Mitochondria are dynamic membrane organelles that undergo division and fusion. The balance between these opposing activities plays a critical role in controlling mitochondrial structure and function. Mitochondrial division and fusion are mediated by conserved dynamin-related GTPases including Drp1 for division and Opa1 for fusion. Inhibition of mitochondrial division enlarges mitochondria due to ongoing fusion while inhibition of fusion fragments mitochondria. Abnormalities in mitochondrial division and fusion are associated with many neurodegenerative diseases such as autosomal dominant optic atrophy, Charcot-Marie- Tooth neuropathy, Alzheimer's disease, Huntington's disease, and Parkinson's disease. Understanding the pathogenesis of these diseases requires a deeper knowledge of the physiological functions of mitochondrial dynamics. In this proposed research, we will determine how altered mitochondrial dynamics causes neurodegeneration. Specifically, we will test two untested hypotheses. The first hypothesis states that mitochondrial dynamics directly regulates mitochondrial functions. In this model, mitochondria must continuously divide and fuse to maintain their functions for survival of neurons. The second hypothesis states that normal mitochondrial structures, but not dynamics per se, are critical in neurons. In this second model, mitochondrial division and fusion are dispensable if mitochondria can maintain their structure independent of mitochondrial dynamics. To attack this problem, we have developed a straightforward approach by introducing mitochondrial stasis in postmitotic neurons in mice. In these animal animals, mitochondrial division and fusion can be individually or simultaneously inhibited using Cre/loxP-mediated knockout for Drp1 and Opa1. We have shown that neurons lacking both Drp1 and Opa1 restore normal mitochondrial morphology, allowing us to block mitochondrial dynamics without affecting mitochondrial structures and clearly distinguish these two hypotheses described above. Therefore, this study will provide novel insight into the pathogenesis of many familial and sporadic neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS084154-01
Application #
8568892
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (91))
Program Officer
Gwinn, Katrina
Project Start
2013-05-15
Project End
2015-04-30
Budget Start
2013-05-15
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$202,500
Indirect Cost
$77,500
Name
Johns Hopkins University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Adachi, Yoshihiro; Itoh, Kie; Yamada, Tatsuya et al. (2016) Coincident Phosphatidic Acid Interaction Restrains Drp1 in Mitochondrial Division. Mol Cell 63:1034-43
Roy, Madhuparna; Itoh, Kie; Iijima, Miho et al. (2016) Parkin suppresses Drp1-independent mitochondrial division. Biochem Biophys Res Commun 475:283-8
Yang, Jr-Ming; Nguyen, Hoai-Nghia; Sesaki, Hiromi et al. (2015) Engineering PTEN function: membrane association and activity. Methods 77-78:119-24
Nguyen, H-N; Yang Jr, J-M; Rahdar, M et al. (2015) A new class of cancer-associated PTEN mutations defined by membrane translocation defects. Oncogene 34:3737-43
Roy, Madhuparna; Kageyama, Yusuke; Iijima, Miho et al. (2015) PARK2/Parkin becomes critical when DNM1L/Drp1 is absent. Autophagy 11:573-4
Shields, L Y; Kim, H; Zhu, L et al. (2015) Dynamin-related protein 1 is required for normal mitochondrial bioenergetic and synaptic function in CA1 hippocampal neurons. Cell Death Dis 6:e1725
Roy, Madhuparna; Reddy, P Hemachandra; Iijima, Miho et al. (2015) Mitochondrial division and fusion in metabolism. Curr Opin Cell Biol 33:111-8
Sesaki, Hiromi; Adachi, Yoshihiro; Kageyama, Yusuke et al. (2014) In vivo functions of Drp1: lessons learned from yeast genetics and mouse knockouts. Biochim Biophys Acta 1842:1179-85
Nguyen, H N; Afkari, Y; Senoo, H et al. (2014) Mechanism of human PTEN localization revealed by heterologous expression in Dictyostelium. Oncogene 33:5688-96
Kageyama, Yusuke; Hoshijima, Masahiko; Seo, Kinya et al. (2014) Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain. EMBO J 33:2798-813

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