Because mitochondria have vital roles in cell metabolism and other functions, it is critical to maintain the quality of the mitochondrial population within cells. Mitophagy, the degradation of mitochondria via autophagy, is thought to be the major pathway for culling dysfunctional or damaged mitochondria. The best- studied mitophagy pathway involves Pink1 and Parkin, but questions remain about the physiological importance of this pathway. Mouse knockouts of Pink1 and Parkin show only subtle defects in basal mitochondrial function, inconsistent with a widespread defect in mitophagy. This observation suggests that there are alternative or redundant pathways for mitophagy. Our preliminary data indicate that Fis1, a protein previously thought to be involved in mitochondrial fission, is a major player in mitophagy, including mitophagy that is Pink1/Parkin-independent. Moreover, mice lacking Fis1 have severe physiological defects. Therefore, the study of Fis1 mutant mice may reveal the physiological functions of mitophagy. The long-term goals of this research project are to understand the molecular mechanism of Fis1-dependent mitophagy and the role of mitophagy in mouse development.
In Aim 1, we develop a functional assay to dissect the molecular mechanism underlying uniparental inheritance of mitochondria in mammals. Using this system, we will identify molecules involved in elimination of paternal mitochondria in the early mouse embryo.
In Aim 2, we develop a cellular system in which increased oxidative phosphorylation stimulates mitophagy. We will use this cellular system to understand the molecular mechanism of mitophagy, including the role of Fis1, the role of ubiquitination, and the recruitment of the autophagy adaptor p62.
In Aim 3, we utilize a Fis1 knockout mouse model to understand the physiological functions of mitophagy. We will study the role of Fis1 in male germ cell maturation, where loss of Fis1 results in increased mitochondrial and peroxisomal density. Taken together, these Aims will lead to a deep understanding of the in vivo roles of Fis1 and the role of mitophagy in mammalian physiology.

Public Health Relevance

Mitochondria are crucial organelles that generate energy for cells, but in many human diseases, they fail to function optimally. Our studies will reveal how the dynamic properties of mitochondria--consisting of fusion, fission, and degradation--regulate their function. This information can be used to improve mitochondrial function and alleviate disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM119388-03
Application #
9461092
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Maas, Stefan
Project Start
2016-04-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Zhang, Ting; Mishra, Prashant; Hay, Bruce A et al. (2017) Valosin-containing protein (VCP/p97) inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants. Elife 6:
Liu, Raymond; Chan, David C (2017) OPA1 and cardiolipin team up for mitochondrial fusion. Nat Cell Biol 19:760-762
Chen, Hsiuchen; Chan, David C (2017) Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells. Cell Metab 26:39-48
Shin, Chun-Shik; Mishra, Prashant; Watrous, Jeramie D et al. (2017) The glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility. Nat Commun 8:15074
Cao, Yu-Lu; Meng, Shuxia; Chen, Yang et al. (2017) MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion. Nature 542:372-376
Rojansky, Rebecca; Cha, Moon-Yong; Chan, David C (2016) Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1. Elife 5:
Cheng, Chun-Ting; Kuo, Ching-Ying; Ouyang, Ching et al. (2016) Metabolic Stress-Induced Phosphorylation of KAP1 Ser473 Blocks Mitochondrial Fusion in Breast Cancer Cells. Cancer Res 76:5006-18
Mishra, Prashant; Chan, David C (2016) Metabolic regulation of mitochondrial dynamics. J Cell Biol 212:379-87