mitochondrial_disease flashcards
Page 1: Introduction
Date: 17 October 2024
Course: Applied Medical Sciences – Molecular Basis of Disease (MEDC0010)
Topic: Mitochondrial DNA diseases
Presenter: Jan-Willem Taanman
Institution: Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London
Page 2: Overview of Mitochondrial DNA (mtDNA) Diseases
Definition:
Diseases caused by qualitative or quantitative abnormalities of mtDNA.
Key Areas Covered:
Mitochondria: structure and function
mtDNA: structure, function, replication, and genetics
Defects of mtDNA and their association with disease
Strategies to reduce transmission of mtDNA point mutations
Page 3: Mitochondria: Structure and Function
Mitochondria are highly dynamic organelles.
They undergo continual fission and fusion.
Visualization Techniques:
Live-cell stimulated emission depletion (STED) microscopy
Transmission electron microscopy
Page 4: Functions of Mitochondria
Essential Functions:
Generation of ATP through oxidative phosphorylation.
Expression of an integral genome.
Page 5: Structure of Mitochondrial DNA (mtDNA)
Characteristics of mtDNA:
Closed-circular, double-stranded DNA approximately 16.6 kb in length.
Somatic cell contains thousands of mtDNA copies.
Organization:
Arranged in nucleoprotein complexes known as nucleoids
Nucleoids dispersed throughout the mitochondrial network.
Page 6: Mitochondrial DNA (mtDNA) (Continued)
Features:
Encodes only 13 proteins.
All 13 proteins are essential subunits of oxidative phosphorylation enzymes.
Other mitochondrial proteins must be imported from the cytosol.
Page 7: Mitochondrial Proteins
Location of Proteins:
mtDNA-encoded proteins within the mitochondrion.
Nuclear DNA-encoded proteins synthesized in cytosolic ribosomes.
Page 8: Bioenergetic Pathways
Overview of the Oxidative Phosphorylation (OXPHOS) System:
Location: Cytosol, Matrix, Intermembrane space.
Components:
Involves various complexes (I to V) for ATP synthesis.
mtDNA and nuclear DNA (nDNA) roles in protein encoding:
Specific counts for each complex's proteins sourced from mtDNA and nDNA.
Page 9: Replication of mtDNA
Constant turnover of mtDNA molecules.
Replication happens consistently across cell cycle phases,
Continues in post-mitotic cells.
Page 10: Immuno-detection Techniques
Methods:
BrdU incorporation into replicating DNA for cell cycle independent replication.
Page 11: Immunocytochemical Detection
BrdU incorporation shows mtDNA replication independence from the cell cycle.
Page 12: Structure of mtDNA Strands
Distinctions in mtDNA duplex strands:
Heavy (H) and Light (L) strands with unique densities.
Page 13: D-loop Structure
Some mtDNA molecules form a three-stranded structure (D-loop),
Important control site for mtDNA replication and transcription.
Page 14: Initiation Complexes of mtDNA Replication
Components involved:
TFAM, POLRMT, TFB2M, other helicases, and more, each plays a role in the replication process.
Page 15: Patterns of Inheritance
Maternal inheritance of mtDNA is established through outcomes post-fertilization.
Page 16: Mechanisms of Maternal Inheritance
Key facts:
High mtDNA copy number in egg cells (150,000–700,000) vs. low in sperm (<10).
Sperm mtDNA is degraded shortly after fertilization.
Page 17: Summarization of mtDNA Defects
Diseases associated with mtDNA defects cover various mechanisms including mutations.
Focus on nuclear DNA mutations that affect mtDNA.
Page 18: Strategies to Reduce mtDNA Mutations
Overview:
Techniques include egg donation, prenatal diagnosis, and preimplantation genetic diagnosis.
Page 19: Ethical Considerations
Discussion surrounding implications of techniques to mitigate mtDNA mutations.
Page 20: Current Research and Future Directions
Continued research focuses on innovative strategies for managing maternal inheritance of mtDNA.
Page 21: Recap of Key Points
Established connections between mtDNA mutations and various diseases essential for the understanding of genetic disorders.