Chapter 9: Mitochondrial Structure and Function
Introduction
2 Billion years ago:
- Early earth atmosphere consisted of molecular
hydrogen (H2), ammonia (NH3) and H2O.
- Anaerobes – organisms that captured and
utilized energy by oxygen-independent
metabolisms such as fermentation and glycolysis
2.4-2.7 Billion years ago:
- Cyanobacteria – carried out photosynthetic
process where water molecules were split and
O2 was released.
- After cyanobacteria, Earth’s atmosphere began
to show significant levels of oxygen
- This lead to a dramatic change in the organisms
that lived on earth
Molecular Oxygen (O2)
- Potentially a very toxic substance
- Takes on extra electrons and can react with a
variety of biological molecules
- Was a powerful agent for natural selection
- Species evolved to protect from the damaging
effects of O2 and also harness the molecule via
metabolic pathways
- Organisms that incorporated O2 could
completely oxidize compounds such as lactic acid
and ethanol into CO2 and H2O, extracting a larger
percentage of energy content from their food
Aerobes
- Organisms dependent of oxygen
- Eventually gave rise to all oxygen-dependent
prokaryotes and eukaryotes
Mitochondria
- Found in eukaryotes
- A specialized organelle where the utilization of
oxygen as a means of energy extraction takes
place
- Evolved from ancient aerobic bacterium that
resided in the cytoplasm of an anaerobic host
9.1 Mitochondrial Structure and Function
Observing the Mitochondria
- Can be seen in the light microscope
- Can appear as individual bean shaped organelles
(1-4um in length)
- Can also appear as a highly branched,
interconnected tubular network
- Fluorescently labelled mitochondria have been
observed to be dynamic organelles capable of
dramatic changes in shape
- Can fuse with one another, or can be split into
two
Mitochondria and the ER
- Engages in extensive interactions
- Mitochondrial fission induced by thin tubules of
ER
- ER tubules encircle mitochondria like a noose
and initiate constriction
- Constriction is completed via soluble proteins
(Drp1 in mammals) from the cytosol
- Fusion-fission balance majorly determines
mitochondrial number, length, and degree of
interconnection
- Fusion > fission : mitochondria more elongated
and interconnected
- Fusion < fission : mitochondria more numerous
and distinct
- Neurologic diseases can be caused by genetic
mutations that encode components of the fusion
machinery of mitochondria
Predominance of Mitochondria in Animals
- 15-20 % of volume of average mammalian liver
cell, contains more than 1000 diff. proteins
- Role in generating ATP: mitochondria associates
with fatty acids (w/ oil droplets) from which the
raw materials that will be oxidized come from
- In sperm, mitochondria are arranged in the
midpiece just behind the nucleus. (Movements
of sperm are powered by ATP from
mitochondria)
Predominance of Mitochondria in Plants
- They are the primary suppliers of ATP in non-
photosynthetic tissues
- Source of ATP during dark periods when
photosynthesis cannot take place
Other functions of the Mitochondria
- Sites of synthesis of numerous substances
including some amino acids and heme groups
- (w/ ER) Vital role in the uptake and release of
calcium ions where they regulate the Ca2+
concentration in the cytosol
- Ca2+ transporters in the inner mitochondrial
membrane takes up excess Ca2+ ions when levels
of calcium are abnormally high in the cytosol
- Cell death is regulated by mitochondrial events
Mitochondrial Membranes
- Two membranes: Outer mitochondrial
membrane (OMM) and Inner mitochondrial
membrane (IMM)
Outer Mitochondrial Membrane:
- Completely encloses mitochondrial
- Serves as outer boundary
- Composed of ≈ 50 % lipid by weight + a mixture
of enzymes involved in oxidation of epinephrine,
degradation of tryptophan, and elongation of
fatty acids
- Thought to be homologous to an outer
membrane as part of a cell wall in gram-negative
bacteria because they both contain porins
- Porins:
o integral proteins with large inner
channels
o not static structures and can reversibly
close in response to intracellular
conditions
 o Channels open: outer membrane is
freely permeable to ATP, NAD, and
coenzyme A (energy metabolism)
Inner Mitochondrial Membrane:
- Consists of >100 different polypeptides
- Has a high protein to lipid ratio (more than 3:1
by weight or 1 protein to every 15 phospholipid)
- Practically without cholesterol, and rich in
cardiolipin (diphosphatidylglycerol)
- Cardiolipin: Facilitates activities of large protein
complexes in electron transport and ATP
synthesis
- Highly impermeable, molecules require special
membrane transporters to enter the matrix
- Bilayer fluidity facilitate interaction of ATP
formation components
- Subdivided into two major domains which have
