A5054654986- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- Metabolomics and Mass Spectrometry Studies
- HIV Research and Treatment
- Forensic and Genetic Research
- Molecular Biology Techniques and Applications
- Adipose Tissue and Metabolism
- COVID-19 Clinical Research Studies
- HIV/AIDS drug development and treatment
- ATP Synthase and ATPases Research
- Inflammasome and immune disorders
- Long-Term Effects of COVID-19
- Cancer, Hypoxia, and Metabolism
- Neurological diseases and metabolism
- Bioinformatics and Genomic Networks
- RNA modifications and cancer
- Hemoglobinopathies and Related Disorders
- Folate and B Vitamins Research
- Birth, Development, and Health
- Diet and metabolism studies
- Alzheimer's disease research and treatments
- RNA Research and Splicing
- Genetic Neurodegenerative Diseases
- RNA and protein synthesis mechanisms
- Cytomegalovirus and herpesvirus research
Children's Hospital of Philadelphia
2017-2025
University of Pennsylvania
2017-2025
New York University
2024
Vanderbilt University
2005-2016
Center for Human Genetics
2007-2016
California University of Pennsylvania
2015
Vanderbilt University Medical Center
2012
Louis Stokes Cleveland VA Medical Center
2011
Emory University
1997-2008
University of Tennessee at Knoxville
2005
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed gene expression in nasopharyngeal autopsy tissues from patients with disease 2019 (COVID-19). In samples declining titers, the virus blocked transcription of a subset nuclear DNA (nDNA)–encoded OXPHOS genes, induced microRNA 2392, activated HIF-1α induce glycolysis, immune defenses...
Nuclear-localized mtDNA pseudogenes might explain a recent report describing heteroplasmic molecule containing five linked missense mutations dispersed over the contiguous CO1 and CO2 genes in Alzheimer’s disease (AD) patients. To test this hypothesis, we have used PCR primers utilized original to amplify sequences from two independent ρ° (mtDNA-less) cell lines. amplified both of cells, demonstrating that these are also present human nuclear DNA. The pseudogene were then tested for each...
Mitochondrial DNA (mtDNA) variation can affect phenotypic variation; therefore, knowing its distribution within and among individuals is of importance to understanding many human diseases. Intra-individual mtDNA (heteroplasmy) has been generally assumed be random. We used massively parallel sequencing assess heteroplasmy across ten tissues demonstrate that in unrelated there are tissue-specific, recurrent mutations. Certain tissues, notably kidney, liver skeletal muscle, displayed the...
Changes in the gut microbiota and mitochondrial genome are both linked with development of disease. To investigate why, we examined mice harboring various mutations genes that alter function. These studies revealed genetic variations altered composition community. In cross-fostering studies, found although initial community newborn was obtained from nursing mother, progressed toward characteristic microbiome unfostered pups same genotype within 2 months. Analysis DNA variants associated...
Background Compared to healthy controls, severe COVID19 patients display increased levels of activated NLRP3-inflammasome (NLRP3-I) and interleukin (IL)-1β. SARS-CoV-2 encodes viroporin proteins E Orf3a(2-E+2-3a) with homologs SARS-CoV-1, 1-E+1-3a, which elevate NLRP3-I activation; by an unknown mechanism. Thus, we investigated how 2-E+2-3a activates the better understand pathophysiology COVID-19. Methods We generated a polycistronic expression-vector co-expressing from single transcript. To...
To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey metabolic pathways modulated by and confirmed their importance for propagation cataloging specific pathway inhibitors. This revealed that strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased reactive oxygen species (mROS) production. The elevated mROS stabilizes HIF-1α which redirects carbon molecules from oxidation through glycolysis pentose...
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection inhibits mitochondrial oxidative phosphorylation (OXPHOS) and elevates reactive oxygen species (ROS, mROS) which activates hypoxia-inducible factor-1alpha (HIF-1α), shifting metabolism toward glycolysis to drive viral biogenesis but also causing the release of DNA (mtDNA) activation innate immunity. To determine whether mitochondrially targeted antioxidants could mitigate these effects, we challenged mice expressing human...
Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA–cancer association, we analyzed conplastic mice C57BL/6J (B6) nucleus but two naturally occurring lineages, B6 NZB , where mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, Foxp3+ T regulatory (Treg) cells supported long-term allograft survival,...
We report that oligonucleotides can be introduced into the mitochondria of living mammalian cells by annealing them to peptide nucleic acids coupled mitochondrial targeting peptides. These complexes are imported matrix through outer and inner membrane import channels isolated mitochondria. They also cultured cells, provided cytosolic uptake is facilitated using synthetic polycations or permeabilizing toxins. Our method now promises provide a viable strategy for genetic modification in...
