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Dev Cell Tian Ye's team at the Chinese Academy of Sciences found that two sensory neurons in Caenorhabditis elegans can coordinate the systemic mitochondrial stress response through GPCR signals

 Last Update: 2022-11-04
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Mitochondrial perturbations within neurons transmit stress signals to peripheral tissues, coordinating mitochondrial homeostasis throughout the organism for optimal adaptation
.
However, neurons' control of systemic stress regulation is still poorly
understood.

On October 28, 2022, Tian Ye's team from the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences published a paper entitled "Two sensory neurons coordinatethe systemic mitochondrial stress response via GPCR signaling" online in Developmental Cell (IF=13).
in C.
elegans", which shows that two sensory neurons in Caenorhabditis elegans can coordinate the systemic mitochondrial stress response
through GPCR signals.
The study identified a G protein-coupled receptor (GPCR), SRZ-75, which binds to Gαq signaling in a pair of chemosensory ADL neurons to drive mitochondrial unfolded protein response (UPR mt) activation in the gut through neuropeptide release from Caenorhabditis elegans.

The constitutive activation of Gαq signaling in ADL neurons is sufficient to induce UPR mt in the gut, thereby increasing resistance to stress and metabolic adaptation
.
Ablation of ADL neurons weakens intestinal UPR^mt activation in response to various forms of neuronal mitochondrial dysfunction
.
Thus, GPCR and its Gαq downstream signaling coordinate the system's UPR mt activation in two sensory neurons, representing a previously undescribed, but potentially conserved, neuronal signaling for organism-wide mitochondrial stress regulation
.

The systematic coordination of metabolic states between different tissues is essential
for the overall adaptation of an organism under stressful conditions.
Mitochondria are metabolic centers and act as signaling hubs to maintain intracellular homeostasis
.
When mitochondrial protein homeostasis is disrupted under stress conditions, the mitochondrial unexpanded protein response (UPR^mt) is activated, resulting in increased expression of mitochondrial chaperone and proteases, exogenous and reactive oxygen species (ROS) detoxification genes and metabolic enzymes to promote the restoration of mitochondrial protein balance and defense
against infection.
UPR^mt is mediated by the transcription factor ATFS-1 (an activating transcription factor associated with stress-1), which contains mitochondrial localization sequences (MTS) and nuclear localization sequences (NLS).

In the absence of mitochondrial stress, ATFS-1 is introduced into mitochondria, where it is degraded
by mitochondrial Lon protease.
However, under stress, mitochondrial introduction is reduced, allowing ATFS-1 to localize to the nucleus and activate UPR^mt
.
In addition to ATFS-1, other proteins are critical for UPR^mt activity, including the transcription factor DVE-1 (homologous to SATB2 in humans), and epigenetic factors
such as histone methyltransferase MET-2/LIN-65 and nucleosome remodeling and deacetylase (NuRD) complexes.
For metazoans, mitochondrial stress from one tissue can induce a UPR^mt in the distal tissue through cellular involuntary signaling, allowing the organism to better cope with local mitochondrial perturbations
.
For example, neurons knock down the mitochondrial electron transport chain (ETC) subcytochrome c-oxidase-1 (cco-1) to induce UPR^mt in the gut, thereby promoting longevity and resistance to
stress.
In addition, neuronal expression of the pathogenic polyglutamine protein (Q40) in Huntington's disease not only causes neurotoxicity, but also activates UPR^mt
in the gut.
Neuronal deletion in the Caenorhabditis elegans mitofusin (FZO-1) also induces activation of intestinal UPR^mt and alters mitochondrial morphology
in surrounding tissues.
Mild mitochondrial stress in mouse hypothalamic proadrenocorticosteroid (POMC) neurons enhances thermogenesis and activates UPR^mt of distal adipose tissue, protecting mice from glucose metabolism defects in
obese mice.
Induction ablation of the adult forebrain mitochondrial fission protein Drp1 activates the comprehensive stress response (ISR) and induces the release of FGF21, a cytokine associated with impaired mitochondrial function in peripheral tissues that enters the blood circulation
.
Mechanistic pattern diagram (figure from Developmental Cell) It has been proposed that mitokine is released by mitokyrdrially stressed tissues and transmits stress signals to distal tissues
.
In recent years, progress
has been made in the identification of mitokines activated by the mediated system UPR^mt.
The neurotransmitter serotonin and several neuropeptides were found to be required for involuntary UPR^mt activation in cells in response to mitochondrial stress in various neurons; However, serotonin does not appear to act on UPR^mt activation
alone.
Previous studies by the authors have found that involuntary UPR^mt activation in cells requires Wnt/EGL-20 secretion
dependent on reverse transcriptase.
In addition, the memory of neuronal mitochondrial stress can also be transmitted to offspring through the genetics of elevated mitochondrial DNA levels within the germline to make offspring more tolerant to stress and live longer
.
Therefore, neuronal control activated by systematic UPR^mt is essential
to coordinate the homeostasis and metabolic state within the body's mitochondria.
However, the mechanisms by which the nervous system senses, integrates, and transmits signals to distant tissues remain largely unknown
.
Here, the study performed a genetic screening to look for genes
specifically needed for involuntary UPR^mt activation in cells.
The study identified a G protein-coupled receptor (GPCR), SRZ-75, expressed in a pair of ADL (bilateral neurons with biciliary sensory endings) chemosensory neurons, which coordinates involuntary UPR^mt activation
by Gαq signaling.
Activation of Gαq in ADL sensory neurons is sufficient to induce UPR^mt in the intestine, thereby changing the metabolic state, improving protein balance, and strengthening pathogen resistance
.
Overall, the results of this study identify mitochondrial stress responses in neuronal GPCR signaling coordination systems that lead to organism-wide stress regulation
.
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