WEEK 13 (Mitochondrial Function) Flashcards
Describe the theory of the evolution of mitochondria
Mitochondria originate from bacteria that were engulfed by an ancestral pre-eukaryotic cell and survived inside it
Describe the outer mitochondrial membrane
- Composed of 50% lipid by weight
- Contains a mixture of enzymes (involved in oxidation of epinephrine, degradation of tryptophan and elongation of fatty acids)
- Contains PORINS
Describe the inner mitochondrial membrane
- Contains more than 100 different PORINS
[Porin channels wide open -> outer membrane is freely permeable to ATP, NAD & CoA -> Energy metabolism within the mitochondrion] - Folded into numerous Cristae
- Contains proteins that carry out oxidative phosphorylation (including the electron-transport chain + ATP synthase)
Describe the Matrix
- Contains highly concentrated mixture of enzymes
- Oxidation of pyruvate & fatty acids and Citric acid cycle
Describe the Intermembrane space
- Contains enzymes that use the ATP passing out of the matrix to phosphorylate other nucleotides
- Contains proteins released during apoptosis
What are the other functions of mitochondria apart from energy production?
- Biosynthetic pathways (amino acids, nucleotides, glutathione etc)
- Regulate Ca2+ concentration of the cytosol
- Apoptosis
- Maintenance of redox potential (NADH/NAD levels)
- Aging
- Immune function (differentiation and activation processes of immune cells)
What does the balance between fusion and fission determine?
- Mitochondrial number
- Length
- Degree of interconnection
What happens when fusion becomes more frequent and when fission becomes more frequent?
When fusion becomes more frequent than fission = mitochondria tend to become more elongated and interconnected
When fission becomes more frequent than fusion = formation of more numerous and distinct mitochondria
Describe the mitochondria found in a yeast cell
- Form a continuous network tucked against the plasma membrane
- Networks are DYNAMIC (continually breaking apart by fission and fusing again)
Describe the mitochondria found in a heart cell
Located close to the contractile apparatus
What are mitochondrial transporters?
Membrane-inserted proteins that provide a link between metabolic reactions occurring in the mitochondrial matrix and outside the organelles by catalysing the translocation of numerous solutes across the mitochondrial membrane
What are examples of Mitochondrial transporters?
- Mitochondrial carrier family members
- Proteins involved in pyruvate transport
- ABC transporters and channels
What is Citrin and what can Citrin deficiency cause?
CITRIN = The mitochondrial aspartate/glutamate carrier (AGC2) plays a significant role in nitrogen metabolism due to its shuttle activity
CITRIN DEFICIENCY:
- Neonatal intrahepatic cholestasis
- Adult onset neuropshychiatric, hepatic and pancreatic disease
What is Cholestasis?
Reduced bile formation or flow
Describe how proteins are transported across both the mitochondrial membranes
1) MITOCHONDRIAL SIGNAL SEQUENCE on a mitochondrial precursor protein is recognised by a receptor in the OUTER MITOCHONDRIAL MEMBRANE which is associated with a PROTEIN TRANSLOCATOR
2) Complex of RECEPTOR, PRECURSOR PROTEIN and TRANSLOCATOR diffuses laterally in the outer membrane until it encounters a second translocator in the inner membrane -> UNFOLDING the protein in the process
3) CHAPERONE PROTEINS inside the organelles help to pull the protein across the two membranes and fold it inside
How are phospholipids transported in the mitochondria?
By LIPID-CARRYING PROTEINS that extract a phospholipid molecule from one membrane and deliver it into another
Describe Mitochondrial DNA
- Double stranded (Heavy and Light strand)
- Circular
- Introns are absent
- Gene repetitions present
What does Human mtDNA encode?
- 2 Ribosomal RNAs (rRNAs)
- 22 Transfer RNAs (tRNAs)
- 13 Polypeptides
[essential to the oxidative respiration functions of the organelle]
How is the Mitochondrial genome transcripted?