Significance Mitochondrial dysfunction is associated with type II diabetes and metabolic syndrome, but whether it cause or consequence debated. By showing that increased mitochondrial respiration can impart glucose tolerance, insulin sensitivity, resistance to high fat diet (HFD) toxicity, we provide evidence mitochondria contributes the etiology of disease. Inactivation adenine nucleotide translocator isoform 1 (ANT1) results in proliferation partially uncoupled muscle respiration, creating...
Defects in mitochondrial oxidative phosphorylation (OXPHOS) have been reported COVID-19 patients, but the timing and organs affected vary among reports. Here, we reveal dynamics of through transcription profiles nasopharyngeal autopsy samples from patients infected rodent models. While bioenergetics is repressed viral portal entry, it up regulated lung tissues deceased patients. In most disease stages organs, discrete OXPHOS functions are blocked by virus, this countered host broadly...
The peptide nucleic acid (PNA)-directed PCR clamping technique was modified and applied to the detection of mitochondrial DNA mutations with low heteroplasmy. This method is extremely specific, eliminating false positives in absence mutant molecules, highly sensitive, being capable detecting at level 0.1% total molecules. Moreover, reaction can be multiplexed identify more than one mutation per reaction. Using this technique, levels three point mutations, tRNALeu(UUA) 3243 causing...
Limited data exist about the timing and significance of mitochondrial alterations in children with sepsis. We therefore sought to determine if respiration content within circulating peripheral blood mononuclear cells were associated organ dysfunction pediatric
Mice deficient in the heart/muscle specific isoform of adenine nucleotide translocator (ANT1) exhibit many hallmarks human oxidative phosphorylation (OXPHOS) disease, including a dramatic proliferation skeletal muscle mitochondria. Because genes necessary for mitochondrial biosynthesis, OXPHOS function, and response to disease might be expected up-regulated Ant1(-/-) mouse, we used differential display reverse transcription-polymerase chain reaction techniques an effort identify these genes....
Despite the presence of a cytosolic fatty acid synthesis pathway, mitochondria have retained their own means creating acids via mitochondrial (mtFASII) pathway. The reason for its conservation has not yet been elucidated. Therefore, to better understand role mtFASII in cell, we used thin layer chromatography characterize contribution pathway composition selected lipids. Next, performed metabolomic analysis on HeLa cells which was either hypofunctional (through knockdown acyl carrier protein,...
Lethal COVID-19 outcomes are attributed to classic cytokine storm. We revisit this using RNA sequencing of nasopharyngeal and 40 autopsy samples from patients dying SARS-CoV-2. Subsets the 100 top-upregulated genes in nasal swabs upregulated heart, lung, kidney, liver, but not mediastinal lymph nodes. Twenty-two these “noncanonical” immune genes, which we link components renin-angiotensin-activation-system that manifest as increased fibrin deposition, leaky vessels, thrombotic tendency,...
Susceptibility to peripheral neuropathy during antiretroviral therapy with nucleoside reverse-transcriptase inhibitors was previously associated a European mitochondrial DNA (mtDNA) haplogroup among non-Hispanic white persons. To determine whether inhibitor-associated related mtDNA variation in black persons, we sequenced of participants from AIDS Clinical Trials Group study 384. Of 156 persons genomic data, 51 (33%) developed neuropathy. In multivariate model, African subhaplogroup L1c an...
HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously iron-regulatory genetic polymorphisms a reduced risk of during more neurotoxic types cART. here evaluated the impact in 19 genes on DNP 560 HIV-infected subjects from prospective, observational study, who underwent neurological examinations to ascertain peripheral structured interviews DNP. Genotype-DNP associations were...
Background. Neurocognitive impairment (NCI) remains an important complication in persons infected with human immunodeficiency virus (HIV). Ancestry-related mitochondrial DNA (mtDNA) haplogroups have been associated outcomes of HIV infection and combination antiretroviral therapy (CART), neurodegenerative diseases. We hypothesize that mtDNA are NCI HIV-infected adults performed a genetic association study the CNS Antiretroviral Therapy Effects Research (CHARTER) cohort. Methods. CHARTER is...
Mitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report family complex phenotype including combinations connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis the maternally inherited mtDNA revealed novel genotype encompassing haplogroup J - defining mitochondrial DNA (mtDNA) ND5 m.13708G>A (A458T) variant arising H7A background, an extremely rare combination. transmitochondrial cybrids...
By using current biological understanding, a conceptually simple, but mathematically complex, model is proposed for the dynamics of gene circuit responsible regulating nitrogen catabolite repression (NCR) in yeast. A variety mathematical “structure” theorems are described that allow one to determine asymptotic complicated systems under very weak hypotheses. It shown these apply several subcircuits full NCR circuit, most importantly URE2–GLN3 subcircuit independent other constituents governs...