Mitochondria: Structure and Disease Connections

Nov 1, 2024

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.