Breaking News
September 24, 2018 - King’s commemorates opening of new NMR facility with one-day symposium
September 24, 2018 - Eisai receives approval for partial label change of DC Bead device for transcatheter arterial embolization
September 24, 2018 - High-resolution genomic map gives scientists unprecedented view of brain development
September 24, 2018 - Alexion announces positive results from Phase 3 PREVENT study of Soliris in patients with NMOSD
September 24, 2018 - First evaluation of benefits, harms of Alzheimer’s screening for family members of older adults
September 24, 2018 - Children of mothers using cannabis may start using it at an earlier age, finds study
September 24, 2018 - Most patients who underwent transcatheter valve replacement experience prosthesis-patient mismatch
September 24, 2018 - New study provides basis for Air Canada to change its facial hair policy for aircrew
September 24, 2018 - Infant walkers lead to thousands of emergency visits for babies
September 24, 2018 - Genes predicting person’s height may provide clues about causes of varicose veins
September 24, 2018 - EPA Plan Will Maintain Carbon Emissions From Power Plants
September 24, 2018 - Characterizing pig hippocampus could improve translational neuroscience
September 24, 2018 - Element3 Health reports social and mental engagement play key role in overall health
September 24, 2018 - Paralympic medalists support Fight for Sight’s unique virtual event
September 24, 2018 - ADCETRIS drug receives approval in Japan as frontline treatment option for Hodgkin lymphoma
September 24, 2018 - Public awareness of urological conditions found to be alarmingly low across Europe
September 24, 2018 - Fitter Folks Suffer Milder Strokes: Study
September 24, 2018 - Novel botulinum toxin compound relieves chronic pain
September 24, 2018 - CHMP recommends approval of Gilenya for treatment of multiple sclerosis in children, adolescents
September 24, 2018 - National Friendly’s private medical insurance is a hit with women living in the South East
September 24, 2018 - Academics receive prestigious awards for achievements in blood pressure research
September 24, 2018 - Obese pregnant women can restrict weight gain safely with proper nutrition guidance
September 24, 2018 - CHMP adopts positive opinion of Takeda’s ALUNBRIG for treatment of ALK+ non-small cell lung cancer
September 24, 2018 - China NMPA approves LENVIMA for treatment of unresectable hepatocellular carcinoma
September 24, 2018 - A new approach for finding Alzheimer’s treatments
September 24, 2018 - USC research uncovers previously unknown genetic risk factor for dementia
September 24, 2018 - Study examining mental health among students finds significant disparities in treatment across race
September 24, 2018 - Breakthrough discovery paves way for future test to identify drowsy drivers
September 24, 2018 - Transcatheter mitral-valve repair in patients with heart failure
September 24, 2018 - Study opens new avenues for treatment of Laing distal myopathy
September 24, 2018 - Stroke Facts | cdc.gov
September 24, 2018 - Sarcolipin tricks muscle cells into using more energy, burning fat
September 24, 2018 - Enrollment in opioid controlled substance agreement reduces primary care visits
September 24, 2018 - UTA researchers patent new smart seat cushion technology that helps prevent painful ulcers
September 24, 2018 - Second HPV-Related Primary Cancers Common in Survivors
September 24, 2018 - How a virus destabilizes the genome
September 24, 2018 - Old letters provide insight into Spanish flu pandemic horror
September 23, 2018 - Smart textile-based soft robotic exosuit helps wearers save energy and traverse difficult terrain
September 23, 2018 - New research hub to drive radical change in development and manufacturing of vaccines
September 23, 2018 - AHA: For Hispanics, Neighborhood May Be Key Factor in Heart Disease Risk
September 23, 2018 - Excessive airway nerves tied to more severe asthma symptoms, study finds
September 23, 2018 - Study highlights need to remain vigilant in maintaining key infection control processes
September 23, 2018 - Novel therapeutic strategy for blood vessel related disorders, such as cancer and retinopathy
September 23, 2018 - New naturally occurring antibiotic found effective against Mycobacterium tuberculosis
September 23, 2018 - First-in-human phase 0 study shows clinically-relevant activity of new drug in glioblastoma
September 23, 2018 - Removing tobacco product display from shops reduced number of children buying cigarettes
September 23, 2018 - Random fraction of specialized immune cells leads the charge in battling invaders
September 23, 2018 - Few minutes of sprinting exercise may be as effective as longer exercise sessions
September 23, 2018 - Researchers use neutrons to make first direct observations of water in lipid bilayers
September 23, 2018 - Researchers demonstrate pre-clinical success for universal flu vaccine in new paper
September 23, 2018 - Study reveals surprising gaps in some HIV medical providers’ knowledge of ACA
September 23, 2018 - Oxehealth secures European medical device accreditation for vital signs measurement software
September 23, 2018 - HTN Tx Intensification Common Upon Discharge in U.S. Vets
September 23, 2018 - Fibre can strengthen the intestinal barrier
September 23, 2018 - New platform examines infectious pathogens that may spread from animals to humans
September 23, 2018 - Demographers create detailed color map of population aging in Europe
September 23, 2018 - New type of fatty acid can slow down overreactive immune system
September 23, 2018 - Innovative procedure could provide breakthrough in treating early-stage lung cancer
September 23, 2018 - Research finds drop in number of measles cases in the EU/EEA since March 2018
September 23, 2018 - Researchers acquire new insights into DNA polymerases
September 23, 2018 - Alzheimer’s diagnosis might become simpler with new brain imaging method
September 23, 2018 - Reports Warn of Growing Opioid Crisis Among Seniors
September 23, 2018 - Researchers unravel why people with HIV suffer from more neurologic diseases
September 23, 2018 - Human brain structured to make best possible decision with limited resources
September 23, 2018 - KHN’s ‘What the Health?’ Health on the hill
September 23, 2018 - Bad air and inadequate data prove an unhealthy mix
September 23, 2018 - Regular bedtime and wake time important for heart, metabolic health even among adults
September 23, 2018 - HIV and a tale of a few cities
September 23, 2018 - NIH launches clinical trial to test infusions of combination antibodies in people with HIV
September 23, 2018 - Researchers develop new system to detect consumption of synthetic cannabinoids
September 23, 2018 - Vax-Hub to influenze radical change in development and manufacturing of vaccines
September 23, 2018 - People who have slept lesser than seven hours have higher risks of car crashes
September 23, 2018 - an ancient art may work best to prevent falls in old age
September 23, 2018 - Consumption of foods with lower nutritional quality related to increased cancer risk
September 23, 2018 - Patient Health Information Often Shared Electronically
September 23, 2018 - Can machine learning bring more humanity to health care?
September 23, 2018 - Body organs undergo structural changes in response to diet
September 23, 2018 - Genetic polymorphisms linked with muscle injury and stiffness
September 23, 2018 - As states try to rein in drug spending, feds slap down one bold Medicaid move
September 22, 2018 - Why Eczema Is Tougher to Treat for Black Patients
Differences in mitochondrial DNA determine severity of heart disease caused by nDNA mutation

