Biology Chapter on Mitochondria and Energy Metabolism

Mitochondria and Peroxisomes

• Mitochondria are responsible for generating most of the useful energy from the breakdown of lipids and carbohydrates.
• Peroxisomes contain enzymes involved in various metabolic pathways such as fatty acid breakdown and photorespiration.
• Proteins destined for mitochondria and peroxisomes are mainly synthesized on free ribosomes in the cytosol, except for membrane proteins of the peroxisome.
• Proteins are imported into their target organelles in the form of complete polypeptide chains.
• Mitochondria have their own genomes that contain genes which are transcribed and translated in the organelle itself.
• Mitochondrial membranes are organized into inner and outer mitochondrial membranes separated by an intermembrane space. The inner membrane forms folds called cristae.
• The mitochondrial matrix contains the mitochondrial genetic system and enzymes responsible for central reactions of oxidative metabolism.
• Oxidative breakdown of glucose and fatty acids generates ATP through oxidative phosphorylation.
• The oxidation of acetyl CoA to CO2 is coupled with the reduction of NAD+ and FAD to NADH and FADH2, respectively.
• Most energy from oxidative metabolism is produced by oxidative phosphorylation in the inner mitochondrial membrane.
• High-energy electrons from NADH and FADH2 are transferred to molecular oxygen through membrane transporters.
• Mitochondria have a double membrane system.
• Mitochondria fuse (fusion) with each other and divide (fission).
• The inner membrane of the mitochondria is impermeable to most ions and small molecules.
• Inner mitochondrial membrane is responsible for oxidative phosphorylation.
• Outer mitochondrial membrane is permeable to small molecules.
• The outer mitochondrial membrane is permeable to small molecules.

Mitochondria

• Organization and function of mitochondria
• Genetic system of mitochondria
• Mitochondrial diseases
• Protein internalization and mitochondria formation
• Mitochondrial lipids

Genetic System of Mitochondria

• Mitochondria are thought to have evolved from bacteria that developed a symbiotic relationship living inside larger cells (endosymbiosis).
• The mitochondrial genome is made of circular DNA molecules in multiple copies.
• Mitochondrial genomes vary considerably in size between different species.
• Mitochondria contain their own genes, including those that produce the rRNAs and tRNAs necessary for oxidative phosphorylation.
• Other proteins encoded by nuclear genes, which may have been transferred to the nucleus are also found in mitochondria.

Mitochondrial Diseases

• Mitochondrial DNA (mtDNA) undergoes mutations that are often harmful to the organelle.
• Almost all mitochondria in the fertilized egg are supplied by the oocyte, and germline mutations in mtDNA are generally transmitted by the mother.
• Mitochondrial inheritance
• Homoplasmy: Multiple identical copies
• Heteroplasmy: a mix of wild type and altered mtDNA.
• The proportion of mutated mitochondria needed for disease manifestation will vary depending on several factors like the mutation itself, the tissue affected and environmental factors.

Peroxisomes

• Peroxisome functions
• Assembly of peroxisomes
• They are small organelles (0.1-1 µm) surrounded by a membrane.
• Human cells contain between 100 and 1000, depending on cell activity
• They contain enzymes involved in various metabolic reactions.
• They do not have their own genome, all proteins are synthesized in free ribosomes in the cytoplasm.
• They can be replicated by division or generated by the cell
• Some peroxisome proteins resemble prokaryotic proteins, reflecting an endosymbiotic origin.
• Oxidative reactions in peroxisomes produce hydrogen peroxide.
• Peroxisomes contain catalase, to break down hydrogen peroxide.
• Oxidation of uric acid, amino acids and some fatty acids occurs in peroxisomes.
• Peroxisomes are involved in synthesis of plasmalogens.

Protein Internalization

• Mammalian mitochondria contain around 1,500 proteins that are encoded by the nuclear genome of the cell.
• The proteins encoded by these nuclear genes are synthesized by free ribosomes in the cytoplasm
• Proteins needed for oxidative phosphorylation and mitochondrial metabolism are also encoded by the nuclear genome.
• Mitochondrial proteins are transported as proteins or across double membrane systems through various protein complexes. Proteins targeted to specific regions within the mitochondria have different signals that direct them.
• Mitochondrial matrix proteins cross the inner membrane through Tim23 and are directed by electrochemical potential established across this membrane.
• Other proteins will have other sequences that allow them to be inserted into specific regions within the inner membrane.

Protein Targeting of Peroxisomes

• Internal peroxisomal proteins originate from the cytosol's free ribosomes, whereas most transmembrane proteins derive from the endoplasmic reticulum (ER).
• The membrane proteins of peroxisomes are called peroxins (Pex).
• Most internal proteins are recognized and targeted to peroxisomes by short amino acid sequences (signals) located at the carboxyl or amino termini, referred to as PTS1 and PTS2 respectively.
• These are recognized by cytosolic receptors (peroxins, such as Pex5 & Pex7) in the cytosol.
• The receptor-protein complexes are transported to the peroxisomal membrane, where they are bound to specific translocons within the membrane to allow proteins to be inserted into the membrane itself, and are later recycled.
• Some peroxisomal membrane proteins are also synthesized on free ribosomes, instead of being transported from the ER
• These proteins have a different targeting signal (mPTS) that is recognized by the Pex19 protein and then guided into the lipid bilayer of the inner membrane of the peroxisome.

Lipid transfer between ER and mitochondria

• Lipid transfer between the ER and mitochondria occurs at contact points mediated by phospholipid transfer proteins.
• The proteins transfer lipids from ER membranes to the mitochondrial membranes and move through the aqueous cytosol.
• Other components, for example, phospholipid transfer proteins, extract phospholipid molecules from the ER membrane to the mitochondrial outer membrane.

Formation of New Peroxisomes

• Peroxisomes can be generated by budding, division or growth of pre-existing peroxisomes.

• The development of new peroxisomes involves specific steps, for example, budding from the ER (endoplasmic reticulum).

• The vesicles formed do not have a protein coat and do not first pass through the Golgi apparatus.

• Vesicles that bud from the peroxisomal region of the ER contain proteins and peroxins, necessary for the assembly and function of the peroxisome.