Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response

Abstract

Neurons have a central role in the systemic coordination of mitochondrial unfolded protein response (UPRmt) and the cell non-autonomous modulation of longevity. However, the mechanism by which the nervous system senses mitochondrial stress and communicates to the distal tissues to induce UPRmt remains unclear. Here we employ the tissue-specific CRISPR-Cas9 approach to disrupt mitochondrial function only in the nervous system of Caenorhabditis elegans, and reveal a cell non-autonomous induction of UPRmt in peripheral cells. We further show that a neural sub-circuit composed of three types of sensory neurons, and one interneuron is required for sensing and transducing neuronal mitochondrial stress. In addition, neuropeptide FLP-2 functions in this neural sub-circuit to signal the non-autonomous UPRmt. Taken together, our results suggest a neuropeptide coordination of mitochondrial stress response in the nervous system.

The mitochondrial unfolded protein response: Signaling from the powerhouse

“…Flp-2 transcript levels are enhanced in the presence of neuronal mitochondrial stress, consistent with a role in the cell non-autonomous regulation of the UPR mt . Indeed, overexpression of FLP-2 specifically activates the UPR mt and not other stress responses (27). Together, these studies suggest that neuronal control of the UPR mt in distal tissues is likely complex involving the secretion of multiple mitokine signals.…”

“…In the first study, the bioamine neurotransmitter serotonin was found to be required for activation of the UPR mt in the intestine as a consequence of mitochondrial protein aggregate accumulation in neurons (26). In a parallel study, interneuron secretion of the neuropeptide FLP-2 was necessary and sufficient for UPR mt activation in the intestine (27). Flp-2 transcript levels are enhanced in the presence of neuronal mitochondrial stress, consistent with a role in the cell non-autonomous regulation of the UPR mt .…”

The mitokine quest(ion)

“…While the relationship between FLP-2 and serotonin has not been examined, it is safe to assume that a number of interesting signaling events occur downstream of both molecules to affect the regulation of intestinal ATFS-1. Both studies indicate that ATFS-1 is essential in both the sensing neurons as well as in the intestinal cells for non-autonomous UPR mt activa-tion [3,5]. In neurons where mitochondria are perturbed directly, ATFS-1 activation is likely achieved by impaired mitochondrial protein import effi ciency.…”

“…However, those cell types and the receptor remain to be identified as expression of FLP-2 specifically by intestinal cells was not sufficient to activate the intestinal UPR mt [5]. Thus, FLP-2 likely functions elsewhere.…”

“…Using an impressive variety of cell type-specific CRISPR techniques, Shao and colleagues now demonstrate that multiple forms mitochondrial dysfunction (impairment of a mitochondrial protease, the respiratory chain, localized reactive oxygen species or depletion of inner membrane potential) administered specifically within neurons are capable of stimulating UPR mt activation in neurons [5]. Interestingly, all of the neuronal mitochondrial stresses other than membrane potential depletion caused subsequent intestinal cell UPR mt activation suggesting that not all forms of mitochondrial dysfunction activate the non-autonomous UPR mt .…”