Respiratory Metabolism and Mitochondrial Disorders
Note on Respiratory Metabolism and ATP Synthesis
Page 1: Introduction
Dr. Mark Shepherd
Reader in Microbial Biochemistry
Focus on respiratory metabolism and ATP synthesis
Additional resources:
Biochemistry, Garrett & Grisham – ebook
Biochemistry, Lehninger
Page 2: Krebs/Citric Acid/TCA Cycle
Main Mechanism for Energy Capture
Captures energy from carbohydrates, amino acids, and fats.
CO2 is liberated from substrates.
Metabolite Flexibility
Metabolites can be added or removed from the cycle, enhancing metabolic options.
Page 3: Glycolysis
Definition
"Breaking sugar" - splits glucose into two pyruvate molecules.
Key Points
Energy captured in ATP (steps 7 & 10) and NADH (step 6).
NADH is used in aerobic metabolism.
All reactions occur in the cytoplasm.
Page 4: Krebs Cycle
Production per Acetyl CoA
3 x NADH, 1 x FADH2, and 1 x GTP.
Location
Occurs in the mitochondrial matrix.
Page 5: Mitochondrial Structure
Outer Membrane
Permeable to small molecules and ions, but not proteins.
Inner Membrane
Convolutions (cristae) increase surface area.
Contains numerous electron-transfer systems and ATP synthase molecules.
Page 6: Chemiosmotic Model for ATP Synthesis
Proton-Motive Force
Established by electron transport.
Drives ATP synthesis.
Page 8: Mitochondrial Genome
Genetic Components
37 genes including rRNA and tRNA.
Key respiratory chain subunits: NADH Dehydrogenase, Cytochrome bc1, Cytochrome c oxidase.
Page 10: Mitochondrial Heterogeneity
Unequal Separation
Mitochondria can segregate unevenly during cell division, leading to heterogeneity in daughter cells.
Page 11: Maternal Inheritance
Diseases Associated with Mitochondrial Genome
Inherited maternally.
Page 12: Mutations and Respiratory Chain Deficiency
Genetic Origins
Most ETC complexes have both mitochondrial and autosomal origins.
RC deficiency can cause various symptoms and affect any organ or tissue.
Page 13: Point Mutations in Mitochondrial Genes
Examples of Mutations
A3243G mutation leads to MELAS syndrome.
A8344G mutation causes MERRF syndrome.
Page 14: Large-Scale mtDNA Rearrangements
Characteristics
Deletions often lead to loss of encoding and tRNA genes.
Examples: Kearns-Sayre syndrome (KSS) and Pearson syndrome.
Page 15: mtDNA Replication Defects
Associated Conditions
Autosomal-dominant external ophthalmoplegia and mitochondrial DNA depletion syndrome (MDS).
Page 16: mtDNA Translation Defects
Key Genes and Conditions
PUS1, DARS2, MRPS16, and TSFM associated with various myopathies and lactic acidosis.
Page 18: Treatments for Respiratory Chain Disorders
Dichloroacetate (DCA)
Activates pyruvate dehydrogenase, lowers blood lactate in mitochondrial dysfunction.
Page 19: L-arginine
Function
Promotes vasodilation and reduces stroke-like episodes.
Page 20: Coenzyme Q and Idebenone
Role in Treatment
Used for inadequate electron flux in RC disorders.
Antioxidant properties help mitigate reactive oxygen species.
Page 21: Riboflavin
Importance
Precursor for prosthetic groups in respiratory complexes.
High dietary intake treats defects in mitochondrial transporters and complex assembly.
Page 22: Genome Editing Approaches
Gene Therapy Techniques
In vivo and ex vivo gene therapy using retroviruses and adenoviruses.
Page 23: Mitochondrial Replacement Therapy (MRT)
Overview
New IVF technique replacing mutant mtDNA with donor DNA.
Approved in the UK in February 2015 to prevent respiratory chain