Download Can environmental exposures that damage mitochondria contribute

Can environmental exposures that damage
mitochondria contribute to cancer?
Joel Meyer
Duke University
Durham, North Carolina
USA
Chronic diseases such as cancer will be
increasingly important in the future
-- Cancer is the leading cause of death in many high-income
countries (In US in 2009: ~560,000 deaths, $240 billion).
-- Incidence increasing: over 22 million new cancer cases
projected annually by 2030, up from 12.7 million in 2008. *
-- Treatments very costly and not always effective.
-- Prevention is important! What causes cancer?
*Bray et al. Lancet Oncology S1470-2045(12)70211-5, 2012
Can environmental exposures that damage
mitochondria contribute to cancer?
I.
Environment and cancer
II.
Mitochondria and cancer
III. Environment and mitochondria
IV. Can environmental exposures that damage
mitochondria contribute to cancer?
Nature vs nurture (genes vs
environment) in cancer
15-30% of risk of most cancers is genetic.
What accounts for the rest?
-- environment
“The Panel was particularly concerned to find that the true
burden of environmentally induced cancer has been grossly
underestimated.” President’s Cancer Panel 2009
http://www.ncbi.nlm.nih.gov/pubmed/24659601
http://www.ncbi.nlm.nih.gov/pubmed/11979442
http://www.ncbi.nlm.nih.gov/pubmed/10891514
Which
environmental
factors matter?
“Other than genetic”
…is a very broad
definition of…
“environment”
Rappaport, 2012
The same exposure affects
different people differently
Environmentally caused diseases are influenced by genetic
susceptibility.
– More than 90% of lung cancer is caused by cigarette
smoking; only 10%-15% of smokers will develop lung
cancer.
Why?
- Genetic variation
- Disease
- Dietary and other lifestyle differences
- Other chemical exposures
- Other
How can environmental exposures
cause cancer?
Exposure leads to mutation or signaling,
which alter the function of genes in critical pathways.
Luch, 2005
Outline
I.
Environment and cancer
II.
Mitochondria and cancer
III. Environment and mitochondria
IV. Can environmental exposures that damage
mitochondria contribute to cancer?
Why do we have mitochondria?
ATP: energy (“powerhouse of the
cell”)
Apoptosis, thermogenesis, steroid
synthesis, heme synthesis,
epigenetic cofactors, and more!
The mitochondrial
genome
Small, 1000s/cell (usually)
Importance:
diseases
effects of drugs
mtRNAs 5-30% of cellular mRNA
Sensitivity to many genotoxicants,
limited repair
Mitochondria generate reactive oxygen species and
attract many pollutants (Meyer et al., 2013)
Is altered mitochondrial function one of the
critical cancer pathways?
-- Cancer cells often exhibit aerobic glycolysis (Warburg effect).
-- Mutations in genes coding mitochondrial proteins cause some
cancers.
-- Cancerous cells often have a high level of mutations in the
mitochondrial genome.
-- Mitochondrial regulation of calcium levels, reactive oxygen
species, apoptosis, epigenetics, and more…
Outline
I.
Environment and cancer
II.
Mitochondria and cancer
III. Environment and mitochondria
IV. Can environmental exposures that damage
mitochondria contribute to cancer?
Mitochondrial DNA is particularly sensitive
to important pollutants
Also: aflatoxin,
hydrogen peroxide,
benzo[a]pyrene,
many others
(reviewed in Meyer
et al., 2013)
González-Hunt et al., 2014
Some mitochondrial DNA damage is
irreparable
UV radiation
Meyer et al., 2007
Environmental exposures often cause
irreparable mtDNA damage
Polycyclic aromatic
hydrocarbons
mycotoxins
UV radiation
Outline
I.
Environment and cancer
II.
Mitochondria and cancer
III. Environment and mitochondria
IV. Can environmental exposures that damage
mitochondria contribute to cancer?
Model organism:
Caenorhaditis elegans
-- transparent 1 mm
nematode
-- 3-4 day generation time
-- hundreds of progeny
-- excellent genetic, genomic
tools
-- grown on solid or in liquid
media; relatively cheap and
easy to maintain
-- good model for cancerrelated processes.
What happens to mitochondrial function
later in life after early-life mtDNA damage?
Days
Persistent mtDNA damage in larvae
results in life-long reduction in ATP
How is mitochondrial metabolism reset?
-- insufficient mtDNA
templates?
--insufficient mtRNAs?
Stay tuned!
Arsenic is a mitochondrial toxicant
Arsenite (AsIII) & metabolites inhibit many key mitochondrial
enzymes and lead to mitochondrial dysfunction
Mitochondrial fusion-deficient mutants
are hypersensitive to arsenite-induced
reduction in spare respiratory capacity
Conclusions
Environmental contributions to cancer are poorly
understood
Frontier: the role of mitochondrial dysfunction in
cancer
(better understanding  treatment)
Frontier: the role of pollutants in altering
mitochondrial function in cancer
(better understanding  prevention)
Frontier: understanding which people will be most
senstive
(better understanding  prevention and
treatment)