Membrane Protein Quality Control, Mitochondria, Cancer, and Neurodegenerative Diseases

Mitochondria are endosymbiotic organelles that serve as key hubs for apoptotic regulation, metabolism, and cellular signaling in eukaryotic cells. Over 99% of the ~1500 mitochondrial proteins are encoded in the nuclear genome and depend on specific targeting signals to direct them from the site of synthesis in the cytosol to the appropriate subcompartment. Proper mitochondrial function depends on a process called proteostasis, which ensures that functional proteins are in the right location at the right concentration at the right time. Membrane proteins present unique challenges to the proteostasis network as they must be targeted to the correct membrane and overcome substantial thermodynamic barriers to enter and exit the lipid bilayer, all while avoiding the formation of potentially toxic aggregates in the cytosol. Failures in proteostasis are associated with many neurodegenerative diseases, whereas cancer cells are acutely dependent on robust proteostasis networks to counteract the protein imbalances caused by aneuploidy and dysregulated protein synthesis.

Despite the clear physiological importance, our mechanistic understanding of mitochondrial proteostasis is remarkably incomplete. My lab addresses this critical knowledge gap by focusing on three questions: (1) How do quality control factors discriminate between bona fide substrates and functional proteins in a complex cellular environment, such as the lipid bilayer; (2) once a substrate is recognized, what are the downstream steps that lead to resolution of proteotoxic stress; and (3) how can we leverage the resulting mechanistic insights to develop therapeutic interventions in cancer and neurodegenerative disease? We address these questions using a combination of biochemistry, biophysics, and structural, molecular, and cell biology.

Education

• Education: Ph.D. 2013, MIT
  
  

Postdoctoral Training

• Postdoctoral Training: 2018, University of Chicago

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Lab location:
Department of Cell Biology
3500 Terrace Street
S326 Biomedical Science Tower
Pittsburgh, PA 15261

Office: 412-648-7482
Lab: 412-648-9713

Email: Wohlever@pitt.edu

Website link: https://wohleverlab.wordpress.com/