Gerald Shadel, Departments of Pathology and Genetics

gerald.shadel@yale.edu

~1,200 proteins
metabolic crossroads
apoptosis
signaling
disease
aging
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Mitochondria are centralized hubs for innate antiviral signaling and
type I interferon production

MAVS
Mitochondrial Antiviral Signaling

aka,
IPS1
CARDIF
VISA

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 Nuclear-Mitochondrial Signaling

anterograde signaling

retrograde signaling

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 mitochondrial OXPHOS system

ROS O2- H2O2 OH

DNA/RNA genetic mutation

DISEASE
lipids oxidative damage membrane dysfunction
AGING
proteins enzyme/signaling defects
Copyright 2001 Benjamin Cummings, an imprint of Addison Wesley Longman, Inc. 6
 Mitochondrial Stress Signaling Pathways

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 Reactive oxygen species signaling
stimulus sensor outcome

Insulin signaling PPAR mitochondria function

Starvation
AMPK apoptosis

TORC1
HIF1 redox homeostasis
Hypoxia
NF-B immunity
TLR

JNK1 stress resistance

PGC-1

UCP2 p53 genomic stability

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 13 OXPHOS mRNAs
22 tRNAs
mitochondrial OXPHOS system

2 rRNAs
(12S and 16S)
ROS ATP mitochondrial
ROS ATP ribosome

mtDNA

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 dual genetic origin of the OXPHOS system

Schon, DiMauro and Hirano 2012 Nat Rev Genet 10

 Inherited pathogenic mtDNA mutations

~300 identified so far

affect every gene, but
>50% in tRNA genes

common
deletion

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 Deafness

www.mda.org

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mtDNA exists usually at thousands of copies /cell and packaged into nucleoids

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 complexities of mitochondrial disease due to mtDNA

heteroplasmy vs. homoplasmy

mitotic segregation/genetic drift

maternal bottleneck

threshold effects

complex genotype versus phenotype relationships

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http://www.nimr.mrc.ac.uk/research/antonella-spinazzola/segregation-selection-and-epigenetic-control-of-mitochondrial-dna-variants 15
 Mitotic segregation can lead to mtDNA genetic drift

during gametogenesis, embryogenesis or

cell division
in adult dividing cell populations

normal/asymptomatic respiration

Threshold effect
16 Some cell/tissue types may drift toward homoplasmy
 maternal bottleneck

17
Yabuuchi et al. 2011 BBA 1820:637
 maternal bottleneck

Primordial Germ Cells

18 Mitochondrial research society website

 small number of templates
in PGCs are used for
amplification
to generate oocytes

There are also proposed

mechanisms of purifying selection
to eliminate most
deleterious mutations

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 What about natural variation
and
normal levels of heteroplasmy?

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 some haplotypes have been linked to metabolic
21 alterations and disease predisposition
 oxidative damage, certain
environmental exposures and
carcinogens, chemotherapy, disease states mtDNA replication errors can cause
somatic mtDNA mutations
endogenous mtDNA
damage/mutagenesis over time
in normal individuals
and as a function of age
reduced mitochondrial
gene expression
sporadic mutations
(i.e. not in mother)
can also occur during
mtDNA reduced respiratory germline development
damage capacity
or embryogenesis

ROS these can clonally expand in

tissues and there are unique
tissue-specific mechanisms
at play that are not well
understood
oxidative stress, nuclear DNA damage, apoptosis, (e.g. deletions in muscle)
cellular transformation/cancer

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 homoplasmic mtDNA mutations
in tumors

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 What about carry over of small amounts
of mutant mtDNA from original carrier mother?

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 Keys Points
Mitochondria are multi-functional and tailored to meet the needs of
specific cell types/tissues and can contribute to disease pathology
by a variety of mechanisms in addition to defective energy metabolism

mtDNA is maternally inherited and present usually at thousands of

copies/cell which allows for natural and inherited heteroplasmic (i.e. mixed)
states to exist

The degree of heteroplasmy can drift dramatically during somatic cell division,
germ cell development, embryogenesis, under disease states, and aging

A high threshold for inherited pathogenic mtDNA mutations exists, thus

small amounts of mutated mtDNA carried over during nuclear transfer
may not be a major concern

However, it remains unclear what effects might occur from mixed haplotypes or
inherited pathogenic mutations interfacing with other heteroplasmic
mutations simultaneously inherited or acquired with age

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