Mitochondral disorders?

Question 1

Mitochondria?

Answer 1

ATP production

apoptosis (ROS)- glutathione, catalase, superoxide dismutase

Question 2

Clinical presentation of mitochondrial disorder?

Answer 2

on/off presentation

work in spurts, get lethargic

Question 3

Diagnose mito disorders?

Answer 3

Metabolic testing: blood, urine, CSF

muscle testing: liver tissue respiromtry, muscle pathology, OXPHOSEnzymology, protein chemistry, CoQ10 levels

genetic testing: mt DNA, nuclear DNA

Question 4

inheritance of mito disorder?

Answer 4

mothers to all children

vary degree of affect, none, mild, mod, severe symptoms

Question 5

why mito have high mutation rate?

Answer 5

lack histones
lack proper DNA repair enzymes
ROS

Question 6

Electron transfer chain is decreased from mito problems and causes?

Answer 6

pyruvate and fatty acids accumulate
lactate acidosis
accumulate triglycerides
ATP synthesis decrease

Question 7

ATP synth decreases leads to?

Answer 7

muscle weakness and exercise intolerance
formation of ragged red fibers (RRF)
due to increased mitochondrial proliferation

Question 8

Leber’s hereditary optic neuropathy (LHON)?

Answer 8

point mutations in complex I
-ND1, ND4, ND6
patients present with loss of vision in young adults caused by death of the optic nerve
muscle biopsy is normal
-no ragged red fibers

Question 9

Leigh’s Syndrome MILS?

Answer 9

mutations in ATPase
most severe clinical symptoms in 1-2 yrs
developmental delay, hypotonia, ataxia, spasticity, and respiratory defects

Question 10

Myoclonus epilepsy with ragged red fibers? MERRF

Answer 10

myoclonus, seizures cerebellar ataxia, myopathy
onset in childhood or adult life
muscles have RRF and are cytochrome oxidase deficient
most frequent mutations occur in the lysine tRNA gene

Question 11

Parkinson’s disease?

Answer 11

bradykinesia, rigidity, and tumor
degredation of dopaminergic neurons
-primarily substantia nigra pars compacta

Question 12

Formation of dopamine?

Answer 12

Tyrosine- L-dopa - dopamine

stored in vesicles in the presynaptic cleft
released and binds to metabotropic/ G protein coupled receptors

Question 13

2 enzymes in liver responsible for liver reuptake of dopamine?

Answer 13

MAO and COMT

Question 14

Mitochondrial dysfunction leads to parkinson’s?

Answer 14

mitochondrial problems leads to neuronal death

Question 15

Pathogenesis of mito parkinsons?

Answer 15

oxidative stress

• dopamine oxidation H2O2 and ROS
• reason SNC most severe damage

cell death might result from
-increased dopamine turnover, a deficiency of glutathione, increase in reactive iron, greater production of ROS due to complex I def

Question 16

Free radical theory?

Answer 16

reduction in complex I activity in SNc of PD patients
results in defect within the mitochondrial genome
show a selective decrease in Glutathione (result of lewy bodies)

Question 17

Evidence of OX damage in parkinsons disease patients?

Answer 17

lipid peroxidation found in SNc but not cerebellum of PD patients
protein carbonyls increased
decrease in GSH in SNc in PD (impair H2O2 clearance via GSH peroxidase)
SNc dopaminergic neurons are rich in glutamate receptors
increase in intracellular Ca activates nitric oxide synthase to form NO

Question 18

NO plus superoxide forms?

Answer 18

peroxynitrite (ONOO) and hydroxy radical (OH)

Question 19

NO causes damage?

Answer 19

damages electron transport

no GSH to prevent in Snc

Question 20

Rotenone?

Answer 20

pesticide, complex I inhibitor, increase free radical production