2. Mitochondria,Role &Function GR.Zamani, Pediatric Neurologist Children’s Medical Center,Tums,Dec.2013

3. Mitochondria Organelles present in almost all human cells Produce bulk of energy for all cellular functions ATP production via the electron transport chain Over 1000 proteins localized to mitochondria 13 are mitochondrial-encoded Remainder are nuclear-encoded

4. Defect in mitochondrial function is the cause for numerous inherited diseases Problems Associated with Mitochondrial Cytopathies, Brain Developmental delays, mental retardation, dementia, seizures, neuro-psychiatric disturbances, atypical cerebral palsy, migraines, strokes Nerves Weakness (which may be intermittent), neuropathic pain, absent reflexes Gastrointestinal problem (gastroesophogeal reflux, delayed gastric emptying, constipation, pseudo-obstruction) Muscles Weakness, hypotonia, cramping, muscle pain Kidneys Proximal renal tubular wasting resulting in loss of protein, magnesium, phosphorous, calcium and other electrolytes Heart Cardiac conduction defects (heart blocks), cardiomyopathy Liver Hypoglycemia (low blood sugar), liver failure Eyes Visual loss and blindness Ears Hearing loss and deafness Pancreas Diabetes and exocrine pancreatic failure (inability to make digestive enzymes) Systemic Failure to gain weight, short stature, fatigue, respiratory problems including intermittent air hunger

5. Mitochondria are responsible for producing most of the energy that's needed for our cells to function. In fact, they are motor house of the cell providing energy. A mitochondrial disease can shut down some or all the mitochondria in the cells, cutting off this essential energy supply. Mitochondria Diseases

6. Mitochondria Mitochondria are intracellular organelles found in almost all human cells, responsible for aerobic metabolism through oxidative phosphorylation, which leads to energy production as (ATP).Each human cell contains on average hundreds to thousands of mitochondria. The exception is mature RBCs, which rely exclusively on anaerobic metabolism and contain no mitochondria. Over 1000 proteins localized to mitochondria 13 are mitochondrial-encoded Remainder are nuclear-encoded

7. Causes of mitochondrial disease Mt.DNA (Nuclear DNA Mutation Mitochondria DNA inheritance Combination of mt.DNA and n.DNA defects Random occurrences Mitochondria are under the dual control of mitochondrial DNA and nuclear DNA.

9. Structure Mitochondria have a double membrane structure There is a single outer membrane and a folded inner membrane 9

10. Mitochondria are organized into 4 distinct compartments Outer membrane: Perforated with large channels (porins) that allow entry of molecules < 5000 kD Enzymes involved in mitochondrial lipid synthesis

11. Outer membrane The outer mitochondrial membrane contains a variety of enzymes involved in diverse activities such as: elongation of fatty acids oxidation of epinephrine (adrenaline), and the degradation of tryptophan. 11

12. Intermembrane space: Enzymes that use newly- made ATP to phosphorylate other nucleotides Compartment into which H+ is pumped Mitochondria are organized into 4 distinct compartments

13. Inner membrane: Folded into christae to maximize surface area Proteins that carry out redox reactions of the electron transport chain Proteins that synthesize ATP Transport proteins that move molecules into and out of the matrix

14. Inner membrane The inner membrane contains proteins with three types of functions : those that carry out the oxidation reactions of the respiratory chain composed of five enzyme complexes(complex I,II,III,IV,V) ATP synthesis, which makes ATP in the matrix specific transport proteins that regulate the passage of metabolites into and out of the matrix 14

15. Matrix: Internal space containing enzymes for Krebs cycle Contains mitochondrial DNA, special ribosomes, tRNAs, and enzymes required for gene expression Mitochondria are organized into 4 distinct compartments

16. Function Mitochondria are the site of most of the energy production in eukaryotic cells. They use complex molecules and oxygen to produce a high energy molecule know as ATP (Adenosine Triphosphate) process called aerobic respiration Energy production the mitochondria has been called the "powerhouse of the cell". Mitochondria are very abundant in cells that require lots of energy. 16

17. Mithochondrial function In addition to ATP generation through the respiratory chain, mitochondria perform multiple other metabolic functions, including pyruvate oxidation, the Krebs cycle, fatty acid oxidation, and amino acid metabolism. All of these tasks take place in the matrix.

18. Other functios of Mithocondria Although the primary many metabolic function of mitochondria is to convert organic materials into cellular energy in as ATP mitochondria play other important roles such as: Apoptosis-Programmed cell death Glutamate-mediated excitotoxic neuronal injury Cellular proliferation, Regulation of the cellular redox state,Heme synthesis and Steroid synthesis 18

19. . Although any abnormality in the oxidative pathways could be technically designated as a mitochondrial disorder, only defects in the respiratory chain are traditionally referred to as primary mitochondrial diseases

20. Thank You