Zhou Z et al. (2022) Ageing Res Rev "The mitochondrial unfolded protein response: A multitasking giant in the fight against human diseases."

Fan Y, Tan K, Zhou Z, Zong R

[Ageing Res Rev, 2022]

Mitochondria, which serve as the energy factories of cells, are involved in cell differentiation, calcium homeostasis, amino acid and fatty acid metabolism and apoptosis. In response to environmental stresses, mitochondrial homeostasis is regulated at both the organelle and molecular levels to effectively maintain the number and function of mitochondria. The mitochondrial unfolded protein response (UPRmt) is an adaptive intracellular stress mechanism that responds to stress signals by promoting the transcription of genes encoding mitochondrial chaperones and proteases. The mechanism of the UPRmt in Caenorhabditis elegans (C. elegans) has been clarified over time, and the main regulatory factors include ATFS-1, UBL-5 and DVE-1. In mammals, the activation of the UPRmt involves eIF2α phosphorylation and the uORF-regulated expression of CHOP, ATF4 and ATF5. Several additional factors, such as SIRT3 and HSF1, are also involved in regulating the UPRmt. A deep and comprehensive exploration of the UPRmt can provide new directions and strategies for the treatment of human diseases, including aging, neurodegenerative diseases, cardiovascular diseases and diabetes. In this review, we mainly discuss the function of UPRmt, describe the regulatory mechanisms of UPRmt in C. elegans and mammals, and summarize the relationship between UPRmt and various human diseases.

Zhou Z et al. (2004) Curr Top Dev Biol "The genetics of hiding the corpse: engulfment and degradation of apoptotic cells in C. elegans and D. melanogaster."

Zhou Z, Mangahas PM, Yu X

[Curr Top Dev Biol, 2004]

Lu N et al. (2012) Int Rev Cell Mol Biol "Membrane trafficking and phagosome maturation during the clearance of apoptotic cells."

Lu N, Zhou Z

[Int Rev Cell Mol Biol, 2012]

Apoptosis is a cellular suicide process that quietly and efficiently eliminates unwanted or damaged cells. In metazoans, cells that undergo apoptosis are swiftly internalized by phagocytes and subsequently degraded inside phagosomes through phagosome maturation, a process that involves the fusion between phagosomes and multiple kinds of intracellular organelles and the gradual acidification of phagosomal lumen. In recent years, rapid progress has been made, in particular, through studies conducted in the model organism, the nematode Caenorhabditis elegans, in understanding the membrane trafficking events and molecular mechanisms that govern the degradation of apoptotic cells through phagosome maturation. These studies revealed the novel and essential functions of a large number of proteins, including the large GTPase dynamin, multiple Rab small GTPases and their regulatory proteins, the lipid second messenger PtdIns(3)P and its effectors, and unexpectedly, the phagosomal receptors for apoptotic cells, in promoting phagosome maturation. Further, novel signaling pathways essential for phagosome maturation have been delineated. Here, we discuss these exciting new findings, which have significantly deepened and broadened our understanding of the mechanisms that regulate the interaction between intracellular organelles and phagosomes.

Furuta Y et al. (2023) Front Cell Dev Biol "How do necrotic cells expose phosphatidylserine to attract their predators-What's unique and what's in common with apoptotic cells."

Zhou Z, Furuta Y

[Front Cell Dev Biol, 2023]

Phosphatidylserine (PS) is a lipid component of the plasma membrane. It is asymmetrically distributed to the inner leaflet in live cells. In cells undergoing apoptosis, phosphatidylserine is exposed to the outer surfaces. The exposed phosphatidylserine acts as an evolutionarily conserved "eat-me" signal that attracts neighboring engulfing cells in metazoan organisms, including the nematode <i>Caenorhabditis elegans</i>, the fruit fly <i>Drosophila melanogaster</i>, and mammals. During apoptosis, the exposure of phosphatidylserine to the outer surface of a cell is driven by the membrane scramblases and flippases, the activities of which are regulated by caspases. Cells undergoing necrosis, a kind of cell death frequently associated with cellular injuries and morphologically distinct from apoptosis, were initially believed to allow passive exposure of phosphatidylserine through membrane rupture. Later studies revealed that necrotic cells actively expose phosphatidylserine before any rupture occurs. A recent study in <i>C. elegans</i> further reported that the calcium ion (Ca²⁺) plays an essential role in promoting the exposure of phosphatidylserine on the surfaces of necrotic cells. These findings indicate that necrotic and apoptotic cells, which die through different molecular mechanisms, use common and unique mechanisms for promoting the exposure of the same "eat me" signal. This article will review the mechanisms regulating the exposure of phosphatidylserine on the surfaces of necrotic and apoptotic cells and highlight their similarities and differences.

Mangahas PM et al. (2005) Semin Cell Dev Biol "Clearance of apoptotic cells in Caenorhabditis elegans."

Mangahas PM, Zhou Z

[Semin Cell Dev Biol, 2005]

Programmed cell death, or apoptosis, is a genetically controlled process of cell suicide that is a common fate during an animal''s life. In metazoans, apoptotic cells are rapidly removed from the body through the process of phagocytosis. Genetic analyses probing the mechanisms controlling the engulfment of apoptotic cells were pioneered in the nematode Caenorhabditis elegans. So far, at least seven genes have been identified that are required for the recognition and engulfment of apoptotic cells and have been shown to function in two partially redundant signaling pathways. Molecular characterization of their gene products has lead to the finding that similar genes act to control the same processes in other organisms, including mammals. In this paper, we review these exciting findings in C. elegans and discuss their implications in understanding the clearance of apoptotic cells in mammals.

Lecroisey C et al. (2007) J Muscle Res Cell Motil "The C. elegans dense body: anchoring and signaling structure of the muscle."

