Transcript Neurodegeneration or Hereditary Tumor Syndrome?

Neurodegeneration or Hereditary Tumor
Syndrome? The Butterfly Effect of
Mutated Genes Encoding Mitochondrial
Enzymes
* Prasanna G Vibhute MD, * Vivek Gupta MD,
** Girish M Fatterpekar MD, *** James Henry MD
Departments of
* Radiology, Mayo Clinic, Jacksonville, FL
* * Radiology, NYU, New York, NY
* * * Pathology,
Univ. Texas HSC, San Antonio, TX
Neurodegeneration or Hereditary Tumor Syndrome?
The Butterfly Effect of Mutated Genes Encoding
Mitochondrial Enzymes
Poster # eEdE-03
Control # 2060
Disclosures:
– Prasanna Vibhute, MD
– Vivek Gupta, MD
– Girish Fatterpekar, MD
– James Henry, MD
nothing to disclose
nothing to disclose
nothing to disclose
nothing to disclose
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Learning Objectives
•
To understand how mitochondrial enzymes defects
can lead to hereditary tumor syndromes and
neurodegenerative disorders.
•
To describe the cytogenetics, molecular signaling
and the molecular biology related to these
mitochondrial disorders
•
To correlate the imaging findings to histopathology
and phenotype characteristics
Butterfly Effect
A relatively small change in the initial
conditions of a deterministic nonlinear
system can evolve into large differences in
the final states: the possibility that a large
storm in New England may be caused by
fluttering of a butterfly in China, a slight
global warming can cause widespread
climate fluctuation, and slight variation in
biomolecule concentration can change the
outcome from cell death to uncontrolled cell
proliferation.
Introduction:
Salient Krebs Cycle Enzymes
• Succinate dehydrogenase (SDH) and
Fumarate Hydratase (FH) catalyse two
sequential steps of the mitochondrial Krebs or
Tricarboxylic Acid (TCA) cycle.
Malate
FH
TCA cycle
Fumarate
SDH
Succinate
Introduction: SDH and FH
Germline Mutations
Germ line mutations
Heterozygous
Homozygous
SDH
FH
SDH/FH
HPGL
syndrome
HLRCC
syndrome
Neurodegenerative
diseases: Leigh Syndrome
• HPGL: Hereditary paraganglioma syndrome
• HLRCC: Hereditary cutaneous & uterine leiomyoma, &
renal cell carcinoma syndrome
Cell Biology of Mitochondria
Outer membrane: Relatively permeable and
composed predominantly of phospholipids
Inner membrane:
– Highly impermeable with high protein content
– Has protein complexes of electron transport chain
(ETC)
View
ETC Animation
Central matrix:
– Contains components of Krebs i.e.Tricarboxylic acid
(TCA) cycle, mitochondrial DNA and ribosomes.
Succinate Dehydrogenase
(SDH) = ETC Complex II
4 subunits
Each encoded by a different gene
A
B
C and D
Active component of TCA cycle
Projects into mitochondrial matrix
Anchors A
to
C and D
Span the mitochondrial
inner membrane
matrix subunits
transmembrane subunits
Succinate Dehydrogenase
(SDH) = ETC Complex II
• Only ETC complex encoded by nuclear DNA
• Mutations that disrupt the complex will
compromise its function
• These mutations include not only genes
encoding four subunits (A, B, C, and D) of the
SDH complex, but several others involved in
assembly and function of the complex.
Proposed Models of
Tumorigenesis in HPGL
• Model 1: ETC dysfunction - Increased
reactive oxygen species (ROS)
• Model 2: TCA dysfunction -Accumulation of
succinate/fumarate with competitive inhibition
of 𝛼-KG-dependent dioxygenases.
Model 1: Increase Reactive Oxygen Species
ETC II
dysfunction
Damages
macromolecules
– Lipids, Proteins
& DNA
Oxidative
Stress
Increased ROS
View
ROS Animation
Tumorigenesis
HIFs
PI3K
Metabolic
adaptations
Increased
Proliferation,
Survival,
Mobility
HIFs (Hypoxia inducible factors): allow tumor to adapt to diminished oxygen environment.
PI3K (phosphoinositide 3-kinase): an important growth factor response pathway hyperactivated in many cancers
Model 2: Inhibition of 𝛼-KG-dependent
dioxygenases by Succinate & Fumarate
Normal cytosolic
conditions
•
•
•
•
•
•
•
HIFs
Methylated histones
Methylated DNA
Immature collagen
N𝜀-Trimethyllysine
Damaged DNA
m6A RNA
Dioxygenases
O2 + α-KG
CO2 + Succ
•
•
•
•
•
•
•
HO-HIFs
Histones
DNA
Mature collagen
L-Carnitine
DNA
RNA
Examples of Dioxygenases and targets
Prolyl hydroxlase: Hypoxia inducible factor (HIF) proteins
Histone demethylases: Methylated histones
DNA demethylases: Methylated DNA
Model 2: Inhibition of 𝛼-KG-dependent
dioxygenases by Succinate & Fumarate
Increased cytosolic
Succinate/Fumarate
•
•
•
•
•
•
•
HIFs
Methylated histones
Methylated DNA
Immature collagen
N𝜀-Trimethyllysine
Damaged DNA
m6A RNA
Tumorigenesis
Dioxygenases
O2 + α-KG
CO2 + Succ
•
•
•
•
•
•
•
HO-HIFs
Histones
DNA
Mature collagen
L-Carnitine
DNA
RNA
Hypoxia Inducible Transcription
Factor (HIF) Induction
HPGL
Syndrome
HLRCC
Syndrome
-SDH
- FH
Succinate
Fumarate
Inhibition of
𝛼-KG-dependent dioxygenases
Increase
in HIF transcriptional activity.
