MITO DISEASE

Source: BusinessStandard

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Context

• Scientists are currently preparing for a clinical trial to determine whether mitochondrial donation is safe and effective, following the passage of a law in Australia in 2022 that will allow for the practice.

Details

Mitochondrial Donation

• An IVF-based procedure that prevents the transmission of faulty mitochondrial DNA, allowing families to have healthy, genetically related children.
• Process:
  • Hormone Injections: Stimulate egg production in both the donor and the affected individual.
  • Egg Retrieval: Collect eggs from both the donor and the affected individual using an ultrasound-guided procedure.
  • Nuclear DNA Transfer: Extract the nuclear DNA from the affected individual’s egg and insert it into the donor egg with healthy mitochondria.
  • Fertilization: Use sperm from the intending father to fertilize the modified donor egg​​.

Legal and Ethical Considerations

• Maeve's Law: The Mitochondrial Donation Law Reform Bill 2021, passed by the Australian Senate in 2022, allows mitochondrial donation for research and clinical trials under strict regulations.
• Requirements:
  • Facilities must obtain special permits.
  • Initial licenses for pre-clinical and clinical trial research to ensure safety and effectiveness​​.

What is Mitochondrial Disease?

• Mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria, the organelles that generate energy for the cell.
• These diseases can affect multiple organs and systems, including the brain, heart, liver, muscles, kidneys, and endocrine system.
• Affects 1 in every 5,000 people, making it a common inherited metabolic condition.

Causes

• Mitochondrial diseases are primarily genetic, resulting from mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA).
• They can be inherited in several ways:
• Autosomal Recessive/Dominant Inheritance: Mutations in nDNA inherited from both or one parent.
• Mitochondrial Inheritance: Mutations in mtDNA passed down from the mother.
• De Novo Mutations: New mutations that occur spontaneously without a family history​​.

Symptoms

Symptoms of mitochondrial diseases vary widely and can include:

• Muscle weakness and exercise intolerance
• Neurological issues such as seizures, migraines, and developmental delays
• Cardiomyopathy and other heart issues
• Liver and kidney dysfunction
• Endocrine problems, including diabetes and growth delays
• Gastrointestinal disturbances
• Visual and hearing impairments​​.

Types of Mitochondrial Diseases

There are several types of mitochondrial diseases, each with unique characteristics. Some notable types include:

• Leigh Syndrome: Severe neurological disorder
• MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes)
• MERRF (Myoclonic Epilepsy with Ragged Red Fibers)
• Kearns-Sayre Syndrome
• Barth Syndrome
• Alpers Disease
• Chronic Progressive External Ophthalmoplegia (CPEO)
• Friedreich's Ataxia​

Mitochondria

• Mitochondria are double-membrane-bound organelles found in the cytoplasm of almost all eukaryotic cells.
• They are often referred to as the "powerhouses" of the cell because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy.

Structure of Mitochondria

• Outer Membrane
  • Smooth and permeable to small molecules and ions.
  • Contains proteins called porins that allow molecules to pass through.
  • Involved in various functions such as lipid metabolism and the maintenance of mitochondrial shape.
• Intermembrane Space
  • The area between the inner and outer membranes.
  • Contains enzymes that use the ATP moving out of the matrix to phosphorylate other nucleotides.
  • Plays a role in apoptosis (programmed cell death).
• Inner Membrane
  • Folded into structures called cristae to increase surface area.
  • Contains proteins involved in the electron transport chain and ATP synthesis.
  • Impermeable to most ions and molecules; transport is highly regulated.
• Matrix
  • Enclosed by the inner membrane.
  • Contains mitochondrial DNA (mtDNA), ribosomes, and enzymes involved in the citric acid cycle (Krebs cycle) and fatty acid oxidation.
  • The site of ATP production through oxidative phosphorylation.

Functions of Mitochondria

• Energy Production
  • Primary site of ATP production via oxidative phosphorylation.
  • Citric acid cycle (Krebs cycle) takes place in the matrix, generating high-energy electron carriers.
• Regulation of Metabolic Activity
  • Involved in various metabolic tasks including the synthesis of certain steroids and heme.
  • Plays a role in the regulation of cellular metabolism.
• Apoptosis: Mitochondria release cytochrome c, triggering the cascade of events leading to programmed cell death.
• Calcium Storage: Store calcium ions and help maintain cellular calcium homeostasis.
• Heat Production: In brown adipose tissue, mitochondria generate heat through a process called non-shivering thermogenesis.
• ROS Production: By-products of the electron transport chain include reactive oxygen species (ROS), which play roles in cell signaling and homeostasis.

