mitochondrial diseases

Penyakit Mitokondria

Dwi Ari Pujianto

Departemen Biologi

Fakultas Kedokteran Universitas Indonesia

The major intracelluar compartment of an animal cell

Sel

Nukleus ����

(tempat sintesis DNA & RNA)

Sitoplasma

Sitosol ���� tempat sintesis protein & degradasi prot

���� metabolime intermediate

Organel (membrane-bound)

Nucleolus

(Non membrane-bound)

Necleoplasm

Famili organel berdasarkan evolusinya

1. Nukleus dan cytosol � komunikasi lewat nuclear pore complexes

2. Organel yg masuk dlm jalur secretory and endocytic � ER, Golgi apparatus,

Endosomes, lysosomes, transport vesicles yg bermigrasi antar organel, peroxisomes

3. Mitokondria/Plastids (pada tumbuhan)

= Topologically equivalent

Bagian Mitokondria

• Matrix = Tdp berbagai macam enzim utk oksidasipyruvate, asam lemak dan siklus kreb, dan juga enzimutk ekspresi gen mitokondria

• Membran dalam = protein utk reaksi oksidasi pada rantairespirasi, ATP synthase, Transport protein dari matrik

• Membran luar= Protein cahnnel VDAC, enzym utksintesa lipid pada mitokondria

• Ruang antar membran= Enzim yang menggunakan ATP dari matrik utk fosforilasi nuklotida

Mitochondrial genetics system

• mtDNA

• Molecular machinery needed to replicate and express the genes � Transcription, translation

• Many of these macromolecules are encoded by mitochondrial genes, but some are encoded by nuclear genes

Mitochondrial DNA (mtDNA)

• Discovered in 1960s

• 16-17 kb in vertebrate animals to 2500 kb

in some of the flowering plants

• Each mitochondria has several copies of

the DNA

• E.g. in a vertebrate oocyte � 108 copies

• E.g. in somatic cells � < 1000 copies

Mitochondrial DNA (2)

• Most mtDNA are circular

• In the vertebrates: 37 genes are packed

into a 16-17 kb circle

• In human: mtDNA is 16.659 bp = 37 genes• 2 encode for rRNA

• 22 for tRNA

• 13 for polypeptides involved in oxidative

phophorylation

Map of human mtDNA

Expression of Mitochondrial genes

• mtDNA of vertebrate � 2 large transcription units (H & L strands)

(each encoding information of several genes)

• H strand � 2 ribosomal RNA, 14 tRNA, 12 polypeptides

• L strand � 8 tRNA, 1 polypeptide

• Each mRNA is translated into polypeptides using mitochondrial ribosomes and

combination of nuclear and ribosomal tRNA

• Translation in mitochondria = sitosol, except some codons are different

AGA & AGG � Termination codon in mitochondria (arginine in cytosol)

UGA � triptophan (mito), stop codon (sytosol)

• In plant mitochondria, mtRNA transcript undergo editing

• Some mtRNA are formed by the process of trans-splicing (single cis-splicing &

three trans-splicing reactions)

Non Mendelian Inheritance

(Cytoplasmic inheritance)

• Multifactorial disorders

• Somatic cell genetics disorders

• Mitochondrial disorders

Mitochondrial genes are maternally

inherited in many organism

• Sel telur (oocyt) menyumbangkan lebih

banyak sitoplasma pada zygote �

uniparental

Mitocondrial disorders

• All derived from the mother

• Transmission to all children of affected mother

• No risk to the offspring of affected man

• Mitochondria has 10x higher mutation rate than nuclear DNA

• Phenotype effect depends on the location, type of mutation, proportion of the mitochondrial chromosome involved

Mitochondrial Diseases

Leber’s hereditary optic Neuropathy (LHON)

• Kebutaan secara tiba-tiba pada orang dewasa �

Kematian saraf optik

• Disebabkan oleh mutasi DNA mitokondria (lebih dari satumutasi) � DNA penyandi respiratory chain complex 1

• Mutasi menyebabkan perubahan protein mitokondria �

mengurangi efisiensi fosforilasi oksidatif

• Diturunkan melalui/secara garis maternal

Pedigree from family with LHON

Pearson marrow-pancreas

syndromeHilangnya sel-sel sumsum tulang pada usia anak � sering kali menyebabkan kematian

Disebabkan dilesi pada mtDNA

Penderita hampir tidak pernah mempunyai orang tua dengan syndrome yang sama

Delesi terjadi secara spontan selama perkembagan anak atau selamaproses oogenesis pada ibu

Penderita mempunyai campuran antara DNA yg terdelesi dengan yang normal � mosaic � Mitocondrial heteroplasmi

Penderita Pearson Syndrome homoplasmic tidak pernah dilaporkan �

kemungkinan karena lethal pada awal perkembangan

Penyakit mitokondria yang

disebabkan oleh mutasi DNA inti• Penurunan : autosomal atau x-linked

• Cardioencephalomyopathy � defisiensicytocrom C oxidase (Enzim terminal untuk rantaipernafasan)

• Progressive external ophthalmoplegia �weakness of external eye muscle � DelesimtDNA

• Delesi mtDNA dpt disebabkan olehketidaknormalan gen inti (POLG) yang mengkode unit katalitik polymerase gama(enzim yg berperan dalam replikasi DNA mitokondria