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

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

Mitochondria function much more than energy factory Mitochondrial Function

 It takes about 3000 genes to make a mitochondrion, mtDNA encodes just 37 of 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

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

Mitochondrial Disease mtDNA and/or nuclear DNA mutation Mitochondrial dysfunction Mitochondrial-based diseases 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.

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

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

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

How do mitochondria involve in ?

In 1980s, young drug addicts reported with PD, due to a compound called MPTP in their heroin 海洛因 supply. Parkinson ’ s Disease 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 Ca 2 + 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.

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

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

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

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

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

Parkinson ’ s Disease Several PD associated mutant genes are identified

Parkinson ’ s Disease back