Malate
Increase in ROS
HIF Pathway & Hydroxylases
• ? Final mediator in neo- angiogenesis/tumorigenesis
O2
High
g
r
a
d
i
e
n
t
O2
Low
Active
Hydroxylases
Inactivation of HIF-α
through the pVHL
mediated proteolysis
Stabilization of HIF-α
and increase
in HIF transcriptional activity
Inactive
Hydroxylases
Neoangiogenesis
Tumorigenesis
Succinate, ROS and HIF
Ex: Carotid body tumor
Fumarate
HPGL
syndrome
Loss of Succinate
dehydrogenase
Succinate
ETC
Dysfunction
DSA
Hypervascular paraganglioma
ROS
Inhibition of
prolyl
hydroxylases
Increase in HIF
Genophenotype Characteristics
Homozygous
SDHA & FH mutations
Total loss of enzymatic function
Severe energy deficits
Loss of mitochondrial synthetic capacity and ↑↑ ROS
Death of cells with high energy
requirements & O2 consumption under minor hypoxic-ischemic stresses
(e.g. neurons) before activation of metabolic adaptations
Neurodegeneration
Ex. Leigh syndrome
Genophenotype Characteristics
Heterozygous
SDH A, B, C, D mutations
Partial loss of enzymatic function, ↑ ROS
Metabolic adaptive mechanism activated (↑ glycolysis etc.)
Mitochondrial synthetic activity intact, normal development
2nd Hit
Loss or mutation of the wild allele in cells of neural crest origin
Complete loss of SDH function
Active adaptive mechanisms prevent cell death
↑↑ ROS
↑ Expression of antioxidant proteins
↑HIF stabilization
Inherited HPGL syndrome
ROS
Generation: Scavenger
Equilibrium
Cytotoxic
Neurodegeneration
Neoplasia
(Leigh syndrome)
(HPGL,
HLRCC)
Cytostatic
ROS Generation
ROS Scavenger
(mutations, hypoxia)
(Cellular adaptive
mechanisms)
Imaging Spectrum &
Rad-Path Correlation
Leigh Syndrome
• Hereditary neurodegenerative disorder - usually
autosomal recessive
• Usually affects young children and inevitably leads
to death.
• Neuropathologic endpoint of disordered cerebral
mitochondrial energy production
• Caused by gene mutations affecting ETC proteins
and pyruvate dehydrogenase.
Pathology Leigh Syndrome: Histology
Low power
High power
Leigh Syndrome : Early necrosis with focal sparing of neurons (arrows),
attenuation of the neuropil and vascular proliferation (arrowheads). (H &E)
Pathology Leigh Syndrome: Gross
A
B
C
A: Bilateral necrosis of lentiform
nuclei (arrow heads)
B: Bilateral perithird ventricular
(black arrows) and putaminal
necrosis (arrow heads); note
sparing of the mamillary bodies
(white arrows)
C: Symmetric involvement of the
midbrain (arrows)
Putaminal involvement and sparing of the mamillary bodies are consistent but
not constant features.
MRI: Leigh Syndrome
(Subacute necrotizing encephalomyelopathy)
Symmetrical lesions mainly in the basal ganglia, brain stem,
white matter and posterior columns of the spinal cord.
Putaminal involvement and sparing of the mamillary bodies are
consistent but not constant features.
Axial T2-WI
Diffusion-WI
Case courtesy of Dr. Hemant Telkar, Mumbai, India
Hereditary Paraganglioma
(HPGL) Syndrome
WHO Definition:
Pheochromocytoma: (Intra-adrenal paraganglioma):
A tumor arising from chromaffin cells in adrenal
medulla.
Extra-adrenal paraganglioma:
A tumor in extra-adrenal sympathetic &
parasympathetic paraganglia.
• Sporadic Vs familial(30%)
• Familial: MEN 2, NF 1, VHL, HPGL syndrome
Pathology PGL: Microscopy
Paraganglioma: Vascular tumor with nestling and clustering of chief cells –
characteristic “ Zellballen ” (cell ball) growth pattern. The delicate
fibrovascular network (arrows) surrounds each "ball" of cells.
Familial PGL
Example # 1
Three siblings, two brothers and one sister (not shown) all
with head and neck paragangliomas. As no sibling had
stigmata of Neurofibromatosis type 1, VHL disease or
MEN2, these were probably related to SDHD mutations
Sibling # 1
A
B
Axial T2-WI demonstrates bilateral carotid body
tumors (A) and left vagal paraganglioma (B)
Sibling # 2
C
Axial post contrast T1-WI
demonstrates a large right
carotid body tumor in
second sibling
Familial PGL
Example # 2
DSA in another patient: Multiple head and neck hypervascular paragangliomas
(arrows).
