Mitochondria are pivotal organelles for cellular energy production and the regulation of stress responses. Recent research has elucidated complex mechanisms through which mitochondrial stress in one tissue can impact distant tissues, thereby promoting overall organismal health. Two recent studies by Shen et al. and Charmpilas et al. have demonstrated that an intact germline serves as a crucial signaling hub for the activation of the somatic mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans.

The mitochondrial unfolded protein response (UPRmt) is a cytoprotective response in response to cellular stress that is activated in response to mitochondrial stress to maintain intra-protein homeostasis, thereby protecting the cell from a variety of stimuli. The activation of this response has been linked to cardiovascular diseases. Here, we reviewed the current understanding of UPRmt and discussed its specific molecular mechanism, mainly in mammals, as well as addressing its protective role against cardiovascular diseases, so as to provide direction for further research on UPRmt and therapies targeting cardiovascular diseases in the future.

In poultry reproduction, the decline of ovarian function due to aging is related to dysfunction of mitochondria exacerbated by a reduction in antioxidant capacity, ultimately leading to follicle atresia and decreased egg production. However, the mechanisms of mitochondrial dysfunction in the chicken ovary in aging have remained to be understood. Hence, this study aims to investigate the effects of aging on mitochondrial function and cellular homeostasis. We collect ovarian tissue, small white follicles (SWF), large white follicles (LWF), and small yellow follicles (SYF) from three different laying periods of hens. The transmission electron microscopy (TEM) results showed that mitochondrial damage occurred in ovarian tissue during the late laying period (LP), characterized by structural swelling, scattered mitochondrial cristae, and an increase in the vacuoles. At the same time, with age, the synthesis of steroid hormones in the ovaries and follicular tissues is reduced. The levels of autophagy and cell apoptosis in ovarian tissues were both increased in the LP. In addition, aging adversely impacts mitochondrial function, leading to a decrease in mitochondrial unfolded protein response (UPRmt) functions. This study will expand the knowledge about regressing ovarian aging in hens and increasing egg production in older layers for poultry production.

Pathogens target vacuolar ATPase (V-ATPase) to inhibit lysosomal acidification or lysosomal fusion, causing lysosomal dysfunction. However, it remains unknown whether cells can detect dysfunctional lysosomes and initiate an immune response. In this study, we discover that dysfunction of lysosomes caused by inactivation of V-ATPase enhances innate immunity against bacterial infections. We find that lysosomal V-ATPase interacts with DVE-1, whose nuclear localization serves as a proxy for the induction of mitochondrial unfolded protein response (UPRmt). The inactivation of V-ATPase promotes the nuclear localization of DVE-1, activating UPRmt and inducing downstream immune response genes. Furthermore, pathogen resistance conferred by inactivation of V-ATPase requires dve-1 and its downstream immune effectors. Interestingly, animals grow slower after vha RNAi, suggesting that the vha-RNAi-induced immune response costs the most energy through activation of DVE-1, which trades off with growth. This study reveals how dysfunctional lysosomes can trigger an immune response, emphasizing the importance of conserving energy during immune defense.

BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is the first line of defense against mitochondrial dysfunction in several diseases. Baicalein, which is an extract of Scutellaria baicalensis Georgi roots, exerts mitoprotective effects on metabolic disorders and cardiovascular diseases. However, it remains unclear whether baicalein alleviates obesity-induced cardiac damage through the UPRmt.
OBJECTIVE: The present research designed to clarify the role of baicalein in lipotoxicity-induced myocardial apoptosis and investigated the UPRmt-related mechanism.
METHODS: In the in vitro experiment, palmitic acid (PA)-treated AC16 cardiomyocytes were established to mimic obesity-induced myocardial injury. After pretreatment of AC16 cells with baicalein, the levels of cell vitality, apoptosis, mitochondrial membrane potential, mitochondrial oxidative stress, and UPRmt-related proteins were determined. Additionally, AC16 cells were treated with ML385 or siRNA to explore the regulation of the UPRmt by NRF2 signaling. In the in vivo experiment, male db/db mice administered with baicalein for 8 weeks were used to validate the effects of baicalein on cardiac damage induced by obesity, the UPRmt, and the NRF2-related pathway.
RESULTS: In AC16 cardiomyocytes, PA dose-dependently increased the expression of UPRmt markers (HSP60, LONP1, ATF4, and ATF5). This increase was accompanied by enhanced production of mitochondrial ROS, reduced mitochondrial membrane potential, and elevated the expression levels of cytochrome c, cleaved caspase-3, and Bax/Bcl2, eventually leading to cell apoptosis. Baicalein treatment reversed UPRmt activation and mitochondrial damage and impeded mitochondrial-mediated cell apoptosis. Moreover, NRF2 downregulation by its inhibitor ML385 or siRNA diminished baicalein-mediated NRF2 signaling activation and UPRmt inhibition and triggered mitochondrial dysfunction. Additionally, NRF2 deficiency more intensely activated the UPRmt, resulting in mitochondrial oxidative stress and apoptosis of PA-induced cardiomyocytes, thus indicating that NRF2 plays a vital role in mitochondrial homeostasis regulation. In the in vivo study in db/db mice, baicalein inhibited the UPRmt, enhanced the antioxidant capacity, and attenuated cardiac dysfunction through a NRF2-activated pathway.
CONCLUSIONS: To our best knowledge, these results provide the first insight that baicalein inhibits the UPRmt to induce a protective effect against lipotoxicity-induced mitochondrial damage and cardiomyocyte apoptosis via activating NRF2 signaling and suggest a new role of NRF2 in UPRmt regulation.

