Maybe Memorizing the Krebs Cycle Was Worthwhile After All – Medscape
By daniellenierenberg
Like most medical students, I struggled to memorize the Krebs cycle, the complex energy-producing process that takes place in the body's mitochondria. Rote learning of Sir Hans Krebs' eponymous cascade of reactions persists and has been cited as a waste of time in modern medical education. However, it looks like that specialized knowledge about mitochondrial structure and function may finally come in handy in the clinic.
Advances in genetics have contributed to improved diagnostic accuracy of a diverse spectrum of mitochondrial disorders. Respiratory chain, nuclear gene, and mitochondrial proteome mutations can lead to multisystem or organ-specific dysfunction.
A new potential treatment for mitochondrial disorders, elamipretide, has received orphan drug designation from the US Food and Drug Administration (FDA) and is in clinical trials sponsored by Stealth Biotherapeutics. [Dr Wilner has consulted for Stealth Biotherapeutics.] Recently I had the opportunity to interview Hilary Vernon, MD, PhD, associate professor of genetic medicine at Johns Hopkins University, Baltimore, Maryland, and an expert on mitochondrial disorders. Dr Vernon discussed her research on elamipretide as a treatment for Barth syndrome, a rare form of mitochondrial disease.
I am the director of the Mitochondrial Medicine Center at Johns Hopkins Hospital. I work with individuals from infancy through adulthood who have mitochondrial conditions. I became interested in this particular area when I was early in my pediatrics/genetics residency at Johns Hopkins and saw the toll that mitochondrial disorders took on patients' lives and the limited effective therapies. At that point, I decided to focus on patient care and research in this area.
Mitochondrial disorders can be difficult to recognize because of their inherent multisystem nature and variable presentations (even between affected members of the same family). However, there are several considerations that should raise a clinician's suspicion for a mitochondrial condition. Ascertaining a family history of disease inheritance through the maternal line can raise the suspicion for a mitochondrial DNA disorder. Identification of a combination of medical issues in different organ systems that are seemingly unrelated in an individual (ie, optic atrophy and muscle weakness or diabetes and hearing loss) can also raise suspicion for a mitochondrial condition.
Due to the nature of mitochondria as the major energy producers of the cells, high-energy-requiring tissues such as the brain and the muscles are often affected. Perhaps the best known mitochondrial diseases to neurologists are MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke) as well as MERFF (myoclonic epilepsy with ragged red fibers). There is a nice body of literature on the effects of arginine and citrulline in modifying stroke-like episodes in MELAS, and this is a therapy that is in current practice.
Mitochondria are complex organelles whose structure and function are encoded in hundreds of genes originating from both the nucleus of the cell and the mitochondria themselves. Mitochondria have many key roles in cellular function, including energy production through the respiratory chain, coordination of apoptosis, nitrogen metabolism, fatty acid oxidation, and much more.
Various cofactors and vitamins can be employed to improve mitochondrial function for different reasons. For example, if a specific enzyme is dysfunctional, supplying the cofactor for that enzyme may improve its function (ie, pyruvate dehydrogenase and thiamine). Antioxidants have also been considered to help reduce the oxidant load that could potentially cause ongoing damage to the mitochondrial membrane resulting from respiratory chain dysfunction (ie, coenzyme Q-10).
It is important to remember that the highest number of individual mitochondrial disorders result from mutations in genes located in the nuclear DNA. For example, the TAZ gene that is abnormal in Barth syndrome is a nuclear gene located on the X chromosome. These genes are amenable to the "regular" approaches to gene therapy.
Targeting mitochondrial DNA for gene therapy requires a different set of approaches because the gene delivery has to overcome the barrier of the mitochondrial membranes. However, research is ongoing to overcome these obstacles.
Barth syndrome is a very rare genetic X-linked disorder that usually only affects males. The genetic defect leads to an abnormal composition of cardiolipin on the inner mitochondrial membrane. Cardiolipin is an important phospholipid involved in many mitochondrial functions, including organization of inner mitochondrial membrane cristae, involvement in apoptosis, and organization of the respiratory chain (which is responsible for producing ATP via the process of oxidative phosphorylation), and many of these functions are abnormal in Barth syndrome. Individuals with Barth syndrome typically have early-onset cardiomyopathy, myopathy, intermittent neutropenia, fatigue, poor early growth, among other health concerns.
