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