Two key concepts serve to underscore the significance of this research proposal: First, mitochondria generate messengers, such as H2O2 and nitric oxide ('NO), which are involved in the regulation of redox-sensitive cell signaling through the mitogen-activated protein kinase (MAPK; e.g., JNK) pathway. Second, mitochondria are the recipients of the effects of cytosolic signaling molecules, such as JNK, which is translocated to mitochondria under stress conditions and aging and elicits profound metabolic effects in the organelle through the activation of phosphorylation cascades. The interaction between these two processes is essential for the coordination of the cell functional responses and we hypothesize that impairment of this interaction or communication is critical for the development of the loss of function inherent in aging. Long-term goal - The long-term goal of the proposed studies is to elucidate the interactive role of redoxdependent mitochondria-cytosol interactions in the initiation and progression of the aging process. Hypothesis- The hypothesis to be tested is that impairment of mitochondria-cytosol interactions -constituted of mitochondrial H2O2 and 'NO, metabolites such as pyruvate, and MAPK signaling pathways- is critical for the development of the oxidative and nitrosative cellular damage and loss of function inherent in aging.
Specific Aims - The validty of the hypotheses will be tested through four specific aims, which incorporate studies on: : (1) JNK-mediated regulation of mitochondrial functions. (2) Downstream signaling effects of JNK in mitochondria. (3) Modulation of JNK-mediated changes of mitochondrial functions by aging and caloric restriction, and (4) JNK-signaling on mitochondria in a PC12 cell model. The first three specific aims will be carried out with mitochondria isolated from the brain of rats from different age groups, whereas the fourth specific aim is directed at assessing the mitochondrion / JNK interactions in a cellular setting under the control of metabolic-, redox-, and apoptotic stimuli. Significance - This research contributes to the elucidation of the processes involved in the metabolic network that controls cellular energy levels and the redox environment and its impairment during aging by assessing the regulatory mechanism that coordinate mitochondrial functions with the rest of the cell. These mechanisms play a critical role in the progression of the aging process and may precede or modulate age-related oxidative- and nitrosative damages.
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