Wang G et al. (2022) Cell Biosci "Insight into the mitochondrial unfolded protein response and cancer: opportunities and challenges."

Wang G, Tan K, Fan Y, Cao P

[Cell Biosci, 2022]

The mitochondrial unfolded protein response (UPR^mt) is an evolutionarily conserved protective transcriptional response that maintains mitochondrial proteostasis by inducing the expression of mitochondrial chaperones and proteases in response to various stresses. The UPR^mt-mediated transcriptional program requires the participation of various upstream signaling pathways and molecules. The factors regulating the UPR^mt in Caenorhabditis elegans (C. elegans) and mammals are both similar and different. Cancer cells, as malignant cells with uncontrolled proliferation, are exposed to various challenges from endogenous and exogenous stresses. Therefore, in cancer cells, the UPR^mt is hijacked and exploited for the repair of mitochondria and the promotion of tumor growth, invasion and metastasis. In this review, we systematically introduce the inducers of UPR^mt, the biological processes in which UPR^mt participates, the mechanisms regulating the UPR^mt in C. elegans and mammals, cross-tissue signal transduction of the UPR^mt and the roles of the UPR^mt in promoting cancer initiation and progression. Disrupting proteostasis in cancer cells by targeting UPR^mt constitutes a novel anticancer therapeutic strategy.

Lee Y et al. (2020) Biomolecules "Effects of NAD+ in Caenorhabditis elegans Models of Neuronal Damage."

Lee Y, Jeong H, Park KH, Kim KW

[Biomolecules, 2020]

Nicotinamide adenine dinucleotide (NAD⁺) is an essential cofactor that mediates numerous biological processes in all living cells. Multiple NAD⁺ biosynthetic enzymes and NAD⁺-consuming enzymes are involved in neuroprotection and axon regeneration. The nematode <i>Caenorhabditis elegans</i> has served as a model to study the neuronal role of NAD⁺ because many molecular components regulating NAD⁺ are highly conserved. This review focuses on recent findings using <i>C. elegans</i> models of neuronal damage pertaining to the neuronal functions of NAD⁺ and its precursors, including a neuroprotective role against excitotoxicity and axon degeneration as well as an inhibitory role in axon regeneration. The regulation of NAD⁺ levels could be a promising therapeutic strategy to counter many neurodegenerative diseases, as well as neurotoxin-induced and traumatic neuronal damage.

Ye Z et al. (2023) Front Cell Dev Biol "Trends in mitochondrial unfolded protein response research from 2004 to 2022: A bibliometric analysis."

Chai R, Zhang L, Luan Y, Xue W, Wu H, Du Y, Shi S, Wei Y, Ye Z, Hu Y

[Front Cell Dev Biol, 2023]

The mitochondrial unfolded protein response (UPR^mt) is a stress response pathway that regulates the expression of mitochondrial chaperones, proteases, and other proteins involved in protein folding and degradation, thereby ensuring proper mitochondrial function. In addition to this critical function, the UPR^mt also plays a role in other cellular processes such as mitochondrial biogenesis, energy metabolism, and cellular signaling. Moreover, the UPR^mt is strongly associated with various diseases. From 2004 to 2022, there has been a lot of interest in UPR^mt. The present study aims to utilized bibliometric tools to assess the genesis, current areas of focus, and research trends pertaining to UPR^mt, thereby highlighting avenues for future research. There were 442 papers discovered to be related to UPR^mt, with the overall number of publications rising yearly. <i>International Journal of Molecular Sciences</i> was the most prominent journal in this field. 2421 authors from 1,402 institutions in 184 nations published studies on UPR^mt. The United States was the most productive country (197 documents). The top three authors were Johan Auwerx, Cole M Haynes, and Dongryeol Ryu. The early focus of UPR^mt is "protein." And then the UPR^mt research shifted from <i>Caenorhabditis elegans</i> back to mammals, and its close link to aging and various diseases. The top emerging research hotspots are neurodegenerative diseases and metabolic diseases. These findings provide the trends and frontiers in the field of UPR^mt, and valuable information for clinicians and scientists to identify new perspectives with potential collaborators and cooperative countries.

Anderson NS et al. (2020) Trends Cell Biol "Folding the Mitochondrial UPR into the Integrated Stress Response."

