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SUMMARY:THE INAUGURAL SIR JOHN WALKER LECTURE: 'A Mitochondrial Etiology o
 f Metabolic and Degenerative Diseases\, Cancer and Aging' - Dr Douglas Wal
 lace\, Center for Mitochondrial and Epigenomic Medicine (CMEM)\, Children'
 s Hospital of Philadelphia\, USA
DTSTART:20131015T153000Z
DTEND:20131015T163000Z
UID:TALK47276@talks.cam.ac.uk
CONTACT:Penny Peck
DESCRIPTION:For half a millennium Western medicine has focused on anatomy 
 and for the past century on nuclear DNA (nDNA)\, Mendelian\, genetics. Whi
 le these concepts have permitted many biomedical advances\, they have prov
 en insufficient for understanding the common “complex” diseases. In ad
 dition to anatomy\, life requires energy and about 90% of energy comes fro
 m the mitochondrion. The mitochondrial genome consists thousands of copies
  of the maternally inherited mitochondrial DNA (mtDNA) plus between one an
 d two thousand nDNA genes. The mtDNA has a very high mutation rate\, but t
 he most deleterious mutations are removed by an ovarian prefertilization s
 election system.  Hence\, functional mtDNA variants are constantly being i
 ntroduced into the human population\, the more deleterious resulting in re
 cent materially inherited diseases.  The milder mtDNA variants have accumu
 lated sequentially along radiating material lineages as women spread throu
 ghout African and migrated out-of-Africa to colonize Eurasia and the Ameri
 cas.  A subset of the ancient mtDNA variants alter mitochondrial energy me
 tabolism in ways that were beneficial in different regional environments. 
  Lineages with these variants became enriched to generate regional groups 
 of haplotypes\, haplogroups. In alternative environments and/or with age t
 hese same adaptive variants can be maladaptive and increased the risk for 
 disease. The rare tRNAGln nt A4336G variant defines a European lineage tha
 t is predisposed to Alzheimer and Parkinson Diseases.  An ND1 T3394C (Y30H
 ) variant increases the penetrance of Leber Hereditary Optic Atrophy (LHON
 ) mutations\, but is adaptive for high altitude in Tibetans. A homozygous 
 frame shift mutation in the nDNA ADP/ATP translocase isoform 1 gene result
 s in hypertrophic cardiomyopathy when combined with mtDNA haplogroup H but
  life-threatening heart disease when paired with mtDNA haplogroup U. The o
 ut-of-Africa macrohaplogroup N variants have been associated with breast c
 ancer risk and can arise independently in other cancer cells. Mutations in
  the mtDNAs also accumulate with age in both stem and somatic tissue cells
 . These can be associated with various forms of cancer and also constitute
  the aging clock. The introduction of mtDNA variants into the mouse germli
 ne via female embryonic stem cells (mfESCs) has confirmed the causal role 
 of mitochondrial deficiency in diseases.  Mice harboring a COI T6859C V421
 A missense mutation develop a myopathy and cardiomyopathy. Mice harboring 
 a ND6 G13997A P25A missense mutation develop a LHON-like optic neuropathy.
  Simply mixing two normal mtDNAs from 129 and NZB mice within the same cyt
 oplasm causes marked neuropsychiatric symptoms and learning defects. Hence
 \, the pathophysiology of the common diseases may be bioenergetic dysfunct
 ion and the genetic complexity of common diseases the result of the intera
 ction of the thousands of nDNA and mtDNA bioenergetic gene variants.
LOCATION:The Martin Cohen Lecture Theatre\, CRUK\, Cambridge Research Inst
 itute\, Cambridge
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