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~1,200 proteins metabolic crossroads apoptosis signaling disease aging Gerald Shadel, Departments of Pathology and Genetics 1.

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Presentation on theme: "~1,200 proteins metabolic crossroads apoptosis signaling disease aging Gerald Shadel, Departments of Pathology and Genetics 1."— Presentation transcript:

1 ~1,200 proteins metabolic crossroads apoptosis signaling disease aging Gerald Shadel, Departments of Pathology and Genetics 1

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4 Mitochondria are centralized hubs for innate antiviral signaling and type I interferon production MAVS Mitochondrial Antiviral Signaling aka, IPS1 CARDIF VISA 4

5 retrograde signaling anterograde signaling Nuclear-Mitochondrial Signaling 5

6 ROS mitochondrial OXPHOS system O2O2 - H2O2H2O2 OH Copyright 2001 Benjamin Cummings, an imprint of Addison Wesley Longman, Inc. DNA/RNA lipids proteins oxidative damage genetic mutation membrane dysfunction enzyme/signaling defects DISEASE AGING 6

7 Mitochondrial Stress Signaling Pathways 7

8 Reactive oxygen species signaling apoptosisAMPK PPARγInsulin signaling HIF1 JNK1 p53 NF-κB Hypoxia immunity TLR redox homeostasis TORC1 PGC-1α UCP2 Starvation stress resistance genomic stability mitochondria function stimulussensoroutcome 8

9 mtDNA 2 rRNAs (12S and 16S) ATPROS mitochondrial OXPHOS system ROS ATP 13 OXPHOS mRNAs 22 tRNAs mitochondrial ribosome 9

10 dual genetic origin of the OXPHOS system Schon, DiMauro and Hirano 2012 Nat Rev Genet 10

11 Inherited pathogenic mtDNA mutations “common” deletion ~300 identified so far affect every gene, but >50% in tRNA genes 11

12 Deafness 12

13 mtDNA exists usually at thousands of copies /cell and packaged into nucleoids 13

14 heteroplasmy vs. homoplasmy mitotic segregation/genetic drift maternal bottleneck threshold effects complex genotype versus phenotype relationships complexities of mitochondrial disease due to mtDNA 14

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16 during gametogenesis, embryogenesis or in adult dividing cell populations Mitotic segregation can lead to mtDNA genetic drift Threshold effect Some cell/tissue types may drift toward homoplasmy cell division normal/asymptomatic respiration 16

17 Yabuuchi et al BBA 1820:637 maternal bottleneck 17

18 Mitochondrial research society website maternal bottleneck Primordial Germ Cells 18

19 small number of templates in PGCs are used for amplification to generate oocytes There are also proposed mechanisms of purifying selection to eliminate most deleterious mutations 19

20 What about natural variation and “normal” levels of heteroplasmy? 20

21 some haplotypes have been linked to metabolic alterations and disease predisposition 21

22 oxidative damage, certain environmental exposures and mtDNA replication errors can cause somatic mtDNA mutations in normal individuals and as a function of age sporadic mutations (i.e. not in mother) can also occur during germline development or embryogenesis these can clonally expand in tissues and there are unique tissue-specific mechanisms at play that are not well understood (e.g. deletions in muscle) 22

23 homoplasmic mtDNA mutations in tumors 23

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25 What about carry over of small amounts of mutant mtDNA from original carrier mother? 25

26 26 Keys Points Mitochondria are multi-functional and tailored to meet the needs of specific cell types/tissues and can contribute to disease pathology by a variety of mechanisms in addition to defective energy metabolism mtDNA is maternally inherited and present usually at thousands of copies/cell which allows for natural and inherited heteroplasmic (i.e. mixed) states to exist The degree of heteroplasmy can drift dramatically during somatic cell division, germ cell development, embryogenesis, under disease states, and aging A high threshold for inherited pathogenic mtDNA mutations exists, thus small amounts of mutated mtDNA carried over during nuclear transfer may not be a major concern However, it remains unclear what effects might occur from mixed haplotypes or inherited pathogenic mutations interfacing with other heteroplasmic mutations simultaneously inherited or acquired with age


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