Ongoing Research Projects

Dagda Lab

The video shows movement of mitochondria (green) and lysosomes (red) in dendrites of neurons. Ruben Dagda, Monica Rice, Paulo Pires and Scott Early were involved in producing this video.

Persistent dephosphorylation by mitochondrial localized protein phosphatases (protein phosphatase 2A) accelerates neurodegeneration, fragments mitochondria and impairs mitochondrial function. On the other hand, mitochondrial serine/threonine kinases PTEN induced kinase 1 (PINK1) and PKA confer neuroprotection and regulate overlapping mitochondrial functions. Neurons rely on functionally efficient mitochondria to power critical neuronal functions. Given that impaired mitochondrial turnover and dysfunction underlie the etiology of many neurodegenerative diseases, understanding how reversible phosphorylation at the mitochondria regulates mitochondrial function, and turnover will lay the basic groundwork for developing future "mitoprotective" therapies for reversing mitochondrial dysfunction and neurodegeneration. Preliminary data shows that PINK1 and mitochondrial PKA converge at the outer mitochondrial membrane (OMM) to regulate overlapping mitochondrial functions. At the postsynaptic compartment, preliminary data shows that both ser/thr kinases remodel dendritic arbors in developing neurons and regulate mitochondrial transport. First, we will examine how mitochondrial PKA and PINK1 interact at the mitochondria and at the neurites to regulate mitochondrial function, dendritic morphology and survival.

A second area of interest it to determine how mitochondrial turnover (mitophagy) is regulated by reversible phosphorylation. We will examine whether mitochondrial ser/thr kinases and phosphatases regulate mitochondrial turnover by phosphorylating and destabilizing protein-protein interactions of specific components of the "mitophagosome" complex at the OMM by applying proteomics and biochemical approaches in neurons. A final goal this project is to synthesize functionalized nanoreagents that can activate prosurvival signaling pathways at the mitochondria as mitochondrial therapy for reversing mitochondrial pathology induced by neurodegenerative diseases and by normal brain aging.