Mitochondrial Disorder

MITOCHONDRIAL
DISORDER
RINO PATTIATA
ANATOMICAL PATHOLOGY DEPARTMENT
FACULTY OF MEDICINE
UNIVERSITY OF INDONESIA
Cellular Respiration
 Process of oxidizing food molecules to

CO2 and H2O
 The energy released trapped in the form
of ATP
 2 phases
 Glycolysis (breakdown of glucose to pyruvic
acid)
 Oxidation of pyruvic acid into CO2 and H2O
MATRIX (1)
1 -HIGHLY CONCENTRATED MIXTURE

OF HUNDREDS OF ENZYMES FOR:
-PYRUVIC OXIDATION & FATTY
ACID
-CITRIC ACID CYCLE
- mtDNA GENOME, MITOCHONDRIAL
RIBOSOME, tRNA AND VARIOUS
ENZYMES FOR EXPRESSION OF
mtDNA
INNER MEMBRANE
(2)
- FOLDED INTO CRISTAE

-PROTEINS
-CARRY OUT THE OXIDATION
2 REACTIONS OF THE
RESPIRATORY CHAIN
-ATPsynthase
-SPECIFIC TRANSPORT PROTEIN
THAT REGULATE THE PASAGE
OF METABOLITE
-IMPERMEABLE TO SMALL IONS
OUTER MEMBRANE (3)
-CONTAIN LARGE CHANNEL-

FORMING PROTEIN → PERMEABLE
TO MOLECULES 5000 Da OR LESS
-ENZYMES INVOLVED IN
MITOCHONDRIAL LIPID SYNTHESIS
-ENZYMES CONVERT LIPID
SUBSTRATE INTO FORM
METABOLIZED IN THE MATRIX
3
INTERMEMBRANE SPACE (4)
Enzymes that use ATP passing out of

the matrix to phosphorylate other
nucleotide
4
The Argument Against Mitochondria
as the Cellular Mediator of
Photobiomodulation
The Argument Against Mitochondria as the Cellular Mediator of
Photobiomodulation
 “Mitochondria can’t be the answer since all they do is make ATP.”
 They can’t respond to cell stress or injury.
 They can’t regulate cell shape.
 They can’t regulate cell death and survival.
 They can’t regulate inflammation.
 They can’t regulate wound healing.
 They can’t regulate cell dedifferentiation.
 They can’t regulate blastema formation.
 They can’t regulate cell movement and morphogenesis.
 They can’t regulate tissue differentiation.
 They can’t regulate cellular aging.
Cardinal Laws of
Mitochondrial Biology and
Medicine 2004
1. Mitochondrial dysfunction may be
inherited, spontaneous, age-acquired,
physiologically regulated, or drug-
induced
2. Mitochondrial dysfunction may be
transient, fixed, or progressive
3. Mitochondrial dysfunction can cause
“any disease, in any organ, at any age”
How?
Not All Mitochondria Are The Same
 They Have Cell-Specific Structures
 With tissue-specific ultrastructure
 They Have Cell-Specific Functions
 That results from tissue-specific gene
expression
 ATP is just part (1-10%) of the story
 All cells require mitochondria, but not all cells use
them to make energy
Mitochondria Have Different
Shapes
 There is a different mitochondrion for
each of the 250-350 different cell types in
the human body Electron Tomograph of
An Heart Mitochondrion
Liver, Brown Fat, Adrenal Cortex,
and Gonadal Mitochondria
Electrons are Food for
Mitochondria
 All the food we eat is made of organic polymers
 Proteins, Fats, Carbohydrates, DNA, RNA
 These polymers are broken down by oxidation
(burning) in mitochondria to yield electrons
 Electrons are the fundamental food of the cell and
can be used for work
 Cells produce a signal when they are fed
 This signal is a flickering trickle of H2O2 that lets
the nucleus know the cytoplasm is well
The 4 Housekeeping Functions
of Mitochondria
1. Electron consumption--“electrons are food”
2. Oxygen Consumption--is genoprotective
3. Heat Production (60-100% of oxygen redox energy)
4. Reactive Oxygen Synthesis (1-50% of O2 Consumed)--can
occur anaerobically
Primary ROS
- Superoxide (O2-.)
- Hydrogen Peroxide (O2-. + 2H+ H2O2 + O2)
- Singlet Oxygen (HOCl + H2O2 1O2--MPO in
- granulocytes)
- Nitric Oxide (NO.)
Secondary ROS
- Peroxynitrite (NO. + O2-. ONOO-.)
- Hydroxyl Radical (H2O2 + Fe2+ OH.)
- Lipid Peroxides (ROO.)
Redox-Responsive Targets
 Thiols/Cysteines
 Mitochondrial Matrix Proteins
 Sarcoplasmic Reticulum Membrane Proteins
 Calcium release
 Cytoplasmic Transcription Factors
 AP1, NFkB, STAT1
 Redox Modulators and Effectors
 Thioredoxin, Glutathione
 Metal Centers of Cytochromes and
Metalloenzymes
 Fe, Cu, Se, Mn, Zn
Mitochondrial H2O2 has Several
Effects
 Stimulates Ca2+ release