Early in my post-residency career, I followed several patients with Barth syndrome and was quickly welcomed into the Barth syndrome community by the families and the Barth Syndrome Foundation. From there, I founded the only interdisciplinary Barth syndrome clinic in the US and began to focus a significant amount of my clinical and laboratory research on this condition.
Most commonly, these individuals come to medical attention because of cardiomyopathy, but a minority of patients do come to attention due to repeated infections and neutropenia. Patients were identified for study participation through the Barth Syndrome Foundation or because they were already patients of my study team.
All participants were known to have Barth syndrome prior to study entry, and all had confirmatory genetic testing showing a pathogenic mutation in the TAZ gene.
By binding to cardiolipin in the inner mitochondrial membrane, elamipretide is believed to stabilize cristae architecture and electron transport chain structure during oxidative stress. I thought it would be great if this could help to stabilize the abnormal cardiolipin components on the inner mitochondrial membrane in Barth syndrome.
We observed improvements in several areas across the study population in the open-label extension part of the study. This includes a significant improvement in exercise performance (as measured by the 6-minute walk test, with an average improvement of 95.9 meters at 36 weeks) and a significant improvement in muscle strength. We also observed a potential improvement in cardiac stroke volume. Most of the adverse events were local injection-site reactions and were mild to moderate in nature.
The TAZPOWER trial has an ongoing open-label extension with the same endpoints as the placebo-controlled portion evaluated on an ongoing basis. In addition, in my laboratory, we are using induced pluripotent stem cells to learn more about how cardiolipin abnormalities affect different cell types in an effort to understand the tissue specificity of disease. This will help us to understand whether different aspects of Barth syndrome would necessitate individual management or clinical monitoring strategies.
Mitochondrial inner membrane dysfunction is increasingly recognized as a major aspect of the pathology of a wide range of mitochondrial conditions. Therefore, based on the role of stabilizing mitochondrial membrane components, elamipretide has a potential role in many disorders of the mitochondria.
Yes, this is what we would call "secondary mitochondrial dysfunction" (meant to differentiate from "primary mitochondrial disease," which is caused by defects in genes that encode for mitochondrial structure and function). Approaches intended to protect the mitochondria from further damage, such as antioxidants or strategies that can bypass the mitochondria for ATP production, could overlap as treatment for primary mitochondrial disease and secondary mitochondrial dysfunction.
This is something that is much discussed as a newer consideration for families who are affected by disorders of the mitochondrial DNA, but not something I have experience with firsthand.
Yes. The United Mitochondrial Disease Foundation and the Mitochondrial Medicine Society collaborated to develop the Mito Care Network, with 19 sites identified as Mitochondrial Medicine Centers across the US.
Andrew Wilner is an associate professor of neurology at the University of Tennessee Health Science Center in Memphis, a health journalist, and an avid SCUBA diver. His latest book is The Locum Life: A Physician's Guide to Locum Tenens.
Follow Dr Wilner on Twitter
Follow Medscape on Facebook, Twitter, Instagram, and YouTube
Read the original:
Maybe Memorizing the Krebs Cycle Was Worthwhile After All - Medscape
- AIIMS Bathinda Makes Breakthrough in Stem Cell Therapy Research for Heart Ailments - Elets - October 21st, 2024
- USC launches collaboration with StemCardia to advance heart regeneration therapies - University of Southern California - October 13th, 2024
- The heart is a resident tissue for hematopoietic stem and progenitor cells in zebrafish - Nature.com - September 3rd, 2024
- Opthea Announces Results of the A$55.9m (US$36.9m¹) Retail Entitlement Offer - July 16th, 2024
- Benitec Biopharma Reports Continued Durable Improvements in the Radiographic Assessments of Swallowing Efficiency and the Subject-Reported Outcome... - July 16th, 2024
- AstraZeneca Closes Acquisition of Amolyt Pharma - July 16th, 2024