RT
LT
• SDHD mutations and partial inactivation lead to head and neck
paragangliomas.
• SDHB mutations and complete disassembly of complex II
predisposes to pheochromocytoma.
SDH Genotype-Phenotype Mystery
True or false:
Any mutation that abolishes SDH
function should have the same
outcome in susceptible tissues?
FALSE!
SDH Genotype-Phenotype Mystery
Different kinds of SDH loss-of-function
molecular pathologies lead to different tumor
phenotypes!
Probably due to mutation that reduces but
doesn't eliminate a gene’s functionality
(hypomorphic alleles)
SDH Genotype-Phenotype
SDHA
SDHB
SDHC
SDHD
GENE
5p15.33
1p36.1-p35
1q21
11q23
PENETRANCE
Very low
77%
less
penetrant
Highly
penetrant
PHENOTYPE
5 PGL & 1 Pheo
Pheo
H/N PGL
Multiple H/N PGL
Rare
Most common
Often benign
Often benign
Very rare
Often
aggressive
Leigh syndrome
(recessive)
RCC
Pheo: Pheochromocytoma; PGL: Paraganglioma; RCC: Renal cell carcinoma
Other Tumors Associated with
SDH Gene Mutations
3 autosomal dominant hereditary syndromes:
1.~7.5% Gastrointestinal stromal tumor (GIST)
• SDHA (most common), B, C and D germline
mutations and epigenetic silencing
2.GIST with PGL (Carney-Stratakis dyad)
• SDHB, SDHC or SDHD germline mutations
3.GIST with PGL and pulmonary chondroma (Carney
triad)
• SDHC gene locus epigenetic silencing
Carney Triad:
GIST, PGL and pulmonary chondroma
As in most cases this 26 year old female had 2 out of 3
tumors at presentation.
Gastric GIST with hepatic metastasis
Pulmonary chondroma
HLRCC
• Solitary papillary RCC type 2, Collecting duct RCC
• Multiple uterine benign & malignant smooth muscle
neoplasms
• Poor prognosis
Courtesy Dr. Peter Choyke, NIH
Sporadic Paragangliomas
Mutation or deletion of
RET (10%), VHL genes (4%);
Allelic losses at 1p,
3p (45%), 17p, & 22q
chromosomes
A
Retain
full SDH
activity
Not due
to ROS or
Succinate
production
Utilize
HIF
Pathway
CT and DSA:
Left Carotid
Body Tumor
Similar
hypervascular
imaging
appearance
B
Paradox
Neurodegeneration Vs Neoplasia
Neurodegeneration
Early
childhood death
before development
of neoplasia
HIF pathway
in severe hypoxia
induces pro-apoptotic
genes: cell deat
? No
neoplasia
Paradox
Neurodegeneration Vs Neoplasia
ROS induced
Oncogenic mitogen activated
protein kinase pathway
(MAPK)
Mutant SDH & FH
? Loss of tumor
suppression function
Neoplasia
Insufficient energy
dependent apoptosis
HIF induced
transcription of
oncogenic genes
Altered
mitochondrial membrane
composition by mutant SDH prevents
release of mediators of energy
independent apoptosis
Summary
A fascinating group of mitochondrial disorders show
remarkable biological diversity despite sharing a
common gene defect.
Homozygous gene mutations (that encode SDH/FH
enzymes) result in neurodegenerative disorders,
heterozygous mutations of the same genes cause
inherited neoplastic syndromes.
Improved understanding of these disorders may help
understand the imaging manifestations, develop new
imaging survellence protocols and treatment options.
References:
• Eng C, et al; A role for mitochondrial enzymes in inherited neoplasia and
beyond. Nature reviews/Cancer (2003), 3: 193-202
• Gottlieb E and Tomlinson Ian; Mitochondrial tumour suppressors: A
genetic and biochemical update. Nature reviews/Cancer (2005), 5: 857859
• Selak MA, et al; Succinate links TCA cycle dysfunction to oncogenesis
by inhibiting HIF-α prolyl hydroxylase. Cancer Cell (2005), 7: 77-85
• Pollard PJ, et al; The TCA cycle and tumorigenesis: the examples of
fumarate hydratase and succinate dehydrogenase. Ann Med (2003), 35:
632-639
• Plouin P, Gimenez-Roqueplo A; The genetic basis of
pheochromocytoma: who to screen and how? Nature Clinical Practice
(2006), 2(2): 60-61
• Sena and Chandel; Physiological roles of mitochondrial reactive oxygen
species. Mol Cell. 2012 October 26; 48(2): 158–167
• Sullivan and Chandel; Mitochondrial reactive oxygen species and cancer.
Cancer & Metabolism 2014, 2:17
• Yeng F. Her and L. James Maher III; Succinate Dehydrogenase Loss in
Familial Paraganglioma: Biochemistry, Genetics, and Epigenetics.
International Journal of Endocrinology, Volume 2015, Article ID 296167,
14 pages