesis. accurate estimation of essential clinical applications. Quantitative polymerase chain reaction next-generation sequencing commonly employed techniques with distinct advantages limitations. Clinically, serves as valuable indicator early diagnosis, progression, treatment response. For instance, oncology, elevated levels blood samples associated tumor aggressiveness can aid monitoring efficacy. In diseases such Alzheimer’s Parkinson’s, altered patterns provide insights into mechanisms progression. Understanding estimating critical advancing diagnostic therapeutic strategies medical fields. research continues uncover implications alterations, its potential likely expand, thereby enhancing our ability diagnose manage complex diseases.

Language: Английский

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Screening for Maternally Inherited Diabetes and Deafness in Large Cohorts of Hearing Impaired and Diabetic Patients

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 17, 2025

Abstract Objectives Mitochondrial DNA (mtDNA) mutations account for up to 5% of hereditary hearing loss cases. Most commonly, the m.3243A>G mtDNA variant contributes rare monogenic MIDD (Maternally Inherited Diabetes and Deafness) or MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes) syndromes. Different proportions mutated (heteroplasmy) among affected tissues result in variability clinical manifestation severity phenotype. The aim presented study was establish prevalence large cohorts hearing-impaired diabetic patients Slovakia evaluate genotype-phenotype correlations long-term cochlear implantation outcomes. Design Probands (n=5957) were recruited via three independent nationwide studies on (n=1145) diabetes (unselected group, n=4158 Monogenic n=654; total n=4812). from peripheral blood and/or buccal mucosa tested presence using two PCR methods – qPCR dPCR. Audiological other data identified carriers also collected phenotype evaluation. Results We 25 probands/families harboring (0.42%). higher groups where disorder suspected 0.79% Hearing group 1.68% versus 0.14% general ( p < 0.001). Heteroplasmy levels assessed by dPCR ranged between 0.04% 76% 0.01% 92% samples. In most individuals, symptoms manifested fourth decade life subjects with isolated loss/diabetes, but as early second probands MELAS. observed high variability, ranging severe multisystemic involvement through asymptomatic young “dormant” very low heteroplasmy carriers. Only 54% individuals had both loss. swabs showed a better correlation age onset than age-adjusted heteroplasmy. On hand, associated overall disease (i.e., number symptoms). show that typical audiogram configurations are flat sloping. Three implant recipients excellent stable functional addition, authors report first case successful stapes surgery patient confirmed mitochondrial disorder. Conclusions diagnostic yield deafness unselected group. Implementation rigorous inclusion criteria requiring may lead lower detection rate due different incomplete manifestation. Age-adjusted seem be good predictor m.3243A>G-associated diseases, predicted onset. further confirm stapedectomy safe efficient options restoration rehabilitation

Language: Английский

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Stroke-Like Episode, Aphasia, and Hearing Loss in a Young Female With MELAS

Journal of Clinical Neurology, Journal Year: 2025, Volume and Issue: 21

Published: Jan. 1, 2025

Language: Английский

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Saliva and Blood Cell-Free mtDNA Reactivity to Acute Psychosocial Stress

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 12, 2025

Abstract Human blood contains cell-free mitochondrial DNA (cf-mtDNA) that dynamically increases in concentration response to acute mental stress. Like other neuroendocrine stress markers, we previously found cf-mtDNA is also detectable saliva, calling for studies examining saliva reactivity In healthy women and men from the MiSBIE (Mitochondrial Stress, Brain Imaging, Epigenetics) study (n=68, 66% women), a brief socio-evaluative stressor induced striking 280% or 2.8-fold increase within 10 minutes (g=0.55, p<0.0001). drawn concurrently with sampling, increased by an average 32% at 60 min serum (g=0.20), but not anticoagulated plasma where decreased 19% (g=0.25). Examining influence of health on participants rare diseases (MitoD), report subset MitoD exhibit markedly blunted reactivity, suggesting bioenergetic defects mitochondria may magnitude possibly responses. Our results document robust provide methodology examine psychobiological regulation future studies.

Language: Английский

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Taurine supplementation improves physical activity level in a hemodialysis patient with mitochondrial disease: a case report

CEN Case Reports, Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Language: Английский

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