- Addex Presents Positive Results from GABAB PAM Cough Program at the Thirteenth London International Cough Symposium (13th LICS) - July 16th, 2024
- Lexeo Therapeutics Announces Positive Interim Phase 1/2 Clinical Data of LX2006 for the Treatment of Friedreich Ataxia Cardiomyopathy - July 16th, 2024
- ANI Pharmaceuticals Announces the FDA Approval and Launch of L-Glutamine Oral Powder - July 16th, 2024
- MediWound Announces $25 Million Strategic Private Placement Financing - July 16th, 2024
- Atsena Therapeutics Appoints Joseph S. Zakrzewski as Board Chair - July 16th, 2024
- ASLAN Pharmaceuticals Announces Receipt of Nasdaq Delisting Determination; Has Determined Not to Appeal - July 16th, 2024
- Kraig Biocraft Laboratories Completes Phase One of its Spider Silk Production Facility Expansion - July 16th, 2024
- Pliant Therapeutics Announces Positive Long-Term Data from the INTEGRIS-PSC Phase 2a Trial Demonstrating Bexotegrast was Well Tolerated at 320 mg with... - July 16th, 2024
- Oncternal Announces Enrollment Completed and Dosing Initiated for Sixth Dose Cohort of Phase 1/2 Study of ONCT-534 for the Treatment of R/R Metastatic... - July 16th, 2024
- Rectify Pharmaceuticals Appoints Bharat Reddy as Chief Business Officer - July 16th, 2024
- Spectral AI Continues Support of Naked Short Selling Inquiry - July 16th, 2024
- Milestone Pharmaceuticals Refreshes Board of Directors - July 16th, 2024
- New Published Data Highlights Potential Cost-Savings of INPEFA® (sotagliflozin) for Heart Failure - July 16th, 2024
- Regenerative medicine can be a boon for those with Drug-Resistant Tuberculosis - Hindustan Times - April 21st, 2023
- Cardiac stem cells: Current knowledge and future prospects - April 13th, 2023
- Stem cell therapies in cardiac diseases: Current status and future ... - April 13th, 2023
- Stem Cell and Regenerative Biology | Johns Hopkins Heart and Vascular ... - April 13th, 2023
- Center for Regenerative Biotherapeutics - Cardiac Regeneration - April 13th, 2023
- MAGENTA THERAPEUTICS, INC. MANAGEMENT'S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-K) - Marketscreener.com - March 25th, 2023
- CAREDX, INC. MANAGEMENT'S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-K) - Marketscreener.com - March 1st, 2023
- A Possible Connection between Mild Allergic Airway Responses and Cardiovascular Risk Featured in Toxicological Sciences - Newswise - February 4th, 2023
- Baby's life saved by surgeon who carried out world's first surgery ... - December 25th, 2022
- An organoid model of colorectal circulating tumor cells with stem cell ... - December 25th, 2022
- Skeletal Muscle Cell Induction from Pluripotent Stem Cells - December 1st, 2022
- Stem-cell niche - Wikipedia - December 1st, 2022
- Scientists Discover Protein Partners that Could Heal Heart Muscle | Newsroom - UNC Health and UNC School of Medicine - October 13th, 2022
- Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $0 Thousand by 2027 - Yahoo Finance - October 13th, 2022
- Scientists Spliced Human Brain Tissue Into The Brains of Baby Rats - ScienceAlert - October 13th, 2022
- Decoding the transcriptome of calcified atherosclerotic plaque at single-cell resolution | Communications Biology - Nature.com - October 13th, 2022
- Global Synthetic Stem Cells Market Is Expected To Reach Around USD 42 Million By 2025 - openPR - October 13th, 2022
- Merck and Moderna Announce Exercise of Option by Merck for Joint Development and Commercialization of Investigational Personalized Cancer Vaccine -... - October 13th, 2022
- Regenerative Medicine For Heart Diseases: How It Is Better Than Conventional Treatments | TheHealthSite.co - TheHealthSite - October 5th, 2022
- 'Love hormone' oxytocin could help reverse damage from heart attacks via cell regeneration - Study Finds - October 5th, 2022
- Recapitulating Inflammation: How to Use the Colon Intestine-Chip to Study Complex Mechanisms of IBD - Pharmaceutical Executive - September 27th, 2022
- Adult Stem Cells // Center for Stem Cells and Regenerative Medicine ... - September 19th, 2022
- CCL7 as a novel inflammatory mediator in cardiovascular disease, diabetes mellitus, and kidney disease - Cardiovascular Diabetology - Cardiovascular... - September 19th, 2022
- Kite's CAR T-cell Therapy Yescarta First in Europe to Receive Positive CHMP Opinion for Use in Second-line Diffuse Large B-cell Lymphoma and... - September 19th, 2022
- Neural crest - Wikipedia - September 3rd, 2022
