Research Interests:

Scaffold proteins are critical components of signal transduction and integration. Scaffolds influence spatial and temporal aspects of signaling by promoting interactions among signaling components, such as kinases. Recent research has demonstrated that scaffolds located on the outer mitochondrial membrane can assemble signaling complexes that modulate metabolism, stress responsiveness, cell growth, and cell death. It is the mission of the Chambers lab to understand how these scaffolds and their constituents alter cellular biology in the contexts of aging and human disease.

Mitochondrial Signal Integration by Scaffold-based Complexes during Aging and Age-Related Disease:
As mammals age, there are alterations in cellular signaling that promote metabolic decline. The consequences of these changes are age-related phenotypes and the onset of age-related diseases (i.e. Parkinson’s disease). We have identified a shift in mitochondrial scaffold abundance both in aging and in Parkinson’s disease models. As age increases or as disease progresses, the level of AKAP1 decreases, while the concentration of Sab increases with age. These two scaffolds promote different signaling outcomes. AKAP1 coordinates proliferative signaling, while Sab promotes cell death signaling. These data suggest that as mammals age mitochondrial scaffold abundance changes to decrease mitochondrial function contributing to metabolic decline, oxidative stress, and finally cell death.

Regulation of Cancer Cell Metabolism and pH Tolerance by Mitochondrial Signaling Pathways:
Cancer cell use aerobic glycolysis to meet biosynthetic needs for rapid proliferation. A consequence of this metabolism is often increased lactate production and intracellular H+ concentration. To adapt to this change most cancer cells up-regulate lactate transporters MCT1 or MCT4. We have recently identified a regulable phosphorylation site on MCT1 that is modulated by mitochondrial-based signaling pathways. Inhibition of Sab-based mitochondrial signaling increases MCT1 phosphorylation and lactate efflux. These data indicate that mitochondria may influence lactate transport by a novel signaling pathways.

Selected recent publications:

1. Chambers, JW, et al. Selective Inhibition of Mitochondrial JNK Signaling Achieved Using Peptide Mimicry of the Sab Kinase Interacting Motif-1 (KIM1). ACS Chemical Biology. 6(8). (2011). 808-818.
2. Chambers, JW and LoGrasso, PV. Mitochondrial c-jun-N-Terminal Kinase (JNK) Signaling Initiates Physiological Changes Resulting in Amplification of Reactive Oxygen Species Generation. Journal of Biological Chemistry. 286(18). (2011). 16052-16062.
3. Chambers, JW, et al. Small Molecule c-jun-N- terminal Kinase (JNK) Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson’s Disease. ACS Chemical Neuroscience. 2(4). (2011). 198-206.