CORE E: MAGNETIC RESONANCE & OPTICS SPECTROSCOPY ? PROJECT SUMMARY Core E provides state-of-the-art in vivo assessment of mitochondrial energetic and redox state. This is made possible by applying Magnetic Resonance (MRS) and Optical Spectroscopy (OS) methods to intact animals. Because the cell environment plays an important role in regulating mitochondrial function in vitro assays of both energetics and redox will not fully reflect the local environment and function of the intact tissue, cell and mitochondria. To that end, we will use new innovative tools to reveal cell and mitochondrial NAD redox states (NAD+ and NADH) in vivo in addition to established measures of cell energy status (ATP, PCr, ADP, pH). This breakthrough in measuring NAD redox states permits measurement of intrinsic factors that underlie mitochondrial inhibition that comes with age and its reversal with a targeted intervention. Changes in mitochondrial energetics and NAD redox status are key aspects of the hypothesized mechanisms underlying age-related dysfunction and reversal by SS-31 tested in all three PPG projects. Therefore, assessment of these properties is an important requirement of the three PPG Projects that are based on enhancing mitochondrial function in heart, skeletal muscle and vision. Here we apply our innovative multimodal (MR and optical) approaches in combination with physiological perturbations to measure key mitochondrial functional properties that change with age and are impacted by interventions. These measures provide ? for the first time in vivo ? the critical measures of mitochondrial function that are the gold-standard in vitro: mitochondrial O2 uptake and ATP synthesis, as well as mitochondrial capacity (ATPmax) and coupling efficiency (P/O). These measures are made non- invasively in rodent models in muscle and heart in vivo. Our preliminary studies demonstrate change in cell energy state, NAD redox states and reduced mitochondrial function in these organs with age. Most importantly, these same techniques are sensitive to detect the impact of interventions to reverse the cell energy state reductions and redox changes, as well as improve mitochondrial function in old tissues. We will use this approach in to assess in vivo cell energy status (ATP, PCr, ADP, pH) and NAD redox status (cell NADH, NAD+ and mitochondrial NADH) by measurement of new spectroscopic signatures (Aim 1) and to assess in vivo mitochondrial energetics by measurement of mitochondrial oxidation, phosphorylation and coupling in vivo (Aim 2).
Showing the most recent 10 out of 285 publications
