Mitochondria: Structure, Functions, and Diseases

Introduction

• Mitochondria play a vital role beyond energy metabolism, including cellular homeostasis.
• Their structure, function, and pathology are interconnected, making isolated study difficult.
• Overview of mitochondrial research contributes to understanding various human diseases, including:
  • Genetic mitochondrial cytopathies
  • Parkinson's and Alzheimer's disease
  • Diabetes
  • Cancer

Part 1: Structure of Mitochondria

A. Morphology and Organelle Interactions

• Traditional view: small, bean-shaped organelles scattered in the cytosol.
• Higher-resolution techniques reveal dynamic structures:
  • Can be punctate or organized as a reticulum.
  • Movement along microtubules (energy focus) and actin filaments (other functions).
  • Switching states is important for cellular processes (e.g., cell cycle dependence).
• Interactions with other organelles (e.g., ER, lysosomes) are crucial for functions such as:
  • Calcium movement and protein response coordination.

B. Fusion-Fission Cycle of Mitochondria

• Fusion involves:
  • Outer membrane fusion (mitofusins Mfn1, Mfn2).
  • Inner membrane fusion (Opa1).
• Fission regulated by Drp1 and Fis1, crucial for quality control.
• Mutations in key proteins (Pink1, Parkin, Drp1) associated with diseases like Parkinson's.

C. Internal Structure

• Three distinct membranes: outer, inner boundary, and cristae membranes.
• Each space has different protein compositions, with cristae being central to oxidative phosphorylation.
• Morphological changes reflect functional states (orthodox vs. condensed states).

D. MtDNA: Structure and Packaging

• Mitochondria have their own DNA (mtDNA), 16kb in humans, encoding 13 proteins.
• Nucleoids: irregularly shaped complexes containing mtDNA and transcription factors.
• Limited repair leads to mutations, resulting in heteroplasmy.

E. Import of Proteins into Mitochondria

• Mitochondrial proteins are primarily encoded by nuclear genes.
• Several translocation pathways exist, including:
  • TOM complex for outer membrane entry.
  • TIM complexes for inner membrane and matrix targeting.
  • SAM for outer membrane assembly.

Part 2: Mitochondrial Functioning in Intermediary Metabolism

A. Post-Translational Modifications

• Mitochondria are central to carbohydrate, fat, and amino acid metabolism.
• Integration involves feedback by metabolites and signaling pathways.
• Key metabolites (ATP, NAD, acetyl CoA) influence metabolic processes via:
  • Direct effects on enzymes.
  • Inducing post-translational modifications.

B. Pyruvate Dehydrogenase

• Converts pyruvate to acetyl CoA, linking glucose metabolism.
• Regulated by reversible phosphorylation and affected by various tissue conditions.

C. Succinate Dehydrogenase

• Complex II of the respiratory chain, linking Krebs cycle and energy metabolism.
• Deficiencies can lead to tumors (e.g., paragangliomas).

D. ATP Synthase

• Essential for ATP production; organized in distinct subunits.
• Involved in apoptosis as part of the mitochondrial permeability transition pore (MPT).
• Can also be found in the plasma membrane under certain conditions.

Part 3: Mitochondria in Apoptosis

• Mitochondria act as central executioners in apoptosis, responding to both extrinsic and intrinsic signals.
• Release of cytochrome c activates caspase cascade leading to cell death.
• Bcl-2 family proteins regulate apoptosis by controlling pro-apoptotic and anti-apoptotic signals.

Part 4: Control of Mitochondrial Levels

A. Biogenesis

• Mitochondrial biogenesis is triggered by various intrinsic signaling pathways monitoring mitochondrial function (e.g., AMP kinase, PGC-1).

B. Mitophagy

• Process of removing dysfunctional mitochondria, crucial for quality control.
• Triggered by several receptor proteins and mechanisms involving PINK1 and Parkin.

Part 5: Mitochondria in Disease

A. Oxidative Phosphorylation Deficiencies

• Most common inborn errors of metabolism, leading to various syndromes.
• Mutations can affect both mtDNA and nuclear genes involved in OXPHOS.

B. Fatty Acid Oxidation Disorders

• Key for energy homeostasis; defects can lead to severe clinical presentations.

C. Mitochondria and Cancer

• Altered metabolism in cancer cells (Warburg effect); high levels of free radicals and mitochondrial damage are observed.

D. Mitochondria in the Innate Immune Response

• Critical role in antiviral responses, involving signaling pathways and mitochondrial proteins.

E. Mitochondria and Neurodegeneration

• Mitochondrial dysfunction linked to neurodegenerative diseases (e.g., Parkinson's, Alzheimer's).
• Focus on oxidative stress, mitochondrial dynamics, and quality control.