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