An RNA Polymerase contains TWO PROMOTER SEQUENCES, one for each strand of the circular genome -> Each strand is transcribed -> Mitochondrial transcripts are processed to generate individual mitochondrial mRNAs, tRNAs and rRNAs
Replication in mitochondria is dependent on enzymes encoded by ____________ DNA
Nuclear
Why is Mitochondrial DNA inherited maternally?
FEMALE OVUM has nucleus as well as mitochondria and MALE SPERM has only nucleus in the head region -> Nuclear from both parents will fuse but mitochondrial DNA will only come from female not from male
What is Myoclonic Epilepsy and ragged-red fibre disease (MERRF) and what are the symptoms?
Myoclonic Epilepsy with ragged-red fibres (MERRF) is a multi system mitochondrial syndrome characterised by progressive myoclonus and seizures. Patients with MERRF have a mutation in one of the mitochondrial genes encoding a transfer RNA and is maternally transmitted. Symptoms begin in childhood, adolescence or early adulthood.
Ragged-red fibers in skeletal muscle cells has mild proliferation of mitochondria which has replaced most cellular structures
SYMPTOMS:
- Myoclonus (involuntary twitching)
- Seizures
- Ataxia
- Muscle weakness
- Dementia
- Worsening eyesight
- Hearing loss
- Altered sensation feeling
What is Leber Hereditary Optic Neuropathy (LHON)?
Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; Vision loss occurs because the cells in the optic nerve die.
Four mutations have been identified at a gene encoding a subunit of NADH dehydrogenase which disrupt normal oxidative phosphorylation. MT-ND1, MT-ND4, MT-ND4L or MT-ND6
Average age of vision loss is 27 and affects predominantly young adult males
What is Kearns-Sayre syndrome (KSS) and what are the symptoms?
Kearns-Sayre syndrome (KSS) is a rare neuromuscular disorder with onset usually before the age of 20 years. Deletions of mtDNA result in impairment of oxidative phosphorylation and a decrease in cellular energy production. All steps of oxidative phosphorylation are affected.
SYMPTOMS:
- loss of vision
- hearing loss
- heart conditions
- muscle weakness
- deafness
- kidney problems
- deterioration of cognitive function (dementia)
- short stature
- diabetes mellitus
How is mitochondria linked with ageing?
Accumulation of SPORADIC MUTATIONS in mtDNA leads to an increased prevalence of defective mitochondria over a lifetime -> Increased levels of DNA damage leads to ageing
What is Parkinson’s disease and what are the symptoms?
Parkinson’s disease is a brain disorder that causes unintended or uncontrollable movements, such as shaking, stiffness, and difficulty with balance and coordination. It is caused by certain neurons that gradually break down or die.
CAUSES OF SYMPTOMS:
Symptoms due to a loss of neurons that produce a chemical messenger in the brain called dopamine -> Dopamine levels decrease -> Abnormal brain activity
RISK FACTORS:
- Age
- Heredity
- Exposure to toxins
SYMPTOMS:
- Thinking difficulties
- Swallowing problems
- Chewing and eating problems
- Bladder problems
- Constipation
- Movement disorders
- Cognitive and behavioural disorders (Dementia, Depression & Hallucination)
- Sensory, sleep and emotional problems
What are the properties of Peroxisomes?
- Contain oxidases rather than hydrolases
- Destroy hydrogen peroxide
- Alcohol is detoxified by peroxisomes
- Break down toxins, alcohol and fatty acids
How do proteins enter the peroxisome?
Proteins do not need to unfold to enter the peroxisome
What are the different Peroxisome biogenesis disorders?
- Zellweger syndrome (most severe)
- Neonatal Adrenoleukodystrophy
- Infantile Refsum Disease (least severe)
What is Zellweger syndrome and what are the symptoms?
Zellweger syndrome is caused by mutations in any one of at least 12 genes but mutations in the PEX1 gene are the most common cause. It is an autosomal recessive disorder in which there is no cure; treatment is generally symptomatic and supportive. Signs and symptoms usually appear during the newborn period.
SYMPTOMS:
- poor muscle tone (hypotonia)
- poor feeding
- seizures
- hearing loss
- vision loss
- distinctive facial features
- skeletal abnormalities
