Dev Cell—Tian Ye's team found that the GPCR signaling pathway coordinates the body's mitochondrial stress response in a pair of sensory neurons

The nervous system plays an important role
in sensing and coordinating the body's stress response.
When the mitochondria of nerve cells are damaged, by releasing secretion signals, it induces the mitochondrial unfolded protein response (UPR^mt) in the intestine, thereby coordinating the body's overall stress adaptation and anti-aging ability
。 GPCR (G Protein-Coupled Receptor), that is, G protein-coupled receptor, as the largest class of membrane protein receptor families and the most famous drug target molecule, plays a very key role in cell signal transduction
。 However, research on whether the GPCR signaling pathway is involved in mediating mitochondrial stress signaling communication in neuro-peripheral tissues and related physiological functions remains to be answered
.

On October 28, 2022, Tian Ye's research group from the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences published a long cover article online in the journal Developmental Cell The research paper "Two sensory neurons coordinate the systemic mitochondrial stress response via GPCR signaling in C.
elegans" discovered GPCR-Gαq The signaling pathway mediates neuron-gut cross-tissue mitochondrial stress response signal communication in a pair of sensory neurons in the head of the nematode by releasing neuropeptides, revealing the regulatory effect
of GPCR-Gαq signaling pathway on peripheral metabolism, protein homeostasis and immunity.

In order to explore the mechanism of cross-tissue mitochondrial stress signal communication, the research team used C.
elegans to establish a neuro-gut cross-tissue UPR^mt model for studying expression in the nerve cells of nematodes Wnt/EGL-20 ligand protein, which can induce the activation of UPR^mt in intestinal cells[1].

Through genetic screening, a G protein-coupled receptor, srz-75, was specifically involved in the signaling of cross-tissue UPR^mt without participating in the cross-tissue endoplasmic reticulum and cytoplasmic stress response
。

The researchers found by fluorescent labeling that SRZ-75 was expressed in a pair of neurons in
the head of the nematode.
Co-localized with marker proteins of nematode head neurons, SRZ-75 was found to be localized to sensory neurons ADL (amphid neurons with dual ciliated sensory endings
。 Further, the researchers drove SRZ-75 expression in srz-75 mutants through promoters specifically expressed by ADL, finding complementation in ADL neurons SRZ-75 is well qualified to rescue the UPR^mt phenotype (Figure 1).

These results show that: GPCR SRZ-75 in ADL neurons mediates neuronal-gut UPR^mt signaling communication
.

Figure 1 SRZ-75 is localized in ADL sensory neurons and mediates cross-tissue UPR^mt signaling communication

(Source: Liu, YL.
et al.
, Dev Cell, 2022).

In order to further explore the mechanism of GPCR SRZ-75-mediated activation of cross-tissue UPR^mt, the researchers used tissue-specific knockout and knockdown techniques to discover ADL neuronal-specific knockout/ Knockdown Gα protein Gαq inhibits nerve cell overexpression Wnt/EGL-20 and SRZ-75 overexpression induced intestinal cells Activation
of UPR mt.
Overexpressing functionally acquired form of Gαq in ADL neurons, persistent activation of Gαq signaling was found to induce UPR^mt activation in intestinal cells, This process requires the downstream effector of Gαq, Trio Rho Guanylate Exchange Factor (Figure 2).

These results illustrate that GPCR SRZ-75 in ADL neurons mediates cross-tissue UPR^mt activation
via the Gαq signaling pathway.

Figure 2 GPCR SRZ-75-Gαq signaling pathway in ADL neurons mediates cross-tissue UPR^mt signaling

(Source: Liu, YL.
et al.
, Dev Cell, 2022).

Sustained activation of ADL-Gαq signaling induces significant upregulation of neuropeptide signaling pathway genes, suggesting that SRZ-75-Gαq may mediate cross-tissue UPR^mt activation
through neuropeptide secretion.
Neuropeptides regulate a wide variety of physiological functions in the body, and their precursors are usually post-translational and cleaved by a series of enzymes to produce mature neuropeptides
.
EGL-3 is one of the main enzymes responsible for
neuropeptide processing.
Egl-3 knockdown in ADL neurons can inhibit nerve cell overexpression of Wnt/EGL-20 and ADL-Gαq activation-induced UPR^mt
。 Further, the researchers used tissue-specific knockdown techniques to perform small-scale screening of neuropeptides in ADL neurons and found that INS-14 and NLP-76 were involved in cross-tissue UPR^mt Activate
.
Interestingly, previous studies have found that the neurotransmitter serotonin, which is involved in cross-tissue UPR^mt signaling, is not involved in SRZ-75-Gαq-mediated transtissue in ADL neurons UPR^mt signaling suggests that mitochondrial stress in different neurons may regulate mitochondrial homeostasis in peripheral tissues through multiple mechanisms [1-3].

The above evidence suggests that the GPCR SRZ-75-Gαq signaling pathway in ADL neurons mediates neurointestinal UPR^mt activation by releasing neuropeptides
。

To demonstrate that ADL neurons play a key role in neuro-gut cross-tissue UPR^mt signaling, the researchers induced ADL neuron death through optical and genetic methods.
Activation of cross-tissue UPR^mt signals can be attenuated.

Subsequently, the GPCR/SRZ-75-Gαq signaling pathway is continuously activated in ADL neurons, which induces UPR^mt signaling activation in intestinal tissue, thereby enhancing the response of nematodes to pathogenic bacteria Resistance to PA14
.
At the same time, activation of the ADL-GPCR/SRZ-75-Gαq signaling pathway alleviates the accumulation in muscle tissue of α-synuclein aggregates that accompany aging, reduces fat content in intestinal tissue, and causes fragmentation of mitochondria in epidermis and muscle tissue (Figure 3）
。

Figure 3 ADL chemosensory neurons coordinate the body's stress response and regulate various physiological functions through GPCR signals

(Source: Liu, YL.
et al.
, Dev Cell, 2022).