 ER, Mitochondria
 Activates Transcription Factors
 AP1 (fos, jun), NFB
 Activates Inflammatory Mediators
 MCP-1, TNF-, IL1- , IL6, IL8. STAT1-
 Activates Adhesion Molecules
 ICAM-1, VCAM-1, E-Selectin
 Changes Cell Shape--Mechanotransduction
Caspase Dependent
Apoptosis
Caspase Dependent
Apoptosis
Six themes
 Cells can make ATP in 2 ways
 Glycolysis (does not require oxygen)
 Oxidative Phosphorylation (absolutely requires oxygen)
 Mitochondria are cell-specific, have hundreds of functions, and
can be segmentally activated
 Mitochondria never work alone
 Electrons are food for mitochondria
 Reactive Oxygen Species connect mitochondria to cytoplasmic
and nuclear activating events
 Directly (H2O2)
 Indirectly (via Ca2+ Release, NO, NFkB, AP1, Lipid Mediators)
 Mechanotransduction connects mitochondrial function with cell
shape, movement, activation, dedifferentiation, and differentiation
COMPLEXES ENZYMES
 NADH DEHYDROGENASE (COMPLEX I)
 SUCCINATE DEHYDROGENASE
(COMPLEX II)
 CYTOCHROME C REDUCTASE
(DOMPLEX III OR CYTOCHROME B-C
COMPLEX)
 CYTOCHROME C OXIDASE (COMPLEX
IV)
 ATP SYNTHASE (COMPLEX V)
MITOCHONDRIAL
GENETIC
COMPLEX TOTAL mt CODES NUCLEAR
SUBUNIT
I 42 7 35
II 4 0 4
III 11 1 10
IV 13 3 10
V 14 2 12
MITOCHONDRIAL
DISORDER
 DEFECTS IN THE TERMINAL
COMPONENT OF THE mt ENERGY
PATHWAY (OXPHOS SYSTEM)
 SINGLE/MULTIPLE DEFECTS OF 5
COMPLEXES
MITOCHONDRIAL
GENETIC
 16500 bp
 CIRCULAR, DOUBLE
STRANDED
 MATERNALLY INHERITED
 22 tRNA
 2 rRNA
 13 polipeptida
 MUTATES 10x NUCLEAR
DNA
 NO HISTONE AND
EFFECTIVE REPAIR
SYSTEM
 EXPOSED TO FREE
RADICAL
Polyplasmy
 Multiple mitochondrial present in cell

 Each mitochondrial contains multiple
genome
 A cell contain hundreds/thousands
mtDNA
 During mitosis mitochondria distributed
haphazardly
heteroplasmy
 Normal tissue : mtDNA identic

 Mutation: coexistence of 2 population of
mtDNA
Threshold effect
 Minimum critical number of mtDNA

needed to impair energy metabolism to
cause dysfunctional organ/tissue
 Vary from tissue to tissue
 Depends on vulnerability of tissue to
impairments of oxidative metabolism
Maternal inheritance
 mtDNA derived from oocyte

Mitotic segregation
 At cell division proportion of mutant

mitochondrial genome may shift in
daughter cell → phenotype change
 Pearson’s syndrome and Kearns Sayre
syndrome
Genetic code
 Genetic code different

