Summary - Targeting cellular processes to treat disease (MED-BMS42)

LE mitochondrial diseases
Mitochondrial function and disease
 Function: generating ATP, heat generation (in brown fat)




 ATP generation
 Adaptive thermogenesis
 Ion homeostasis
 Innate immune responses
 Production of reactive oxygen species (ROS)
 Programmed cell death (apoptosis)


Mitochondrial DNA (mtDNA) = inherited from the mother


Energy production by the glycolysis pathway and oxidative phosphorylation
(OXPHOS)
 Glucose is converted to pyruvate through glycolysis pathway in the cytosol
 Taken up by mitochondria: Pyruvate > acetyl coenzyme A (CoA)
before it goes into the citric acid cycle (oxygen present)
 Citric acid cycle generates reduced forms of NADH and FADH 2
 These forms fuel the OXPHOS system
 When there is not enough oxygen present pyruvate is converted to
lactate

,  OXPHOS system is bi-genomic (nDNA, mtDNA)


Mitochondrial OXPHOS (oxidative phosphorylation) system is embedded in the
mitochondrial inner membrane (MIM) and represents the final step in the
conversion of nutrients to energy by catalyzing the generation of ATP.


Other cellular ATP producing pathways
 Glycolysis pathway (cytosol)
 Pyruvate dehydrogenase complex (PDHC, mitochondrial matrix)
 Tricarboxylic acid (TCA) cycle
 OXPHOS system (MIM)
The mitochondrial electron transport chain (ETC)




 Complex I get electrons from oxireductase/dehydrogenase of NADH to
NAD+ (has proton pump but also donates electrons to Q)
 Complex II get electrons from oxireductase of FADH2 to FAD (complex II has
no proton pump so donates to Q)

,  Donating of electrons to the different complexes
 Q = Coenzyme Q10
 C = cytochrome C


Electron transport chain (ETC) complex = complex I - IV
o Complex I and II abstract electrons from reduced nicotinamide adenine
dinucleotide (NADH) and reduced flavin adenine dinucleotide (FADH 2)
 These electrons are donated to the electron carrier coenzyme Q 10
which transports them to complex III
o Complex III transfers electrons to the electron carrier cytochrome c which
transports to complex IV
o Complex IV (latter complex) donated electrons to molecular oxygen (O 2) to
form water
o Energy released by the electron transport is used to drive trans-MIM proton
(H+) efflux from the mitochondrial matrix by complexes I, III and IV, and
thereby creating an inward-directed proton-motive force (PMF)
o Latter consists of chemical (pH) and electrical component that
complex V uses to generate ATP




Complex V = ATP synthese
 Gradient difference of pH and electrons, therefore protein motive force
(PMF) occurs and ATP synthese can occur
 ADP > ATP, therefore PMF are needed
 ATP-producing F0F1-ATPase = complex V


Mitochondrial have there own DNA
 Looks like bacterial plasmid

,  Contains 37 genes, encode 13 different proteins, 22 transfer RNAs, 2
subunits of mitochondrial ribosome
 13 different proteins are made in the mitochondria > these proteins are in
oxidative phosphorylation system
o Complex I has 7 proteins
o Complex II has 0
o Complex III has 1
o Complex IV has 3
o Complex C has 2
 Mutations can cause many different diseases


MELAS = mitochondrial encephalomyopathy, lactic acidosis, and stroke-
like episodes
 Neurodegenerative diseases


Inheritance of mtDNA-encoded mutations: heteroplasmy
 For mtDNA mutations, their effect is linked to the fraction of mutated
mtDNAs
 If one mutation is in DNA of mitochondrial, daughter cells can have
multiple mutations because division is not predictable
 Threshold effect: when >70% of the DNA is mutated this oxygen
consumption decreases




Mitochondrial bottleneck causes heteroplasmy during oogenesis
 Bottleneck phenomenon = homogeneity of mitochondrial genomes with
organisms
Mitochondrial is received from the mother > maternal inheritance (mtDNA)
 Mendelian (nDNA) is the normal inheritance from generations