Mitochondrial Diseases and Genetics

Mitochondrial Network

• Mitochondria consist of the Outer Mitochondrial Membrane (OMM) and Inner Mitochondrial Membrane (IMM) with a matrix and intermembrane space.
• Key proteins involved in mitochondrial fusion include LAM and OPA1.

Mitochondrial Diseases Overview

Definition

• Mitochondrial Diseases are disorders caused by dysfunction of the mitochondrial respiratory chain.
• They can be clinically heterogeneous, with some individuals harboring pathogenic variants not showing any illness.

Key Characteristics

• Can affect single or multiple organs and may onset at any age.

Causes of Mitochondrial Diseases

Genetic Mutations

• Mutations may affect:
  • Nuclear DNA (nDNA)
  • Mitochondrial DNA (mtDNA)
• Both genomes work together in cellular bioenergetics; disruption leads to cellular dysfunction and disease.

Structure of Mitochondria

Overview

• Mitochondria originated through an endosymbiotic event over 2 billion years ago (proposed by Margulis in 1960).
• Present in all tissues and contain hundreds of mtDNA copies.

Components

• Mitochondria have:
  • Outer Membrane
  • Inner Membrane (site of oxidative phosphorylation)
  • Intermembrane space
  • Matrix
  • Cristae (folds of the inner membrane).

Mitochondrial Dynamics

Generation & Maintenance

• Mitochondria are dynamic; new ones are generated from existing mitochondria, unable to synthesize de novo.
• Fission and fusion processes help maintain mitochondrial health, separating damaged mitochondria from functional ones.

Functions of Mitochondria

• Responsible for:
  • ATP energy production via oxidative phosphorylation (OXPHOS).
  • Regulation of cytosolic calcium levels and cellular REDOX state.
  • Control of reactive oxygen species (ROS) production.
  • Initiation of apoptosis under stress conditions.

Genetic Requirements for Mitochondrial Function

• Requires expression of 1000-2000 nuclear genes and 37 mtDNA genes.
• OXPHOS machinery includes 45 subunits derived from nuclear and mitochondrial genes.

Mitochondrial Genome Structure

• The mitochondrial genome contains specific genes:
  • Blue: 7 genes for Complex I subunits (ND1-ND6, ND4L).
  • Brown: 3 genes for cytochrome c oxidase (COXI-COXIII).
  • Yellow: 1 gene for cytochrome b (Complex III).
  • Green: 2 subunits for ATP synthase (ATPase 6 and 8).
  • Purple: 2 ribosomal RNA genes (12S and 16S).
  • Red circles: 22 tRNAs coded by their single-letter codes.

Distinctive Features of mtDNA

• Fewer genes than nDNA, organized as polycistronic sequences.
• Higher copy number in cells, with thousands of mtDNA copies.
• Less effective repair system leading to higher mutation rates.
• Majority maternal inheritance, heteroplasmy, and genetic bottlenecks during oogenesis.

Inheritance Patterns

Maternal Inheritance

• Demonstrated in 1980: sperm mitochondria are typically not transmitted to the offspring because of reduction and degradation.

Paternal Inheritance

• Rarely observed in some species, including fruit flies and certain mammals, with evidence suggesting it is highly unusual in humans.

NUMTs and Evolutionary Insights

• Nuclear-encoded mitochondrial sequences (NUMTs) result from natural DNA transfer; their significance in mtDNA transmission is debated.
• As per Wei & Chinnery (2020), paternal transmission of mtDNA seems unlikely.

Heteroplasmy and Pathophysiology

• Defined as the presence of different mitochondrial genomes within the same cell.
• Exhibits a threshold effect affecting energy production and may differ by tissue.

Disease Associations

• mtDNA mutations are linked to disorders such as MELAS and MERRF.
• Genetic bottlenecks can lead to unpredictable inheritance patterns of mutations.

Environment's Role

• Exposures (e.g., smoking, alcohol, certain antibiotics) can amplify risks for those with specific mtDNA mutations.