 Although it’s an “autonomy”, still
mitochondria depends on nDNA for
syntesis and import most constitutive
protein
 Requires nDNA encoded factors for
replication, transcription and translation
Genetic classification
 Defect in mitochondrial DNA

 Point mutations (maternal inheritance)
 Deletion and duplication (sporadic)
 Defects in nuclear DNA
 Defects in genes encoding mitochondrial
proteins
 Defects in mitochondrial protein import
 Defects in intergenomic communication
Presenting in infancy
Leigh disease
 Subacute necrotizing encephalopathy

 Defects of pyruvate carboxylase,
pyruvate dehydrogenase, other
components of respiratory chain
 T8993G mutation on ATPase gene
 NARP also harbour the same mutation
 90% mutant DNA : Leigh disease
Alpers syndrome
 Progressive infantile poliodystrophy

 Autosomal recessive inheritance
Lethal infantile mitochondrial
encephalopathy
 Defects in complexes I or IV
 Muscle biopsy : RRF and cytochrome
oxidase deficiency
Pearson’s marrow-
pancreas syndrome
 Deletion and duplication in COX III gene
 Episodes of lactic acidosis
 Survive : Kearns-Sayre syndrome
Presenting in
childhood/adolescense
Kearn-Sayre syndrome and
Chronic progressive external
ophtalmoplegia
 Deletion and duplication COX III gene
 Degenerative Purkinje system and
progressive infranodal block
Mitochondrial
encephalopathy with lactic
acidosis and stroke likes
episodes (MELAS)
 Stroke like episodes

 Lactic acidosis
 RRF
 A3243G in tRNALeu(UUR)
Myoclonic epilepsy with
ragged red fiber (MERRF)
 A to G transitionat nt8344 in the tRNA
gene of mtDNA
 nt 8356
 Blood and muscles
Neuropathy, ataxia and
retinitis pigmentosa (NARP)
 Nt 8993 mutations
Leber’s hereditary optic
neuroretinopathy (LHON)
 G11778A in ND4 gene
Myoneurogastrontestinal
disorder and encephalopathy
(MNGIE)
 Thymidine phophorylase gene
 Autosomal recessive
PARAGANGLIOMA
 TUMOR
 ABUNDANT EOSINOPHILIC
GRANULES
 COMPLEX II, SDHB (IRON SULFUR
PROTEIN), SDHC (the large cytochrome
b, cybL or C, subunit )
Diagnostic tools
 Lactate, pyruvate and lactate/pyruvate

ratio)
 Venous lactate
 CSF lactate
 Depends on the disorder
electromyography
 Not very important

 Normal/near normal EMG in patient with
muscle weakness highly suggestive
electroencephalogram
 Calcification of basal ganglia

Muscle biopsy
 RRF
 Cytochrome C
 NADH
 SDH
Diagnostic criteria
Shock and mitochondria
Mitochondrial distress
 Rat model of early hypoxic : endotoxemia

→ hypoxia
 Progress from early to severe :
microcirculation dysfunction →
mitochondrial dysfunction
 Mitochondrial failure → respiratory distress
→ organ failure

Mitochondrial Disorder

Uploaded by

Document Informationclick to expand document information

Copyright:

Available Formats

Mitochondrial Disorder

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Mitochondrial Disorder

Uploaded by

Copyright:

Available Formats

MITOCHONDRIAL

 Process of oxidizing food molecules to

1 -HIGHLY CONCENTRATED MIXTURE

- FOLDED INTO CRISTAE

-CONTAIN LARGE CHANNEL-

Enzymes that use ATP passing out of

 Stimulates Ca2+ release

 Multiple mitochondrial present in cell

 Normal tissue : mtDNA identic

 Minimum critical number of mtDNA

 mtDNA derived from oocyte

 At cell division proportion of mutant

 Genetic code different

 Defect in mitochondrial DNA

 Subacute necrotizing encephalopathy

 Progressive infantile poliodystrophy

 Stroke like episodes

 Lactate, pyruvate and lactate/pyruvate

 Not very important

 Calcification of basal ganglia

 Rat model of early hypoxic : endotoxemia

You might also like