Diseases that Result from Abnormal Mitochondrial Function

1. Diseases that Result from Abnormal Mitochondrial Function Lu Qiping 1070800106 April 15, 2011

2. Mitochondrial Function • Essential organelle in eukaryotic cells • Energy factory: oxidize fat, protein, carbohydrate generate ATP run activities • a glucose36 ATPs

3. Mitochondrial Function Mitochondria function much more than energy factory

4. Mitochondrial Function • It takes about 3000 genes to make a mitochondrion, mtDNA encodes just 37of these genes, nuclear DNA encodes the remaining genes. • 3% of the genes are allocated for making ATP, • More than 95% are involved with other functions. • Mitochondria are involved in • energy metabolism • calcium homeostasis稳态 • lipid, cholesterol, heme亚铁血红素 synthesis • Apoptosis细胞凋亡

5. Mitochondrial Function Given its fundamental role in the human body, defects of mitochondrial function can have disastrous consequences.

6. Mitochondrial Disease Mitochondrial diseases are the result of either inherited遗传的 or spontaneous自发的mutations in mtDNA or nDNA which lead to altered functions of the proteins or RNA molecules in mitochondria. mtDNA and/or nuclear DNA mutation Mitochondrial dysfunction Mitochondrial-based diseases

7. Mitochondrial Disease Neurodegenerative disease 神经退行性疾病

8. Neurodegenerative Disease • Characterized by the progressive death of neurons. • Results in • memory loss • movement problems • Behavioral problems • Cognitive认知 deficits • emotional alterations

9. Parkinson’s Disease • Named after English doctor James Parkinson • Affects 1-2% of individualsover 60 years old • Motor syndrome • Akinesia失去活动能力 • Rigidity僵硬 • Tremor震颤 • imbalance

10. Parkinson’s Disease PD is a degenerative disorder of the central nervous system. It results from the death of dopamine neurons多巴胺神经元in the substantia nigra（SN）黑质 of midbrain. Dopamine is a neurotransmitter神经递质 that transmit impulses across the synapses突触间隙.

11. Parkinson’s Disease How do mitochondria involve in ?

12. Parkinson’s Disease In 1980s, young drug addicts reported with PD, due to a compound called MPTP in their heroin海洛因 supply. MPTP is metabolized in the brain into MPP+. MPP+ selectively enters dopamine neurons, blocks oxidative phosphorylation氧化磷酸化 by inhibiting mitochondrial complex I, results in increased oxidative stress, intracellular Ca2+ levels and excitotoxicity兴奋毒性, and decreased energy production. leading to the death of nerve cells in SN. Then, the dopamine neurons from SN of PD patients were studied: The complex I activity decreased remarkably and selectively.

13. Parkinson’s Disease Dopamine neurons are sensitive to mitochondrial dysfunction. What is the molecular mechanism ?

14. Parkinson’s Disease • Risk Factors: toxin, genetic mutation, old age. • Brief Mechanism: Mitophagy PD genes

15. Parkinson’s Disease • Risk Factors: toxin, genetic mutation, old age. • Brief Mechanism: Mitophagy PD genes

16. Perspective • Is there a common pathway • for the PD associated mutation genes? • Some hypothesis were proposed, however, no clear mechanisms were proved. The field of mitochondrial disease has progressed rapidly, but much remains to be learnt about molecularmechanisms in pathogenesis and about how we might treat patients with these disorders.

17. Thank you!

18. Parkinson’s Disease back Mitochondrial autophage. Protect cells from damaged mitochondria. Related proteins: PINK1 & PARKIN Mitophagy Lysosome

19. Parkinson’s Disease Several PD associated mutant genes are identified

20. Parkinson’s Disease back