Mitochondria are central to ischemia-reperfusion (IR) injury and protection. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway that responds to mitochondrial dysfunction and proteotoxic stress. Our preliminary data suggests that the UPRmt protects against IR injury, consistent with up-regulation of mitochondrial chaperone genes, ROS detoxification machinery, and glycolytic capacity. In the genetic model organism C. elegans, the UPRmt's central mechanism of action has recently been described: mitochondrial proteotoxic stress regulates the matrix import and subsequent degradation of ATFS-1, a bZip transcription factor with dual targeting motifs. Under conditions of mild proteotoxic stress, matrix import is prevented through an ABC transport protein, HAF-1, acting in an undefined manner to suppress TIM/TOM activity. ATFS-1 instead traffics to the nucleus and activates a pro-survival repertoire of genes. Nuclear trafficking is both necessary and sufficient for protection, suggesting that the import of ATFS-1 into mitochondria provides a uniquely specific focal point for eliciting adaptation. This proposal aims to identify mechanisms through which the UPRmt protects C. elegans and to translate these findings to a mammalian cardiac model. Our approach will include defining mechanistic crosstalk with other signaling pathways that are also protective and will result in the identification of functional orthologs tha perform similarly in mammals as ATFS-1 and HAF-1.

Public Health Relevance

There are striking similarities in how stress is dealt with in the genetic model organism C. elegans and in mammals, including their response to ischemia (low oxygen). Recently, a novel signaling pathway has been identified in C. elegans that senses stress in the energy producing organelles of the cell (the mitochondria) and communicates that stress to the nucleus, where adaptive changes are initiated. Our focus is to dissect the role of these various signaling proteins in integrating the mitochondrial stress response to ischemia, in both C. elegans and mice. The results of this research are likely to be broadly relevant, as the ability of mitochondria to adapt to stress is central to cell viability in a variety of different physiologic and disease states.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL127891-01
Application #
8907809
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wong, Renee P
Project Start
2015-04-01
Project End
2019-02-28
Budget Start
2015-04-01
Budget End
2016-02-29
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Rochester
Department
Anesthesiology
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Nadtochiy, Sergiy M; Wang, Yves T; Nehrke, Keith et al. (2018) Cardioprotection by nicotinamide mononucleotide (NMN): Involvement of glycolysis and acidic pH. J Mol Cell Cardiol 121:155-162
Smith, Charles Owen; Nehrke, Keith; Brookes, Paul S (2017) The Slo(w) path to identifying the mitochondrial channels responsible for ischemic protection. Biochem J 474:2067-2094
Brookes, Paul S; Taegtmeyer, Heinrich (2017) Metabolism: A Direct Link Between Cardiac Structure and Function. Circulation 136:2158-2161
Nadtochiy, Sergiy M; Wang, Yves T; Zhang, Jimmy et al. (2017) Potential mechanisms linking SIRT activity and hypoxic 2-hydroxyglutarate generation: no role for direct enzyme (de)acetylation. Biochem J 474:2829-2839
Fiorese, Christopher J; Haynes, Cole M (2017) Integrating the UPRmt into the mitochondrial maintenance network. Crit Rev Biochem Mol Biol 52:304-313
Deng, Pan; Haynes, Cole M (2017) Mitochondrial dysfunction in cancer: Potential roles of ATF5 and the mitochondrial UPR. Semin Cancer Biol 47:43-49
Nadtochiy, Sergiy M; Schafer, Xenia; Fu, Dragony et al. (2016) Acidic pH Is a Metabolic Switch for 2-Hydroxyglutarate Generation and Signaling. J Biol Chem 291:20188-97
Brand, Martin D; Goncalves, Renata L S; Orr, Adam L et al. (2016) Suppressors of Superoxide-H2O2 Production at Site IQ of Mitochondrial Complex I Protect against Stem Cell Hyperplasia and Ischemia-Reperfusion Injury. Cell Metab 24:582-592
Peña, Salvador; Sherman, Teresa; Brookes, Paul S et al. (2016) The Mitochondrial Unfolded Protein Response Protects against Anoxia in Caenorhabditis elegans. PLoS One 11:e0159989
Nehrke, Keith (2016) H(OH), H(OH), H(OH): a holiday perspective. Focus on ""Mouse Slc4a11 expressed in Xenopus oocytes is an ideally selective H+/OH- conductance pathway that is stimulated by rises in intracellular and extracellular pH"". Am J Physiol Cell Physiol 311:C942-C944

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