Mitochondrial Energy Sensing and Neuronal Function

Neurons integrate multiple inputs and coordinate a series of molecular events to drive cellular function. During neurotransmission, electrical depolarization at the pre-synaptic axon is transduced to chemical signals that affect post-synaptic dendrites. Neurons depend on mitochondrial function for survival. At the center of mitochondrial function is the protonmotive force (PMF), an electrochemical proton gradient that coordinates metabolic signaling and energetic responses. The PMF acts like a ‘bioenergetic battery’ and the stored electrical energy is used to uptake metabolites, make ATP, alter reactive oxygen species production, and buffer cellular calcium signaling. The PMF is dynamic and fluctuates in biology to drive cellular differentiation and autophagy, while the loss of PMF is associated with neurodegeneration and cell death. Maintaining PMF is required for neuronal function, and the neuronal architecture offer unique cellular environments. Distinct neuronal regions have unique biological constraints and mitochondrial energetic demands. Likewise, mitochondrial morphology and function are also specialized in a compartment-dependent manner. How neurons fuel cellular processes and how individual mitochondrial populations modulate energetics in each neuronal compartment remains poorly understood in part due to the lack of tools offering cell-specific and spatiotemporal control of the PMF. This R01 renewal addresses this gap in the field by leveraging discoveries from the previous funding period, where we developed a novel optogenetic approach to independently control, both spatially and temporally, the PMF in vivo. The neuronal cell membrane potential integrates and regulates numerous facets of neuronal signaling and health. Much like the neuronal membrane potential, we propose that the mitochondrial PMF acts as a central integrator to transduce signaling and power a wide array of cellular pathways and functions. We hypothesize that neuronal responses to mitochondrial energetics are highly dependent on the timing, duration, and location of the mitochondrial perturbation. Controlling the PMF has been a long-standing challenge in mitochondrial biology. Here, we propose to use light to increase or decrease the PMF in distinct neuronal compartments and dissect the effects on neuronal function. Accumulating evidence demonstrates that altering energy status has wide ranging effects on neuronal function. We will determine the spatiotemporal tenets defining mitochondrial PMF signaling across neuronal compartments and how these signals affect neuronal activity and in vivo behavior. Addressing the neuropathologic heterogeneity of mitochondrial function in neurons will advance the field and define novel, targeted approaches to guide therapeutic strategies targeting neurodegeneration.