Haynes CM, Anderson NS

[Trends Cell Biol, 2020]

Eukaryotic cells must accurately monitor the integrity of the mitochondrial network to overcome environmental insults and respond to physiological cues. The mitochondrial unfolded protein response (UPR^mt) is a mitochondrial-to-nuclear signaling pathway that maintains mitochondrial proteostasis, mediates signaling between tissues, and regulates organismal aging. Aberrant UPR^mt signaling is associated with a wide spectrum of disorders, including congenital diseases as well as cancers and neurodegenerative diseases. Here, we review recent research into the mechanisms underlying UPR^mt signaling in Caenorhabditis elegans and discuss emerging connections between the UPR^mt signaling and a translational regulation program called the 'integrated stress response'. Further study of the UPR^mt will potentially enable development of new therapeutic strategies for inherited metabolic disorders and diseases of aging.

Cuong Tran H et al. (2020) Mitochondrion "Mitochondrial unfolded protein-related responses across kingdoms: similar problems, different regulators."

Cuong Tran H, Van Aken O

[Mitochondrion, 2020]

Mitochondria are key components of eukaryotic cells, so their proper functioning is monitored via different mitochondrial signalling responses. One of these mitochondria-to-nuclear 'retrograde' responses to maintain mitochondrial homeostasis is the mitochondrial unfolded protein response (UPR^mt), which can be activated by a variety of defects including blocking mitochondrial translation, respiration, protein import or transmembrane potential. Although UPR^mt was first reported in cultured mammalian cells, this signalling pathway has also been extensively studied in the nematode Caenorhabditis elegans. In yeast, there are no published studies focusing on UPR^mt in a strict sense, but other unfolded protein responses (UPR) that appear related to UPR^mt have been described, such as the UPR activated by protein mistargeting (UPR^am) and mitochondrial compromised protein import response (mitoCPR). In plants, very little is known about UPR^mt and only recently some of the regulators have been identified. In this paper, we summarise and compare the current knowledge of the UPR^mt and related responses across eukaryotic kingdoms: animals, fungi and plants. Our comparison suggests that each kingdom has evolved its own specific set of regulators, however, the functional categories represented among UPR^mt-related target genes appear to be largely overlapping. This indicates that the strategies for preserving proper mitochondrial functions are partially conserved, targeting mitochondrial chaperones, proteases, import components, dynamics and stress response, but likely also non-mitochondrial functions including growth regulators/hormone balance and amino acid metabolism. We also identify homologs of known UPR^mt regulators and responsive genes across kingdoms, which may be interesting targets for future research.

Luan T et al. (2024) Aging Dis "Mechanisms of the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans and Mammals and Its Roles in Striated Muscles."

Luan T, Duan Y, Xu M, An N, Mao Y, Liu J, Hu S, Zhou J, Nie W, Wang A, Jia L, Wang S

[Aging Dis, 2024]

Throughout the course of evolution, organisms and cells have evolved a suite of mechanisms to manage persistent stimuli, thereby preserving cellular and organismal homeostasis. Upon detecting stress signals, cells activate a transcriptional response termed the mitochondrial unfolded protein response (UPR^mt). This response is crucial for maintaining protein homeostasis, facilitating mitochondrial function recovery, promoting cell survival, and ultimately influencing lifespan. Striated muscles play a pivotal role in oxygen supply, movement, and metabolism. The aging of these muscles can lead to heart failure, arrhythmias, and sarcopenia, significantly impacting quality of life and lifespan. Given the intimate connection between UPR^mt and striated muscle aging, UPR^mt emerges as a potential therapeutic target for mitigating the effects of striated muscle aging. In this review, we delve into the role of UPR^mt in striated muscle aging, drawing upon the extant molecular regulatory mechanisms of UPR^mt. This exploration may enhance our understanding of the underlying mechanisms of striated muscle aging and aid in the identification of potential drug targets.

Alvarez J et al. (2020) Cells "The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models."

