Free Courses Sale ends Soon, Get It Now


MITO DISEASE

10th July, 2024

MITO DISEASE

Source: BusinessStandard

Disclaimer: Copyright infringement not intended.

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

MITO DISEASE

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):

  1. Mitochondrial DNA is circular and contains 37 genes essential for mitochondrial function.
  2. Unlike nuclear DNA, mitochondrial DNA is inherited exclusively from the mother.
  3. 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)