- Rise In Number Of CROS In Various Regions Such As Europe Is Expected To Fuel The Growth Of Induced Pluripotent Stem Cell Market At An Impressive CAGR... - September 3rd, 2022
- Discover the Mental and Physical Health Benefits of Fasting - Intelligent Living - September 3rd, 2022
- Heart Association fellowship to support research - Binghamton - August 26th, 2022
- Repeated intravenous administration of hiPSC-MSCs enhance the efficacy of cell-based therapy in tissue regeneration | Communications Biology -... - August 26th, 2022
- High intensity interval training protects the heart against acute myocardial infarction through SDF-1a, CXCR4 receptors and c-kit levels - Newswise - August 26th, 2022
- Yale University: Uncovering New Approaches to a Common Inherited Heart Disorder | India Education - India Education Diary - August 10th, 2022
- Heart failure in obesity: insights from proteomics in patients treated with or without weight-loss surgery | International Journal of Obesity -... - August 10th, 2022
- Pigs died after heart attacks. Scientists brought their cells back to life. - Popular Science - August 10th, 2022
- Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort - Cureus - August 10th, 2022
- Autologous Cell Therapy Market Size to Grow by USD 4.11 billion, Bayer AG and Brainstorm Cell Therapeutics Inc. Among Key Vendors - Technavio - PR... - August 2nd, 2022
- UTSW researcher part of team awarded $36 million heart research grant - The Dallas Morning News - August 2nd, 2022
- Buffalo center fuels research that can save your life from heart disease and stroke - Buffalo News - August 2nd, 2022
- Hyperglycaemia-Induced Impairment of the Autorhythmicity and Gap Junction Activity of Mouse Embryonic Stem Cell-Derived Cardiomyocyte-Like Cells -... - July 25th, 2022
- NASA's Solution to Stem Cell Production is Out of this World - BioSpace - July 25th, 2022
- Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor | Signal Transduction and Targeted Therapy - Nature.com - July 25th, 2022
- 'My Teen Sweetheart And I Drifted Apart. 30 Years Later I Made a Shocking Discovery' - Newsweek - July 25th, 2022
- EU: New Blood? Proposed Revisions to the EUs Blood, Tissues and Cells Rules - GlobalComplianceNews - July 25th, 2022
- Stem Cells Market to Expand at a CAGR of 10.4% from 2021 to 2028 Travel Adventure Cinema - Travel Adventure Cinema - July 25th, 2022
- Cell Separation Technologies Market Expands with Rise in Prevalence of Chronic Diseases, States TMR Study - GlobeNewswire - July 25th, 2022
- Dental Membrane and Bone Graft Substitutes Market to Exceed Value of US$ 1,337 Mn by 2031 - PR Newswire UK - July 25th, 2022
- Stem Cells Used to Repair Heart Defects in Children - NBC 5 Dallas-Fort Worth - July 16th, 2022
- Pneumonia and Heart Disease: What You Should Know - Healthline - July 16th, 2022
- Promising solution to fatal genetic-disorder complications discovered by University professor and Ph.D. candidate - Nevada Today - July 16th, 2022
- Current and advanced therapies for chronic wound infection - The Pharmaceutical Journal - July 16th, 2022
- Why do some women struggle to breastfeed? A UCSC researcher on what we know, and don't - Lookout Santa Cruz - July 16th, 2022
- Mesenchymal stem cells: from roots to boost - PMC - July 8th, 2022
- New study allows researchers to more efficiently form human heart cells from stem cells - University of Wisconsin-Madison - July 8th, 2022
- Dr Victor Chang saved hundreds of lives. 31 years ago today, he was murdered. - Mamamia - July 8th, 2022
- Exosome Therapeutics Market Research Report Size, Share, New Trends and Opportunity, Competitive Analysis and Future Forecast Designer Women -... - July 8th, 2022
- Cell Line Development Market: Increase in Prevalence of Cancer and Other Chronic Diseases to Drive the Market - BioSpace - July 8th, 2022
- Homology Medicines Announces Peer-Reviewed Publication on Novel Discovery of AAVHSC with Robust Distribution to the Central Nervous System and... - July 8th, 2022
- What New Advances are there in 3D Bioprinting Tissues? - AZoM - June 30th, 2022
- Technical Advancements & Innovative Products Likely to Expand Application of Surgical Meshes in Untapped Domains, States Fact.MR - BioSpace - June 30th, 2022
- Liso-cel Approval Provides Earlier, Expanded Access to CAR T-cell Therapy in Second-line LBCL - OncLive - June 30th, 2022
- Stem cells, embryos, and the environment: a context for both science ... - June 20th, 2022
- Getting to the heart of engineering a heart - Harvard School of Engineering and Applied Sciences - June 11th, 2022