Monogenic mitochondrial disorders Pathologic conditions such as Alzheimers disease Parkinsons disease Huntingtons disease cancer diabetes obesity epilepsy cardiac disease Progressive decline in the expression of mitochondrial genes is a central feature of normal human aging ID: 344811
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Mitochondrial dysfunction
Monogenic mitochondrial disorders
Pathologic conditions such as:
Alzheimer’s disease
Parkinson’s disease
Huntington’s disease
cancer
diabetes
obesity
epilepsy
cardiac disease
Progressive decline in the expression of mitochondrial genes is a central feature of normal human aging
It is not entirely clear whether these changes in expression have positive of negative effect on life spanSlide3
off target effects of environmental toxins (e.g.
rotenon
)
frequently used drugs (e.g.
statins
,
amiodarone , antipsychotic drugs, valproic acid-epilepsy, zidovudine- HIV treatment)antibioticsaspirinchemotherapeutic agents (e.g. doxorubicin)
Mitochondrial dysfunction – additional sourcesSlide4
Monogenic mitochondrial diseases has considerably advanced
our understanding of the cellular
pathophysiology
of
mitochondrial dysfunction
This review summarizes these insights and explain how they can
contribute to the rational design of intervention strategies for mitochondrial dysfunction
Monogenic mitochondrial diseasesSlide5
Mitochondrial internal and external structure varies with
cell type
metabolic state
and often becomes altered during mitochondrial dysfunction
Structure
Mutation in
NDUFS2 –
Complex I Slide6
The inner membrane contains many matrix- protruding folds (
cristae
)
that increase the surface area of the inner membrane and have a
dynamic structure.
These structural dynamics may serve to regulate mitochondrial
metabolism
StructureSlide7
Best known – production of ATP
But also metabolite exchange, ion transport, protein import, production of
reactive oxygen species, apoptosis
FunctionSlide8
With the use of mitochondrial proteome analysis -
~1000 genes encoding mitochondrial proteins were discovered
in humans
(
Pagliarini
, Cell 2008)
Mitochondrial dusfunction can arise from a mutation in one of these genes – primary mitochondrial disorderor from an outside influence on mitochondria -
secondary
mitochondrial disorder
(e.g. drugs)
Monogenic cell models of mitochondrial dysfunctionSlide9
Mutations in
228
protein-encoding
nDNA
genes
and 13
mtDNA genes have been linked to a human disorder
Epilepsy
Renal cell
cancer
Cancer of colon,
Alzheimer’s disease,
Complex I deficiency
DiabetesSlide10
It is not clear how specific genetic defects are linked to dysfunction at the level of cells, organs, and the whole organism
It is difficult to determine the effects of specific defects because of compensatory stress–response pathways:
Mitochondrial biogenesis
Increased expression of oxidative
phosphorylation
proteins
A switch to a more glycolytic mode of ATP productionRemoval of dysfunctional mitochondria by quality-control systemsThe substrate supply, the mode of ATP generation, the level of demand for ATP, mitochondrial dynamics, rate of oxidative
phosphorylation
differ among cell types and tissue types
Various types of tissues are not equally sensitive to mitochondrial dysfunction
Mutations and phenotypes
cellular level
Genetic background also modifies the phenotype of human
mitochondrial diseases. M
anifested only when a certain threshold of
mitochondrial dysfunction or cellular demand on mitochondrial metabolism is exceeded
Organism levelSlide11
The functional properties of isolated mitochondria differ considerably from those within the cell
Mitochondrial function can also be investigated in intact (patient) cells
Developing a rational intervention strategy Slide12
In a
primary mitochondrial disorder
, the mutation
- affects the expression level of protein, its function, or both
- induces primary cell consequences and secondary cell consequences:
reduced ATP production
increases in the cellular levels of mitochondrial proteins and mitochondrial function upregulation of the detoxification of reactive oxygen speciesIt appears that primary and secondary mitochondrial disorders have similar
consequences at the cellular level
Developing a rational intervention strategy Slide13Slide14
Four intervention strategies for mitochondrial dysfunction have
been described:
Genetic therapy-
carried out at the preclinical level, mainly on
mtDNA
-
associated disorders (not included in the review)Small molecules to target mitochondrial dysfunctionMetabolic manipulationDiet and exercise
Developing a rational intervention strategy
aim to:
1. Increase ATP synthesis
2. Bypass the mitochondrial defect
3. Stimulate mitochondrial biogenesis
4. Reduce levels of ROS
ROS can act as signaling molecules, and therefore, their elimination might also have detrimental effects
?Slide15
Specific targeting of mitochondria by small molecules (referred to as “cargo”)
can be achieved by
Protein-based cargo can be coupled to a mitochondrial targeting sequence recognized by the mitochondrial protein import machinery
Coupling the cargo to a delocalized
lipophilic
cation, leading to its accumulation in mitochondria (Several antioxidants have been successfully targeted using the cation approach such as CoQ variant )Mitochondria-penetrating peptides are engineered cell-penetrating peptides that target mitochondria on the basis of their membrane potential and
lipophilicity
Vesicle-based transporters that target mitochondria through
macropinocytosis
,
endosomal
escape, and membrane fusion
Small moleculesSlide16
Intervention strategies for mitochondrial diseaseSlide17Slide18
In 2006 – large scale review of published clinical trials of treatments for primary mitochondrial disorders revealed no evidence supporting the use of any intervention
Several recent trials in which a variety of treatments for mitochondrial disease were studied, including
dichloroacetate
, vitamins, and a cocktail of specific food components showed a positive effect
CoQ
10
variant (idebenone)- was approved for the treatment of Friedreich’s ataxia (iron)A ketogenic diet was effective in preventing epileptic seizures in children with electron-transport-chain defects - suggesting that it may be worthwhile to pursue nutritional treatment strategies
Ullrich’s
congenital muscular dystrophy and
Bethlem’s
myopathy
are associated with mitochondrial dysfunction and muscle-cell apoptosis (inappropriate opening of the mitochondrial permeability transition pore) prevented in patients treated with a permeability transition- pore desensitizer,
cyclosporin
A
TreatmentSlide19
A field that began more than 50 years ago, when a physician detected a mitochondrial disorder in a single patient with
hypermetabolism
, has now evolved into the discipline of mitochondrial medicine
Lessons learned from studies of rare diseases have implications for a broad range of medical disciplines
Within the next few years, the application of new technologies (e.g. whole-
exome
sequencing) will result in a huge expansion of the number of known causative nuclear gene defects in patients with mitochondrial diseasesThe challenge - to increase our understanding of the consequences of mitochondrial dysfunction at all levels of complexity in order to drive the development of rational treatment strategiesDirect enzyme-replacement therapy may be feasible in addressing single-protein enzymes, such as those in the tricarboxylic
acid cycle
Future perspectivesSlide20
Given the metabolic individuality in humans, we do not expect
monotherapeutic
metabolic manipulation strategies to be a magic bullet but predict that the next step in treatment development will be the use of
combinations of manipulation strategies
applied in an individualized way
In the meantime, efforts must be made on a global scale to genetically categorize patient cohorts, monitor them in a standardized way by means of prognostic scoring systems, and develop new biomarkers to allow for proper monitoring of the effect of
intervention strategies
Future perspectives