Differences in mitochondrial DNA determine severity of heart disease caused by nDNA mutation

image_pdfDownload PDFimage_print

Differences in the DNA within the mitochondria, the energy-producing structures within cells, can determine the severity and progression of heart disease caused by a nuclear DNA mutation. A new study found that when a nuclear DNA (nDNA) mutation was combined with different mild variants of mitochondrial (mtDNA) in mice, the severity of heart disease was markedly different. One mtDNA variant dramatically worsened heart disease, while another mtDNA variant conferred protection from heart damage.

Greater understanding of these genetic interactions may eventually permit improved diagnostics and therapies for patients with cardiomyopathy, a leading worldwide cause of heart failure.

“When people think of genetic changes, they most commonly consider mutations and variations in nuclear DNA–the familiar genes within cell nuclei,” said study leader Douglas C. Wallace, PhD, director of the

Wallace and colleagues, including first author Meagan J. McManus, PhD, also from CHOP, describe their work in an online paper Aug. 30, 2018 in the journal Cell Metabolism.

Like many other metabolic and degenerative diseases, cardiomyopathy, a group of diseases characterized by progressive weakening of the heart muscle, can progress slowly or become sharply severe, even across patients who share the same disease-causing mutation. One example is cardiomyopathy induced by a mutation in the nuclear gene ANT1. “Such broad phenotypic variability isn’t explained by the governing principles of classic Mendelian genetics,” said McManus. “Since mtDNA plays by its own rules, it could be the missing piece in this genetic puzzle.”

McManus added that clues to this variability came from a

However, this clinical correlation didn’t provide conclusive proof that mtDNA determined nDNA expressivity–the degree to which a mutation exerts health-related effects. For this purpose, the research team developed mouse models with specific changes in the mtDNA and crossbred them to Ant1— mice, the genetic equivalent of the human ANT1 mutation implicated in cardiomyopathy.

One mtDNA variant had a change in amino acid 25 (P to L) in the gene ND6 (ND6P25L); the other mtDNA variant had a change in amino acid 421 (V to A) in the gene COI (COIV421A). In isolation, each mitochondrial variant has only mild effects on heart function in mice, but they show strikingly different effects when they interact with the nuclear gene mutation.

Ant1— animals with the mtDNA ND6P25L variant aged rapidly and died of heart failure, while animals with the mtDNA COIV421A variant lived longer, with better heart function. The team then investigated the basis of this relationship at the molecular level. Interestingly, the mtDNA variants shifted mitochondrial shape and size in opposing directions. When combined with nDNA Ant1— , these changes in morphology conferred by the mtDNA were consistent with their respective functional consequences. Ant1— mice with the ND6P25L variant had smaller, abnormal mitochondria and increased age-dependent energetic decline. Ant1– mice with the COIV421A variant had larger mitochondria, and better health and survival.

Given that mtDNA variation determined the severity of the cardiomyopathy phenotype, the next question was whether mtDNA variation could also explain the age-related onset of the symptoms. “In normal aging, our cells lose the ability to clear out and replace defective mitochondria, which may lead to increased mtDNA damage and the accumulation of mutations,” said McManus. “To determine if this was the case, we measured somatic mtDNA mutation levels across the lifespan of all the mtDNA-nDNA combination strains. The correlation was practically perfect: the somatic mutation rate predicted the severity of cardiomyopathy and mortality.” Thus, the accumulation of somatic mtDNA mutations can account for the delayed-onset and progressive course of age-dependent disease.

Although follow-up studies are necessary to determine how closely the findings in animals predict similar processes in humans, the current study provides a new animal model to further investigate possible future clinical treatments. To take one example, there were some indications that abnormal physiology in the ND6P25LAnt1— mice may include defects in mitochondrial fusion (a way that mitochondria adapt to stress), and in autophagy, the cell’s normal cleanup process. If so, future cardiomyopathy patients with a corresponding genetic risk might benefit from future treatments that boost these functions.

“This study proves that mtDNA variation can explain the seemingly aberrant behaviors of classical Mendelian disease genes. Hence, characterizing mtDNA variation should be an important adjunct to studies of nuclear DNA diseases,” concluded Wallace. “This finding may offer opportunities to develop new strategies to treat heart disease, and possibly other conditions affected by interactions between nuclear and mitochondrial genes.”

Tagged with:

About author

Related Articles