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Reference

Thank you for attention!

1. Genetic Home Reference http://ghr.nlm.nih.gov/condition/leigh-syndrome

2. National Institute for Neurological Disorders and Stroke http://www.ninds.nih.gov/disorders/leighsdisease/leighsdisease.htm

3. Mitochondria Research Society http://www.mitoresearch.org/treatmentdisease.html

4. United Mitochondrial Disease Foundation http://www.umdf.org/site/pp.aspx?c=8qKOJ0MvF7LUG&b=7934629

5. Online Mendelian Inheritance in Man http://www.omim.org/entry/185620

Consequences of Complex IV deficiency

Outline

less mitochondrial energy production

electrons are not transferred to oxygen to produce water

4 out of 10 protons per electron pair are not pumped to mitochondrial matrix

increased reliance on glycolysis

build-up of free radicals (reactive oxygen species)

reduced proton gradient is established

1. Description of the disease

- science of the disease

- statistics

- causes

2. Complex IV deficiency

- ETC overview

- structure and function of Complex IV

- genetics of the deficiency

3. Treatment

less ATP production

damage of DNA, cell membranes & mtDNA due to oxidation by ROS

toxic metabolite build-up (lactic acid)

Treatment

  • No cure for Leigh's disease is available
  • Medical treatments to manage and relieve symptoms

Treating lactic acid build-up

Treating free radicals build-up

  • Low-carbohydrate diet
  • Dichloroacetate & Carnitine

Treating energy loss

  • tissues that need large amounts of energy
  • muscle weakness, cardiomyopathy, renal problems, droopy eyelids, cognitive problems and general fatigue
  • symmetrical lesions in the basal ganglia

lack of energy

  • Antioxidants, usually in the form of vitamins or cofactors, help neutralize free radicals
  • Vitamin E, coenzyme Q10, lipoic acid, vitamin C, vitamin K and riboflavin (B2)
  • Researchers:
  • "It probably won't hurt, but it probably won't do much good. It's a bit like emptying the ocean with a teaspoon."

inhibition of pyruvate dehydrogenase kinase

stimulation of pyruvate dehydrogenase

Binds to extra metabolites and escorts them out of the cells and into the kidneys for excretion in the urine

High-fat, low-carbohydrate diet

shifting the metabolism of pyruvate from fermentation towards oxidation in the mitochondria

Cause of the deficiency

SURF1 protein

Complex IV

SURF1 gene - in nuclear DNA - SURF1 protein - helps assemble Complex IV

mutation

Science of Leigh's syndrome

  • Abnormally short
  • Broken down in cells

Reduced formation of Complexes IV

Jacob Nicholas Wright: 12/06/10 - 04/20/12 Leigh's Disease

Impaired mitochondrial energy production

Leigh's syndrome

  • a severe neurological disorder
  • progressive loss of mental and movement abilities
  • in the first year of life

Complex IV

Caleb Jacobs

April 29, 2010

First signs: vomiting, diarrhea, and difficulty swallowing (dysphagia)

Inability to grow and gain weight at the expected rate

September 28, 2011

Lesions of the medulla. Image provided by Dr. Maie Herrick.

  • weak muscle tone (hypotonia)
  • involuntary muscle contractions (dystonia)
  • problems with movement and balance (ataxia)

acute respiratory failure

Severe breathing problems

May of 2012

Complex IV

Hypertrophic cardiomyopathy (a thickening of the heart muscle)

the heart to work harder to pump blood

Lactate can build up in the body (in the blood, cerebrospinal fluid, or urine)

19.09.2012

The copper sites function as 1 electron carriers cycling between the cuprous state Cu+ and the cupric state Cu2+.

Assel Mustakhan

Akmaral Urazbayeva

Aisha Yesbolatova

Summary reaction:

4 Fe2+-cytochrome c + O2 + 4H+ 4 Fe3+-cytochrome c + 2 H2O

Complex IV

How common is Leigh syndrome?

  • integral membrane protein - 14 subunits (in mammals)
  • 2 hemes: cytochrome a & cytochrome a
  • 2 copper centers: Cu & Cu

3

  • very rare disease
  • at least 1 in 40,000 newborns is affected
  • more common in certain populations (1 in 2,000 newborns in the Saguenay Lac-Saint-Jean region of Quebec, Canada)

B

A

Cytochrome c oxidase

can be caused by mutations in one of over 30 different genes

75-80% - mutations in the nuclear DNA

disruption of Complex IV in ETC

(cytochrome c oxidase)

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