1 Mitochondrial homeostasis is required to maintain neuronal health and function, and its 2 dysregulation plays prominent roles in rendering specific neural systems vulnerable. Recently 3 we have found that the activation of the p38 mitogen-activated protein kinase (MAPK; the 4 mammalian p38? ortholog) and the CREB like transcription factor ATF-7-mediated innate 5 immune pathway in the intestine of C. elegans can protect its neurons from degeneration 6 induced by mitochondrial dysfunction. The neuroprotective effects of p38MAPK/ATF-7 7 immunity activated in the gut occurs through the enhancement of mitophagy, and 8 p38MAPK/ATF-7 activity in intestinal cells alone is sufficient to lower mitochondrial numbers, 9 not only in intestinal cells, but also in neurons. Moreover, preliminary data obtained in our lab 10 show that in C. elegans the peripheral increase in disease-related misfolded proteins can 11 disrupt innate immune signaling pathways. Our central hypothesis, therefore, is that 12 aging- and proteotoxicity-induced dysregulation of the immune system can disrupt 13 mitochondrial homeostasis in neurons initiating or aggravating neurodegeneration. 14 The objective of the proposed research is to determine how the p38MAPK/ATF-7-mediated 15 innate immune pathway activated in the gut in C. elegans affects mitochondrial homeostasis 16 in neurons. To do this, we will: 17 18 Aim 1: Examine the role of the innate immune response in the maintenance of neurons 19 upon Complex I dysfunction.
20 Aim 2 : Identify the immune mediators in the gut that affect neuronal health.
21 Aim 3 : Examine the role of peripheral proteotoxic antigens in disrupting immune signaling, 22 leading to the accumulation of dysfunctional neuronal mitochondria. 23 24 Our preliminary data show that the innate immune response modulates mitochondrial 25 homeostasis in a cell non-autonomous manner, and is in turn can be inhibited by specific 26 peripheral proteotoxic antigens. These studies therefore offer the novel possibility that 27 immunosenescence is responsible for the accumulation of dysfunctional mitochondria, and 28 could offer new insights into the role of proteotoxicity in the modulation of mitochondrial 29 homeostasis.
Mitochondrial homeostasis is required for maintenance of neuronal health and function. We have discovered that the activation of the innate immune response in intestinal cells of C. elegans can modulate mitochondrial homeostasis in neurons. We propose to understand how this occurs and how the disruption of innate immunity in peripheral tissue, known to occur during aging, may impact mitochondrial homeostasis in neurons and mediate neurodegeneration.
