Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis

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ABSTRACT Defects of the mitochondria have been implicated in many diseases. Due to the diverse set of mitochondrial functions, many proteins must be imported into the organelle, properly folded, and assembled into large complexes with proper stoichiometry. Failure in any of these processes is disastrous, as unfolding, misfolding, or even improper numbers of proteins may cause loss of function of the organelle. Accordingly, several mitochondrial quality control mechanisms exist, which ensure homeostasis within the organelle. Many – if not all – of these quality control machineries have been shown to functionally decline during the aging process, making mitochondrial quality control an intriguing aspect in our understanding of aging. Over the last decade, we have discovered, using the genetically-tractable nematode C. elegans, that mitochondrial dysfunction in neurons, is capable of eliciting long-range effects of inducing the UPRmt in distal tissues, which has direct implications on organismal physiology. Further, work by our lab showed that inducing the activity of the positive regulator of UPRmt JMJD-1.2/PHF8 solely in neurons is capable of eliciting beneficial effects, including prolonged lifespan, that is mediated by systemic activation of the UPRmt. The capacity of neurons to communicate stress is not specific to UPRmt, as similar findings have been reported in non- autonomous communication of UPRER and the cytosolic heat-shock response (HSR). Moreover, while neurons have been at the center of scientific research in the field of neurobiology, we have recently identified glia as an important cell type mediating cell non-autonomous activation of physiological stress responses and lifespan. In particular, we identified astrocyte-like CEPsh glia to be sufficient in communicating long-range UPRER across the organism, similar to neurons. Therefore, we hypothesize that glial cells may be able to coordinate the activation of the UPRmt between tissues through a mechanism distinct to that of the UPRER. Our main hypothesis is that astrocyte-like glia can initiate the activation of UPRmt in distal tissues, which can directly impact organismal health. In this proposal, we outline our strategy to elucidate the interaction between glia and neurons, and their organismal effects on longevity and stress resistance. Understanding this communication, both on the physiological and molecular level, will not only map the regulatory and cellular changes associated with longevity, but will also shed light on novel functions that glia serve in the nervous system, bringing us closer to understanding the nervous system, and its critical role in regulating lifespan.