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Mitochondrial dysfunction Mitochondrial dysfunction

Mitochondrial dysfunction - PowerPoint Presentation

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Mitochondrial dysfunction - PPT Presentation

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

dysfunction mitochondrial mitochondria cell mitochondrial dysfunction cell mitochondria intervention level strategies disease atp protein treatment genes primary rational cellular

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Slide1
Slide2

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 Slide13
Slide14

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 diseaseSlide17
Slide18

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