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

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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

Words to Look Up

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

Questions