Mitochondrial Function Flashcards
What is the outer membrane of mitochondria permeable to?
small molecules and ions
Describe the permeability of the inner membrane of mitochondria. What structures does it make? What does it contain?
impermeable to most small molecules and ions, including H+
It forms cristae that jut into the matrix
It contains:
- Respiratory electron carriers (I-IV)
- ADP-ATP translocase
- ATP synthase (F0F1)
- Other membrane transporters
What is contained within the matrix of the mitochondria?
- pyruvate dehydrogenase complex
- citric acid cycle enzymes
- fatty acid beta-oxidation enzymes
- amino acid oxidation enzymes
- DNA, ribosomes
- Many other enzymes
- ATP, ADP, Pp, Mg2+, Ca2+, K+
- Many soluble metabolic intermediates
What is the purpose of translocases in the mitochondria? What are they composed of?
Translocases are transport proteins that allow the passage of molecules across the tight mitochondria membrane. Each translocase is compsed of specific membrane spanning helices that bind only specific compounds.
What is the name of the transporters that exchanges ATP for ADP? What type of transporter is this?
ANT (adenine nucleotide translocase)
This is an antiport transporter
What are the types of transporter sresponsible for allowing inorganic phosphate and pyruvate into the mitochondrial matrix?
Symport transporters. They transport a Hydrogen with each phosphate or pyruvate
How is calcium able to enter into the mitochondrial matrix
The mitochondrial matrix is negative, whereas calcium is positive so it is transported by the electrochemical gradient.
What is the name for the nonspecific pores located on the outer mitochondrial membrane? What types of proteins do they bind? Up to what molecular weigt can transport through these pores?
voltage-dependent anion channels (VDACs)
They bind cytosolic proteins, such as hexokinase (HK), which enables HK to have access to newly exported ATP
Up to ~6,000 Da
What type of proteins are VDACs?
At what transmembrane potential are they open? What type of molecules do they prefer?
porin homodimers that form a beta-barrel with a relatively large, nonspecific water-filled pore thorugh the center
They are “open” at low transmembrane potential with a preference fr anions sucha s phosphate, chloride, pyruvate, citrate, and adenine nucleotides
What is the name for the combined transporter junction of an ANT and a VDAC?
What molecules encourage this pore to open? Which molecules encourage it to close?
Mitochondrial permeability transition pore (MPTP)
Open: Ca2+, Pi, ROS,
Closed: cytosolic ATP, low cytosolic pH, electrochemical potential
Which molecules regulate the conformation of ANT?
Which proteins bind VDAC? What do they regulate?
cyclophilin D (CD) and Ca2+
VDAC binds BCl-2 and Bax, which regulate apoptosis, this binding may change the permeability of the outer membrane soa ast to either favor, or block, events leading to apoptosis (such as cytochrome)
Explain why daughter cells show varying degrees of heteroplasmy with relation to mitochondria content?
If some fractin fo maternal mitochondria have a mutant gene, the random distribution of mitochondria durign subsequent cell divisions yields some daughter cells with mostly mutant mitochondria, some with mostly wild-type mitochondria, and some in between.
Different cells in the same tissue are affected to different degrees by the same mitochondrial mutation.
Onset before 20 yrs. of age, characterized by opthalmoplegia, atypical retinitis pigmentosa, mitochondria myopathy, and one of the folowing: cardiac conduction defect, cerebella syndrome, or elevated CSF protein
mtDNA mutation: Deletion contiguous segments of tRNA and OXPHOS polypeptides, or duplication mutations consisting of tandemly arranged normal mtDNA and mtDNA with a deletion mutation
Kearns-Sayre syndrome
Systemic disorder of oxidative phosphyorylation taht predominantly affects bone marrow
mtDNA mutation: Deletion contiguous segments of tRNA and OXPHOS polypeptides, or duplication mutations consisting of tandemly arranged normal mtDNA and mtDNA with a deletion mutation
Pearson syndrome
Progressive myoclonic epilepsy, a mitochondrial myopathy with ragged red fibers, and a slowly progressive dementia; onset of sympromts: late childhood to adult
Point mutation: tRNA^lys
myoclonic epilepsy and ragged red fier disease (MERRF)
Progressive neurodegenerative disease characterized by strokelike episodes first occurring between 5 adn 15 years of age and a mitochondrial myopathy
Point mutation: 80-90% mutations in tRNA^leu
Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS)
Mean age of onset, 1.5-5 years; clinical manifestatiosn include optic atrophy, ophthalmoplegia, nystagmus, respiratory abnormalities, ataxia, hypotonia, spasticity, and developmental delay or regression
Missense mutations: 7-20% of cases have F0 subunits of the F0Fi-ATPase
Leigh disease (subacute necrotizing encephalopathy)
Late onset, acute optic atrophy
Missense mutation: 90% european and asian cases result from mutation in NADH dehydrogenase
Leber hereditary optic neuropathy (LHON)
Mitochondrial DNA encodes for which subunits of the electron transport chain?
- Complex I
- NADH dehydrogenase (ND1-ND6)
- cytochrome b of Complex III
- the subunits of cytochrome oxidase, Complex IV (COI to COIII)
- two subnits of ATP synthase
How many genes does the mitochondrial chromosome encode for?
How many copies does it have of this genome?
37 genes (13 for respiratory chain, the rest for rRNA and tRNA)
5 copies
Is the nuclear of mitochondrial replication system more effective? What implication does this have for genes?
The mitochondral replication system is less effective than the nuclea, therefore defects int eh mtDNA accumulate over time, which leads to mitochondrial inheritance variation
What is the clinical result of a defect in the nuclear-encoded proteins of Complex IV, COX6B1?
sever defects in brain development and thickened walls of the heart muscle
Which types of cells are the least tolerant to low ATP production? What implication does this have for mitochondrial disease?
neurons, myocytes (skeletal and cardiac) and beta-cells of the pancreas.
They are more affected by mutations in mitochondrial proteins
Explain how diabetes (MODI) can be formed from a mitochondrial mutation.
- In normal situation, when the blood glucose level rises, production fo ATP in beta cells increases
- ATP, by blocking K+ channels, depolarizes the plasma membrane and opens voltage-gated Ca2+ channes. The resluting influx of Ca2+ starts exocytosis of insulin-containing secretory vesicles releasing insulin
- If oxidative phosphorylation in beta cells is defective, [ATP] is never sifficient ot trigger this process and iinsulin is not released