Gieseler K, Lecroisey C, Segalat L

[J Muscle Res Cell Motil, 2007]

During evolution, both the architecture and the cellular physiology of muscles have been remarkably maintained. Striated muscles of invertebrates, although less complex, strongly resemble vertebrate skeletal muscles. In particular, the basic contractile unit called the sarcomere is almost identical between vertebrates and invertebrates. In vertebrate muscles, sarcomeric actin filaments are anchored to attachment points called Z-disks, which are linked to the extra-cellular matrix (ECM) by a muscle specific focal adhesion site called the costamere. In this review, we focus on the dense body of the animal model Caenorhabditis elegans. The C. elegans dense body is a structure that performs two in one roles at the same time, that of the Z-disk and of the costamere. The dense body is anchored in the muscle membrane and provides rigidity to the muscle by mechanically linking actin filaments to the ECM. In the last few years, it has become increasingly evident that, in addition to its structural role, the dense body also performs a signaling function in muscle cells. In this paper, we review recent advances in the understanding of the C. elegans dense body composition and function.

Qadota H et al. (2010) J Biomed Biotechnol "Molecular structure of sarcomere-to-membrane attachment at M-Lines in C. elegans muscle."

Qadota H, Benian GM

[J Biomed Biotechnol, 2010]

C. elegans is an excellent model for studying nonmuscle cell focal adhesions and the analogous muscle cell attachment structures. In the major striated muscle of this nematode, all of the M-lines and the Z-disk analogs (dense bodies) are attached to the muscle cell membrane and underlying extracellular matrix. Accumulating at these sites are many proteins associated with integrin. We have found that nematode M-lines contain a set of protein complexes that link integrin-associated proteins to myosin thick filaments. We have also obtained evidence for intriguing additional functions for these muscle cell attachment proteins.

Ziegler C (1994) Comp Biochem Physiol A Physiol "Titin-related proteins in invertebrate muscles."

Ziegler C

[Comp Biochem Physiol A Physiol, 1994]

The localization of filaments connecting the Z-line and the A-band in insect flight muscles and the identification of very large proteins as their components is reviewed. The characterization of twitchin in the obliquely striated muscles of Caenorhabditis elegans is reported and the deductions made from its amino acid sequence are considered. The characterization of mini-titins in obliquely striated molluscan muscles is compared. The identification of projectin in the muscles of Drosophila melanogaster by anti-twitchin-antibodies, its sequence analysis and the characterization of mini-titins in arthropod and mollusc fast-striated muscles are summarized. The possible biological functions of the different proteins in various invertebrate muscles are discussed.

Bullard B et al. (2002) J Muscle Res Cell Motil "Varieties of elastic protein in invertebrate muscles."

Leonard K, Linke WA, Bullard B

[J Muscle Res Cell Motil, 2002]

Elastic proteins in the muscles of a nematode (Caenorhabditis elegans), three insects (Drosophila melanogaster, Anopheles gambiae, Bombyx mori) and a crustacean (Procambus clarkii) were compared. The sequences of thick filament proteins, twitchin in the worm and projectin in the insects, have repeating modules with fibronectin-like (Fn) and immunoglobulin-like (Ig) domains conserved between species. Projectin has additional tandem Igs and an elastic PEVK domain near the N-terminus. All the species have a second elastic protein we have called SLS protein after the Drosophila gene, sallimus. SLS protein is in the I-band. The N-terminal region has the sequence of kettin which is a spliced product of the gene composed of Ig-linker modules binding to actin. Downstream of kettin, SLS protein has two PEVK domains, unique sequence, tandem Igs, and Fn domains at the end. PEVK domains have repeating sequences: some are long and highly conserved and would have varying elasticity appropriate to different muscles. Insect indirect flight muscle (IFM) has short I-bands and electron micrographs of Lethocerus IFM show fine filaments branching from the end of thick filaments to join thin filaments before they enter the Z-disc. Projectin and kettin are in this region and the contribution of these to the high passive stiffness of Drosophila IFM myofibrils was measured from the force response to length oscillations. Kettin is attached both to actin near the Z-disc and to the end of thick filaments, and extraction of actin or digestion of kettin leads to rapid decrease in stiffness; residual tension is attributable to projectin. The wormlike chain model for polymer elasticity fitted the force-extension curve of IFM myofibrils and the number of predicted Igs in the chain is consistent with the tandem Igs in Drosophila SLS protein. We conclude that passive tension is due to kettin and projectin, either separate or

Lucchesi JC (2018) J Genet "Transcriptional modulation of entire chromosomes: dosage compensation."

Lucchesi JC

[J Genet, 2018]

Dosage compensation is a regulatory system designed to equalize the transcription output of the genes of the sex chromosomes that are present in different doses in the sexes (X or Z chromosome, depending on the animal species involved). Different mechanisms of dosage compensation have evolved in different animal groups. In Drosophila males, a complex (male-specific lethal) associates with the X chromosome and enhances the activity of most X-linked genes by increasing the rate of RNAPII elongation. In Caenorhabditis, a complex (dosage compensation complex) that contains a number of proteins involved in condensing chromosomes decreases the level of transcription of both X chromosomes in the XX hermaphrodite. In mammals, dosage compensation is achieved by the inactivation, early during development, of most X-linked genes on one of the two X chromosomes in females. The mechanism involves the synthesis of an RNA (Tsix) that protects one of the two Xs from inactivation, and of another RNA (Xist) that coats the other X chromosome and recruits histone and DNA modifying enzymes. This review will focus on the current progress in understanding the dosage compensation mechanisms in the three taxa where it has been best studied at the molecular level: flies, round worms and mammals.