Methylmercury (MeHg) is a widely distributed environmental pollutant that can easily cross the blood-brain barrier and accumulate in the brain, thereby damaging the central nervous system. Studies have shown that MeHg-induced mitochondrial damage and apoptosis play a crucial role in its neurotoxic effects. Mitochondrial unfolded protein response (UPRmt) is indispensable to maintain mitochondrial protein homeostasis and ensure mitochondrial function, and the ATF4/CHOP axis is one of the signaling pathways to activate UPRmt. In this study, the role of the ATF4/CHOP axis-mediated UPRmt in the neurotoxicity of MeHg has been investigated by C57BL/6 mice and the HT22 cell line. We discovered that mice exposed to MeHg had abnormal neurobehavioral patterns. The pathological section showed a significant decrease in the number of neurons. MeHg also resulted in a reduction in mtDNA copy number and mitochondrial membrane potential (MMP). Additionally, the ATF4/CHOP axis and UPRmt were found to be significantly activated. Subsequently, we used siRNA to knock down ATF4 or CHOP and observed that the expression of UPRmt-related proteins and the apoptosis rate were significantly reduced. Our research showed that exposure to MeHg can over-activate the UPRmt through the ATF4/CHOP axis, leading to mitochondrial damage and ultimately inducing neuronal apoptosis.

OBJECTIVE: The mitochondrial unfolded protein response (UPRmt) is an adaptive cellular response to stress to ensure mitochondrial proteostasis and function. Here we explore the capacity of physical exercise to induce UPRmt in the skeletal muscle.
METHODS: Therefore, we combined mouse models of exercise (swimming and treadmill running), pharmacological intervention, and bioinformatics analyses.
RESULTS: Firstly, RNA sequencing and Western blotting analysis revealed that an acute aerobic session stimulated several mitostress-related genes and protein content in muscle, including the UPRmt markers. Conversely, using a large panel of isogenic strains of BXD mice, we identified that BXD73a and 73b strains displayed low levels of several UPRmt-related genes in the skeletal muscle, and this genotypic feature was accompanied by body weight gain, lower locomotor activity, and aerobic capacity. Finally, we identified that c-Jun N-terminal kinase (JNK) activation was critical in exercise-induced UPRmt in the skeletal muscle since pharmacological JNK pathway inhibition blunted exercise-induced UPRmt markers in mice muscle.
CONCLUSIONS: Our findings provide new insights into how exercise triggers mitostress signals toward the oxidative capacity in the skeletal muscle.

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Aminoacyl-tRNA synthetases (aaRSs) are indispensable players in translation. Usually, two or three genes encode cytoplasmic and mitochondrial threonyl-tRNA synthetases (ThrRSs) in eukaryotes. Here, we reported that Caenorhabditis elegans harbors only one tars-1, generating cytoplasmic and mitochondrial ThrRSs via translational reinitiation. Mitochondrial tars-1 knockdown decreased mitochondrial tRNAThr charging and translation and caused pleotropic phenotypes of delayed development, decreased motor ability and prolonged lifespan, which could be rescued by replenishing mitochondrial tars-1. Mitochondrial tars-1 deficiency leads to compromised mitochondrial functions including the decrease in oxygen consumption rate, complex Ⅰ activity and the activation of the mitochondrial unfolded protein response (UPRmt), which contributes to longevity. Furthermore, deficiency of other eight mitochondrial aaRSs in C. elegans and five in mammal also caused activation of the UPRmt. In summary, we deciphered the mechanism of one tars-1, generating two aaRSs, and elucidated the biochemical features and physiological function of C. elegans tars-1. We further uncovered a conserved connection between mitochondrial translation deficiency and UPRmt.

Organisms use several strategies to mitigate mitochondrial stress, including the activation of the mitochondrial unfolded protein response (UPRmt). The UPRmt in Caenorhabditis elegans, regulated by the transcription factor ATFS-1, expands on this recovery program by inducing an antimicrobial response against pathogens that target mitochondrial function. Here, we show that the mammalian ortholog of ATFS-1, ATF5, protects the host during infection with enteric pathogens but, unexpectedly, by maintaining the integrity of the intestinal barrier. Intriguingly, ATF5 supports intestinal barrier function by promoting a satiety response that prevents obesity and associated hyperglycemia. This consequently averts dysregulated glucose metabolism that is detrimental to barrier function. Mechanistically, we show that intestinal ATF5 stimulates the satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin, which promotes the secretion of the hormone leptin. We propose that ATF5 protects the host from enteric pathogens by promoting intestinal barrier function through a satiety-response-mediated metabolic control mechanism.