Mitochondrial DNA

• mtDNAis circular and maternally inherited.
• Encodes 37 genes, including 13 for proteins, 22 for tRNA, and 2 for rRNA.
• Mutations in mtDNA can lead to various mitochondrial diseases.

Biogenesis and Dynamics Biogenesis Mitochondrial biogenesis is the process by which new mitochondria are formed in the cell. Regulated by several factors including PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha). Dynamics Mitochondria constantly undergo fusion (joining) and fission (splitting). Fusion helps mitigate stress by mixing the contents of partially damaged mitochondria as a form of complementation. Fission helps create new mitochondria and is important for cellular distribution and apoptosis.

 Summary of all major cell organelles

Organelle	Structure	Function	Presence
Nucleus	Double membrane with pores; contains nucleolus and chromatin	Stores genetic material (DNA); controls cellular activities; site of transcription	Eukaryotic cells
Mitochondria	Double membrane; inner membrane folded into cristae	ATP production through oxidative phosphorylation; regulates cellular metabolism	Eukaryotic cells
Ribosomes	Composed of rRNA and proteins; can be free or bound	Protein synthesis	All cells
Endoplasmic Reticulum (ER)	Network of membranous tubules; rough ER has ribosomes, smooth ER does not	Rough ER: Protein synthesis and processing; Smooth ER: Lipid synthesis and detoxification	Eukaryotic cells
Golgi Apparatus	Stacks of flattened membranous sacs	Modifies, sorts, and packages proteins and lipids for secretion or delivery to other organelles	Eukaryotic cells
Lysosomes	Membrane-bound vesicles containing hydrolytic enzymes	Breakdown of macromolecules; recycling of cellular components; apoptosis	Animal cells primarily
Peroxisomes	Membrane-bound vesicles containing oxidative enzymes	Breakdown of fatty acids; detoxification of harmful substances	Eukaryotic cells
Chloroplasts	Double membrane with internal thylakoid stacks	Photosynthesis; conversion of light energy into chemical energy (glucose)	Plant cells and algae
Vacuoles	Membrane-bound sacs; large central vacuole in plant cells	Storage of nutrients and waste products; maintenance of turgor pressure in plant cells	Eukaryotic cells
Cell Membrane	Phospholipid bilayer with embedded proteins	Selective barrier; regulates transport of substances in and out of the cell	All cells
Cell Wall	Rigid structure outside the cell membrane; composed of cellulose in plants	Provides structural support and protection	Plant cells, fungi, some prokaryotes
Cytoskeleton	Network of protein fibers (microfilaments, intermediate filaments, microtubules)	Maintains cell shape; facilitates cell movement and division; transports materials within the cell	Eukaryotic cells
Centrioles	Cylindrical structures composed of microtubules	Involved in cell division; organizes the mitotic spindle	Animal cells primarily
Nucleolus	Dense region within the nucleus	Ribosome biogenesis	Eukaryotic cells
Cytoplasm	Gel-like substance within the cell membrane	Holds organelles; site of many metabolic pathways	All cells
Plastids	Double membrane; includes chloroplasts, chromoplasts, and leucoplasts	Involved in synthesis and storage of food	Plant cells
Cilia and Flagella	Hair-like structures on cell surface	Movement of the cell or movement of fluids over the cell surface	Some eukaryotic cells

Sources:

BusinessStandard

PRACTICE QUESTION Q: Consider the following statements regarding Mitochondrial DNA (mtDNA): Mitochondrial DNA is circular and contains 37 genes essential for mitochondrial function. Unlike nuclear DNA, mitochondrial DNA is inherited exclusively from the mother. Mitochondrial DNA has a higher mutation rate compared to nuclear DNA due to its proximity to the electron transport chain and lack of protective histones. Which of the statements given above is/are correct? a) 1 and 2 only b) 2 and 3 only c) 1 and 3 only d) 1, 2, and 3 Answer: d)