distinct functions and different protein residents
1. Inner Boundary Membrane
o Just inside the OMM
o Forms a double-membrane outer
envelope
o Rich with proteins in charge of import
of mitochondrial proteins
2. Cristae
o Invaginated membranous sheets
o Energy transducers
o Contain a large amount of membrane
surface that houses the machinery
needed for aerobic respiration and ATP
formation
- Cristae and Inner Boundary Membrane are
joined by cristae junctions
- Matrix: Aqueous compartment in the interior of
the mitochondrion, has a gel-like consistency
due to the presence of high conc (<500 mg/ml)
of water soluble proteins
- Intermembrane space: Aqueous compartment
between OMM and IMM, proteins here initiate
cell suicide
The Mitochondrial Matrix
- Contains ribosomes (smaller than cytosol
ribosomes), and several molecules of (circular in
higher plants and animals) DNA
- Possess their own genetic material, and
manufactures their own RNA and proteins
- Non-chromosomal DNA encodes mitochondrial
polypeptides (13 in humans) which are tightly
integrated into the IMM with nuclear
polypeptides
- Human mitochondrial DNA (mtDNA) encodes 2
ribosomal RNAs and 22 tRNAs (for protein
synthesis)
- Genes from ancestor left to encode most
hydrophobic proteins of IMM
- RNA polymerase that synthesizes mtRNA is not
related to the multi-subunit enzyme found in
prokaryotes and eukaryotes
- mtRNA polymerase is similar to single subunit
enzyme in bacteriophages
9.2 Oxidative Metabolism in the Mitochondria
Oxidation of Carbohydrates:
- Begins with glucose, carried out by enzymes of
glycolysis in the cytosol
- Only a small fraction of free energy is available
to the cell during glycolysis (net synthesis: 2 ATP)
- Most energy remains in pyruvate
- Two products of glycolysis: pyruvate and NADH
can be metabolized depending on the type of
cell, and the presence or absence of oxygen
Key Steps of Glycolysis:
1. Phosphorylation of glucose to fructose
phosphate (-1 ATP)
2. Phosphorylation of fructose phosphate to form
Fructose 1,6-bis-phosphate (-1 ATP)
3. Fructose 1,6-bis-phosphate (six-carbon
bisphosphate) is split into Glyceraldehyde 3-
phosphate (three-carbon monophosphate)
4. Glyceraldehyde 3-phosphate is oxidized to an
acid, electrons are removed and used to reduce
NAD+ to NADH. Carbon-1 acid is phosphorylated
to form the acyl phosphate found in 1,3-
bisphosphoglycerate
5. C1 phosphate group from 1,3-
bisphosphoglycerate is transferred to ADP
forming ATP via substrate-level phosphorylation,
forming 3-phosphoglycerrate (+2 ATP)
6. 3-phosphoglycerate undergoes rearrangement
and dehydration forming an enol phosphate at
the C2 atom of Phosphoenol-pyruvate
7. Phosphate group of phsophoenol-pyruvate is
transferred to ADP via substrate-level
phosphorylation, generating a ketone at C2
position of Pyruvate (+2 ATP)
Aerobic respiration:
- In the presence of O2, can extract large amounts
of additional energy from the two products
(enough to synthesize 30 more ATP)
- Extracted in mitochondria
- Pyruvate is transported into the matrix and is
decarboxylated to from two-carbon acetyl group
which is transferred to coenzyme A to produce
acetyl CoA (all catalyzed by pyruvate
dehydrogenase)
The Tricarboxylic Acid (TCA) Cycle AKA Krebs Cycle
- Acetyl CoA is fed into a cyclic pathway where the
substrate is oxidized and energy is conserved
- Aside from succinate dehydrogenase (bound to
the IMM), all other enzymes reside in the soluble
phase of the matrix
1. Condensation of Acetyl CoA (2 C) with
Oxaloacetate (4 C) to form Citrate (6 C)
2. Citrate (6 C) is converted to Isocitrate (6 C) via
Aconitase
 3. Isocitrate (6 C) is converted to α-Ketoglutarate (5
C) by Isocitrate dehydrogenase (NAD+ to NADH +
H+, CO2 is released)
4. Α-Ketoglutarate (5 C) is converted to Succinyl-
CoA (4 C) by α-Ketoglutarate dehydrogenase
(NAD+ to NADH + H+, HS-CoA is added, CO2
released)
5. Succinyl-CoA (4 C) is converted to Succinate (4 C)
by Succinyl-CoA synthase (GDP + Pi to GTP, HS-
CoA is released)
6. Succinate (4 C) is converted to Fumarate (4 C) by
succinate dehydrogenase (FAD to FADH2)
7. Fumarate (4 C) is converted to Malate (4 C) by
fumarase (H2O is added)
8. Malate (4 C) is converted back to Oxaloacetate
(4 C) by Malate dehydrogenase (NAD+ to NADH +
H +)
- The citrate molecule is decreased in chain
length, one carbon at a time to form back to
oxaloacetate
- 2 carbons are removed and completely oxidized
into CO2
- Four reduction reactions (3, 4, 6, 8) occur where
a pair of electrons are transferred to an electron
accepting coenzyme
- Net Equation:
Acetyl CoA + 2 H2O + FAD + 3 NAD+ + GDP + Pi ->
2 CO2 + FADH2 + 3 NADH + 3 H+ + GTP + HS-CoA
- Metabolites of the TCA cycle are the same
compounds generated by most of the cell’s
catabolic pathways
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