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.

Swindell WR (2011) Ageing Res Rev "Metallothionein and the biology of aging."

Swindell WR

[Ageing Res Rev, 2011]

Metallothionein (MT) is a low molecular weight protein with anti-apoptotic properties that has been demonstrated to scavenge free radicals in vitro. MT has not been extensively investigated within the context of aging biology. The purpose of this review, therefore, is to discuss findings on MT that are relevant to basic aging mechanisms and to draw attention to the possible role of MT in pro-longevity interventions. MT is one of just a handful of proteins that, when overexpressed, has been demonstrated to increase mouse lifespan. MT also protects against development of obesity in mice provided a high fat diet as well as diet-induced oxidative stress damage. Abundance of MT is responsive to caloric restriction (CR) and inhibition of the insulin/insulin-like signaling (IIS) pathway, and elevated MT gene expression has been observed in tissues from fasted and CR-fed mice, long-lived dwarf mice, worms maintained under CR conditions, and long-lived daf-2 mutant worms. The dysregulation of MT in these systems is likely to have tissue-specific effects on aging outcomes. Further investigation will therefore be needed to understand how MT contributes to the response of invertebrates and mice to CR and the endocrine mutations studied by aging researchers.

Al-Bassam J et al. (2011) Trends Cell Biol "Regulation of microtubule dynamics by TOG-domain proteins XMAP215/Dis1 and CLASP."

Chang F, Al-Bassam J

[Trends Cell Biol, 2011]

The molecular mechanisms by which microtubule-associated proteins (MAPs) regulate the dynamic properties of microtubules (MTs) are still poorly understood. We review recent advances in our understanding of two conserved families of MAPs, the XMAP215/Dis1 and CLASP family of proteins. In vivo and in vitro studies show that XMAP215 proteins act as microtubule polymerases at MT plus ends to accelerate MT assembly, and CLASP proteins promote MT rescue and suppress MT catastrophe events. These are structurally related proteins that use conserved TOG domains to recruit tubulin dimers to MTs. We discuss models for how these proteins might use these individual tubulin dimers to regulate dynamic behavior of MT plus ends.

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.

Tang NH et al. (2016) F1000Res "Regulation of Microtubule Dynamics in Axon Regeneration: Insights from C. elegans."

Chisholm AD, Tang NH

[F1000Res, 2016]

The capacity of an axon to regenerate is regulated by its external environment and by cell-intrinsic factors. Studies in a variety of organisms suggest that alterations in axonal microtubule (MT) dynamics have potent effects on axon regeneration. We review recent findings on the regulation of MT dynamics during axon regeneration, focusing on the nematode Caenorhabditis elegans. In C. elegans the dual leucine zipper kinase (DLK) promotes axon regeneration, whereas the exchange factor for Arf6 (EFA-6) inhibits axon regeneration. Both DLK and EFA-6 respond to injury and control axon regeneration in part via MT dynamics. How the DLK and EFA-6 pathways are related is a topic of active investigation, as is the mechanism by which EFA-6 responds to axonal injury. We evaluate potential candidates, such as the MT affinity-regulating kinase PAR-1/MARK, in regulation of EFA-6 and axonal MT dynamics in regeneration.

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.

Runkel ED et al. (2014) Exp Gerontol "Mitochondrial stress: balancing friend and foe."

Schulze E, Runkel ED, Baumeister R

[Exp Gerontol, 2014]

Mitochondria are vital organelles of the aerobic eukaryotic cell. Their dysfunction associates with aging and widespread age-related diseases. To sustain mitochondrial integrity, the cell executes a distinct set of stress-induced protective responses. The mitochondrial unfolded protein response (UPR(mt)) is a response of the cell to mitochondrial damage. The transcription factor ATFS-1 triggers UPR(mt) effector gene expression in the nucleus. The selective exclusion of ATFS-1 from mitochondrial import by stress-induced alterations of the mitochondrial membrane potential is currently discussed as key activation mechanism. Surprisingly, UPR(mt) activation often coincides with a lifespan extension in Caenorhabditis elegans and the same has recently been reported for mammalian cells. This review summarizes the current model of the UPR(mt), its inducers, and its crosstalk with other cellular stress responses. It focuses on the role of mitochondrial function as a regulator of aging and longevity.

Signor D et al. (2000) Essays Biochem "Microtubule-based transport along axons, dendrites and axonemes."

Scholey JM, Signor D

[Essays Biochem, 2000]

MTs in cytoplasmic extensions including axons, dendrites and axonemes serve as polarized tracks for vectorial intracellular transport driven by MT-based motor proteins. Although axons and axonemes serve very different functions, increasing evidence suggests that the transport events, MT organization and the motors involved in their formation and function are conserved. Thus, there are obvious similarities in the mechanisms of axonal transport and IFT. The MT arrays of axons and axonemes are parallel, whereas those of dendrites are anti-parallel, but the functional significance of this difference and its consequences for mechanisms of transport along these processes are unclear. MT-based motor proteins of the dynein and kinesin superfamilies transport a variety of cargos including membrane-bound vesicles and macromolecular complexes along MTs of axons, dendrites and axonemes, and thus contribute to the formation, maintenance and function of these cytoplasmic extensions. Chemosensory neurons in the nematode C. elegans represent an appealing system for studying transport events along dendrites and axonemes that occur sequentially in a single cell.