Research Projects

Mitochondrial ROS microdomains and neuronal ischemia

Research Funding: NIH R01 NS092558

Mitochondria are central mediators of cell death and are a main site of ROS production. ROS contribute to cellular damage in many pathologic processes, such as neurodegenerative diseases and stroke. However, antioxidant treatments have been ineffective in clinical trials for diseases associated with increased oxidative damage. These clinical trials may have failed since mild levels of ROS are required to maintain cellular homeostasis. Moreover, ROS are emerging as signaling molecules that are required for the efficacy of several types of protective interventions. Thus, like many other physiological challenges, specific details such as dose, timing, and local environment contribute to ROS outcomes.

This project melds the C. elegans genetic model system with novel optogenetic reagents to give us the ability to control ROS production with unprecedented precision. We aim to determine what factors make some ROS beneficial and other ROS toxic in the context of neuronal ischemic sensitivity and stress resistance. We will integrate our results with conserved stress response pathways, facilitating translation into a mammalian model system.                                                                              

Mitochondrial energy sensing and neuronal ischemia

Research Funding: R01 NS115906

Neuronal survival or death depends strongly on mitochondrial function and metabolic signaling following stroke. Ischemic stroke causes changes in mitochondrial function that, depending on severity or persistence, can result in either damage or protection. However, the mechanisms that regulate the balance between these outcomes are not fully understood, but likely depend on how, when and where mitochondrial function changes. As mitochondrial function and signaling are dependent on the mitochondrial membrane potential, our central hypothesis is that neuronal ischemic outcomes depend on the timing and degree of (de)polarization.

 We propose a novel approach that employs light to directly regulate mitochondrial protonmotive force to determine when, where, and how it alters the balance between damage and protection during ischemic stroke. Combined with the power of C. elegans genetics and epistasis, this approach will probe the molecular mechanisms that mediate mitochondrial signaling in hypoxic pathology. We anticipate that this approach will allow us to better understand how mitochondrial function regulates stroke outcomes.

Multimodal control of mitochondrial energetics to shape biological aging

Research Funding:  R56AG082916

The mitochondrial protonmotive force (PMF) is an electrochemical gradient across the inner mitochondrial membrane that powers ATP synthesis and other mitochondrial signaling. PMF is naturally variable under different situations, and can depend on nutrient status, cell or tissue type, and many other factors. Importantly, evidence suggests that PMF declines with age. This observation holds from yeast to mammalian tissues. However, it is still unclear whether this decline is a cause or a consequence of aging phenotypes. We show that PMF declines with age in C. elegans and human cells and that Dietary Restriction (DR), a well-characterized longevity intervention, prevents this loss. Furthermore, loss of PMF negates the effects of DR on C. elegans longevity, further suggesting that PMF is a fundamental regulator of biological aging. This proposal aims to test and fully characterize how PMF is a determinant of three different, but related, longevity paradigms: normative aging, DR, and hypoxia signaling. New insight into how the PMF specifically controls aging and longevity signaling will be an important investigation into the efficacy of targeting metabolism for protection against disease in humans. Understanding the fundamental parameters of metabolism and PMF in both worms and human cells will offer novel insights into what we already know, and will pave the way for discovering new mechanisms of longevity downstream of mitochondrial PMF.

Mitochondrial dysfunction and tau pathology in Alzheimer's disease (mPI: Dr. Gail Johnson)

Research Funding:  R21AG085324-01 

Alzheimer’s disease (AD) is the most common cause of dementia with no current interventions that halt or substantially slow disease progression. AD is a multifactorial disease characterized by impaired mitochondrial bioenergetics, oxidative stress, and tau pathology. These AD pathologies are interconnected, change over time, and correlate with neuronal dysfunction. Moreover, the hallmarks are dynamic and difficult to isolate experimentally, which makes assigning causation challenging and limits therapeutic development. This proposal uses novel optogenetic technology developed for hypoxic biology to address this gap and test if mitochondrial dysfunction and reactive oxygen species (ROS) production are causal for the progression of tau pathology. Our approach involves directly controlling mitochondrial function and ROS production using light, without interfering with metabolism or using irreversible toxins with off-target effects. Mitochondrial dysfunction and ROS production have long been associated with AD pathology however the cause-and-effect relationship is unclear. Our novel technology provides an approach to directly test the role of mitochondria in AD independent of confounding factors. Overall, these studies will begin to clearly define the role of mitochondria in the evolution of tau pathology and provide mechanistic insights into therapeutic opportunities to attenuate AD pathogenesis.