Garcia-Casas P, Fonteriz RI, Alvarez J, Montero M, Alvarez-Illera P

[Cells, 2020]

Ca²⁺ is a ubiquitous second messenger that plays an essential role in physiological processes such as muscle contraction, neuronal secretion, and cell proliferation or differentiation. There is ample evidence that the dysregulation of Ca²⁺ signaling is one of the key events in the development of neurodegenerative processes, an idea called the &quot;calcium hypothesis&quot; of neurodegeneration. <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) is a very good model for the study of aging and neurodegeneration. In fact, many of the signaling pathways involved in longevity were first discovered in this nematode, and many models of neurodegenerative diseases have also been developed therein, either through mutations in the worm genome or by expressing human proteins involved in neurodegeneration (-amyloid, -synuclein, polyglutamine, or others) in defined worm tissues. The worm is completely transparent throughout its whole life, which makes it possible to carry out Ca²⁺ dynamics studies in vivo at any time, by expressing Ca²⁺ fluorescent probes in defined worm tissues, and even in specific organelles such as mitochondria. This review will summarize the evidence obtained using this model organism to understand the role of Ca²⁺ signaling in aging and neurodegeneration.

Otsuka AJ (1986) "sup-3 suppression affects muscle structure and myosin heavy chain accumulation in C. elegans."

Otsuka AJ

[1986]

Suppression of paramyosin mutations by sup-3 has been shown to result in the formation of thick filaments of normal appearance distributed in regions of partially organized muscle lattice structure. In the presence or absence of muscle mutations, sup-3 results in the elevation of MHCA, one of the two known body-wall myosin heavy chains. The correlation of sup-3 mutations with MHCA increase suggests that sup-3 may regulate the expression or accumulation of MHCA.

Wang L et al. (2021) Exp Neurol "Maintenance of protein homeostasis in glia extends life span in C. elegans."

Bianchi L, Wang L

[Exp Neurol, 2021]

Mounting evidence support that glia play a key role in organismal ageing. However, the mechanisms by which glia impact ageing are not understood. One of the processes that has significant impact on the rate of ageing is the unfolded protein response. The more robust the UPR, the more the organism can counteract the effect of environmental and genetic stressors. However, how decline of cellular UPR translates into organismal ageing and eventual death is not fully understood. Here we discuss recent findings highlighting that neuropeptides released by glia act long distance to regulate ageing in C. elegans. Taking advantage of the short life span and the genetic amenability of this organism, the endoplasmic reticulum unfolded protein responses (UPR^ER) can be activated in C. elegans glia. This leads to cell-nonautonomous activation of the UPR^ER in the intestine. Activation of intestinal UPR^ER requires the function of genes involved in neuropeptide processing and release, suggesting that neuropeptides signal from glia to the intestine to regulate ER stress response. Importantly, the cell-nonautonomous activation of UPR^ER leads to extension of life span. Taken together, these data suggest that environmental and genetic factors that impact the response of glia to stress have the potential to influence organismal ageing. Further research on the specific neuropeptides involved should cast new light on the mechanism of ageing and may suggest novel anti-ageing therapies.

Jentsch TJ et al. (2018) Physiol Rev "CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease."

Jentsch TJ, Pusch M

[Physiol Rev, 2018]

CLC anion transporters are found in all phyla and form a gene family of eight members in mammals. Two CLC proteins, each of which completely contains an ion translocation parthway, assemble to homo- or heteromeric dimers that sometimes require accessory -subunits for function. CLC proteins come in two flavors: anion channels and anion/proton exchangers. Structures of these two CLC protein classes are surprisingly similar. Extensive structure-function analysis identified residues involved in ion permeation, anion-proton coupling and gating and led to attractive biophysical models. In mammals, ClC-1, -2, -Ka/-Kb are plasma membrane Cl^- channels, whereas ClC-3 through ClC-7 are 2Cl^-/H⁺-exchangers in endolysosomal membranes. Biological roles of CLCs were mostly studied in mammals, but also in plants and model organisms like yeast and Caenorhabditis elegans. CLC Cl^- channels have roles in the control of electrical excitability, extra- and intracellular ion homeostasis, and transepithelial transport, whereas anion/proton exchangers influence vesicular ion composition and impinge on endocytosis and lysosomal function. The surprisingly diverse roles of CLCs are highlighted by human and mouse disorders elicited by mutations in their genes. These pathologies include neurodegeneration, leukodystrophy, mental retardation, deafness, blindness, myotonia, hyperaldosteronism, renal salt loss, proteinuria, kidney stones, male infertility, and osteopetrosis. In this review, emphasis is laid on biophysical structure-function analysis and on the cell biological and organismal roles of mammalian CLCs and their role in disease.