Julius B. Lucks/Meetings and Notes/SMBE2007/public lecture 1

= Nick Lane: Power, Sex, Suicide - Mitochondria and the Meaning of Life = Mon Jun 25 18:57:45 EDT 2007
 * Honorary reader, Royal Free and UCL Medical School
 * recent book with same title
 * also wrote book Oxygen: The Molecule that Changed the World

Talk

 * 90% of inhaled oxygen consumed in mitochondria in cell resperation
 * used in research
 * human evolution
 * DNA fingerprinting - last czar of Russia
 * fertility
 * origin of eukaryotes
 * sex determination
 * conflict of selfish genomes
 * apoptosis
 * calcium and redox signaling
 * mitochondrial theory of ageing
 * were once bacteria - why endosymbiosis?, what kind of bacteria?, what host?
 * perhaps ricketsia - but disputable
 * alphaproteobacteria
 * three propositions
 * all complex life composed of eukaryotic cells - bacteria not capable of true complexity
 * all eukaryotes have or have had mitochondria - aquisition of mitochondria key event in origin of eukaryotes
 * all mitochondria retain a genome
 * power - complexity depends on mitochondrial energy generation
 * sex - why there are 2 sexes
 * suicide - why we grow old and die

all complex life composed of eukaryotic cells

 * Ernst Haeckel - illustrationsist (Rando door)

all eukaryotes have or have had mitochondria

 * Tom Kavalier-Smith (here at conference) (1980s)

all mitochondria retain a genome

 * no concensus why
 * maybe not enough time
 * Alberts - no compelling reason why proteins made there and not cytosol
 * Gray, Science, 1993, 283, 1478 - Mitochondrial Evolution
 * overlap of mitochondrial genomes
 * plasmodium mitochondria only retained 3 genes
 * cyanide acts on complex 4 - one of proton pumping proteins
 * maybe retain mitochondrial genes to control respiration
 * with multiple mitochondria - if one deficient in a protein, nucleus sends out to all
 * if each mitochondria retains, can control locally
 * complexes continually overturned
 * requires mitochondria genomes encode core subunits
 * rate of assembly depends on stability of mRNA of mitochondrial genes
 * should have excess of nuclear products
 * Morano-Lashuertos, Nature Genetics, 38, 1261, 2006
 * limit to cell size determined by respiration

power - complexity depends on mitochondrial energy generation

 * surface area to volume ratio falls by mass^2/3
 * respiratory efficiency falls away with larger size, and replication rate falls
 * one way around is to internalize membrane to gain surface area
 * why bacteria don't get past a certain size, and thus complexity
 * eukaryotes retains control with extra gene outposts in mitochondria to manage respiration
 * Amouba dubia has genome of 670,000 Mb - 200x larger than human genome, 80,000x larger than S. ceriviciae
 * karyotypic ration in euxaryotes constant - large cells accumulate more genes and more DNA

sex - why there are 2 sexes

 * 2 sexes limit to 50% of population - seems odd
 * not universal - slime mold Phsarum polycephalum - 13 sexes in a pecking order - mitochondria ranked
 * female sex specializes to pass on mitochondria to next generation
 * male does opposite - mitochondria are eliminated from sperm
 * exception - Chlamydomonas inherets mt from both parents, but paternal digested within a few hours of fertilization
 * explanations
 * selfish cytoplasmic genomes (Herst and Hamilton) - need to cut out competition between genomes (so don't risk throwing away respiration)
 * exception - heteroplasmic (more than one mtDNA genome) - 20% humans, 20% angiosperms, many bats
 * John Allen - requirement for inactive genetic template - mtDNA damaged by free radicals produced during ATPsynthesis
 * why can't sperm by powered by fermentation - humans sperm powered by mt (discovered 2001)
 * yeast can survive on fermentation - not as reliant on mitochondria - mutation that knocks out mitochondria - 10,000 faster rate of mutation
 * falure for mt and nuclear subunits leads to apoptosis
 * best way to co-adapt is to test one set of mt genes against one nuclear background
 * need a sex to pass on the mt so can do this test
 * where does this selection take place - in the embryo. at least 25% die for unknown reasons - perhaps incompatibility between mt genome and nuclear background
 * look to cloning and fertility treatments
 * cloning requires this perfect match - Dolly aged prematurely

suicide - why we grow old and die

 * free radicals produced right next to mtDNA
 * damage accumulates with age as a result of continuous respiration
 * rate of free-radical production correlates with life span
 * Denham Harman - free radical theory of aging in 1954, mt theory of aging in 1970s
 * mutations in mtDNA lead to gradual loss of nuclear-mt subunit co-adaptation
 * leads to loss of cytochrome c - leads to apoptosis
 * problem with aging in tissues not replaced by stem cells - brain, heart
 * rats get same disease as humans - just much faster (3 years rather than 60 years)
 * the clock has something to do with free radical production
 * aging - shrinkage of tissues by apoptosis
 * birds have rather leak proof mitochondria - live much longer
 * rat and pidgeon have about some basal metabolic rate - rat lives 3 years, pidgeon about 30
 * Tanaka, Lancet, 351, 186, 1998 - looked at mt point mutation with age (mt5178A,mt5178C)
 * after age 60 - huge difference in going to a hospital with these 2 mutations
 * mt5178A - 1/2 as likely to have any age onset disease (heart, diabetes, etc.), and 2x likely to live past 100
 * free radical leak depends on reduction state of complex 1
 * rat - highly reduced - more electrons in it
 * pidgeon - more oxidized
 * rate of leakage if chain is blocked is the same
 * perhaps birds have need for more mitochondria - flying needs - so pidgeon might have 'spare capacity' - fewer reductions - higher oxidation state
 * calorie restriction induces biogenesis - PLoS Medecine Calorie Restriction Increases Muscle Mitochondrial Biogenesis in Healthy Humans
 * wine - resveratrol (red grape skins) - doubles mitochondrial density in muscles and brown fat via SIRT-1 (probably)
 * NO-donors stimulates mitochondrial genesis via cyclic GMP - phosphodiesterase inhibitors such as Viagra