The mitochondrial network is not only required for the production of energy, essential cofactors and amino acids, but also serves as a signaling hub for innate immune and apoptotic pathways. Multiple ...mechanisms have evolved to identify and combat mitochondrial dysfunction to maintain the health of the organism. One such pathway is the mitochondrial unfolded protein response (UPRmt ), which is regulated by the mitochondrial import efficiency of the transcription factor ATFS-1 in C. elegans and potentially orthologous transcription factors in mammals (ATF4, ATF5, CHOP). Upon mitochondrial dysfunction, import of ATFS-1 into mitochondria is reduced, allowing it to be trafficked to the nucleus where it promotes the expression of genes that promote survival and recovery of the mitochondrial network. Here, we discuss recent findings underlying UPRmt signal transduction and how this adaptive transcriptional response may interact with other mitochondrial stress response pathways.
The mitochondrial network is not only required for the production of energy, essential cofactors and amino acids, but also serves as a signaling hub for innate immune and apoptotic pathways. Multiple ...mechanisms have evolved to identify and combat mitochondrial dysfunction to maintain the health of the organism. One such pathway is the mitochondrial unfolded protein response (UPR
), which is regulated by the mitochondrial import efficiency of the transcription factor ATFS-1 in C. elegans and potentially orthologous transcription factors in mammals (ATF4, ATF5, CHOP). Upon mitochondrial dysfunction, import of ATFS-1 into mitochondria is reduced, allowing it to be trafficked to the nucleus where it promotes the expression of genes that promote survival and recovery of the mitochondrial network. Here, we discuss recent findings underlying UPR
signal transduction and how this adaptive transcriptional response may interact with other mitochondrial stress response pathways.
Mitochondrial dysfunction is pervasive in human pathologies such as neurodegeneration, diabetes, cancer, and pathogen infections as well as during normal aging. Cells sense and respond to ...mitochondrial dysfunction by activating a protective transcriptional program known as the mitochondrial unfolded protein response (UPRmt), which includes genes that promote mitochondrial protein homeostasis and the recovery of defective organelles 1, 2. Work in Caenorhabditis elegans has shown that the UPRmt is regulated by the transcription factor ATFS-1, which is regulated by organelle partitioning. Normally, ATFS-1 accumulates within mitochondria, but during respiratory chain dysfunction, high levels of reactive oxygen species (ROS), or mitochondrial protein folding stress, a percentage of ATFS-1 accumulates in the cytosol and traffics to the nucleus where it activates the UPRmt 2. While similar transcriptional responses have been described in mammals 3, 4, how the UPRmt is regulated remains unclear. Here, we describe a mammalian transcription factor, ATF5, which is regulated similarly to ATFS-1 and induces a similar transcriptional response. ATF5 expression can rescue UPRmt signaling in atfs-1-deficient worms requiring the same UPRmt promoter element identified in C. elegans. Furthermore, mammalian cells require ATF5 to maintain mitochondrial activity during mitochondrial stress and promote organelle recovery. Combined, these data suggest that regulation of the UPRmt is conserved from worms to mammals.
•Mammalian ATF5 regulates the mitochondrial UPR in worms lacking ATFS-1•ATF5 induces transcription of mammalian mitochondrial proteostasis genes•ATF5 localizes to mitochondria and nuclei, suggesting regulation similar to ATFS-1•ATF5 promotes mitochondrial function and recovery from mitochondrial stress
Fiorese et al. identify the transcription factor ATF5 as a mediator of a mammalian mitochondrial unfolded protein response. Their investigation suggests that ATF5 communicates mitochondrial status to the nucleus to mediate the induction of a mitochondrial protective program that includes mitochondrial chaperone and protease genes.
Mitochondria are required for numerous essential metabolic processes including the regulation of apoptosis; therefore, proper maintenance of the mitochondrial proteome is crucial. The protein-folding ...environment in mitochondria is challenged by organelle architecture, the presence of reactive oxygen species and the difficulties associated with assembly of the electron transport chain, which consists of components encoded by both the mitochondrial and the nuclear genomes. Mitochondria have dedicated molecular chaperones and proteases that promote proper protein folding, complex assembly and quality control. Work in cultured mammalian cells and Caenorhabditis elegans has yielded clues to the mechanisms linking perturbations in the protein-folding environment in the mitochondrial matrix to the expression of nuclear genes encoding mitochondrial proteins. Here, we review the current knowledge of this mitochondrial unfolded protein response (UPRmt), compare it with the better understood UPR of the endoplasmic reticulum and highlight its potential impact on development and disease.
The mitochondrial proteome encompasses more than a thousand proteins, which are encoded by the mitochondrial and nuclear genomes. Mitochondrial biogenesis and network health relies on maintenance of ...protein import pathways and the protein-folding environment. Cell-extrinsic or -intrinsic stressors that challenge mitochondrial proteostasis negatively affect organellar function. During conditions of stress, cells use impaired protein import as a sensor for mitochondrial dysfunction to activate a stress response called the mitochondrial unfolded protein response (UPR
). UPR
activation leads to an adaptive transcriptional program that promotes mitochondrial recovery, metabolic adaptations, and innate immunity. In this review, we discuss the regulation of UPR
activation as well as its role in maintaining mitochondrial homeostasis in physiological and pathological scenarios.
Abstract Mitochondria form a cellular network of organelles, or cellular compartments, that efficiently couple nutrients to energy production in the form of ATP. As cancer cells rely heavily on ...glycolysis, historically mitochondria and the cellular pathways in place to maintain mitochondrial activities were thought to be more relevant to diseases observed in non-dividing cells such as muscles and neurons. However, more recently it has become clear that cancers rely heavily on mitochondrial activities including lipid, nucleotide and amino acid synthesis, suppression of mitochondria-mediated apoptosis as well as oxidative phosphorylation (OXPHOS) for growth and survival. Considering the variety of conditions and stresses that cancer cell mitochondria may incur such as hypoxia, reactive oxygen species and mitochondrial genome mutagenesis, we examine potential roles for a mitochondrial-protective transcriptional response known as the mitochondrial unfolded protein response (UPRmt ) in cancer cell biology.
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 ...(UPRmt) is a mitochondrial-to-nuclear signaling pathway that maintains mitochondrial proteostasis, mediates signaling between tissues, and regulates organismal aging. Aberrant UPRmt 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 UPRmt signaling in Caenorhabditis elegans and discuss emerging connections between the UPRmt signaling and a translational regulation program called the ‘integrated stress response’. Further study of the UPRmt will potentially enable development of new therapeutic strategies for inherited metabolic disorders and diseases of aging.
The mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans is a transcriptional program that requires chromatin remodeling and the transcription factor ATFS-1, which is regulated by mitochondrial protein import efficiency.The UPRmt in C. elegans rewires cellular metabolism, contributes to innate immunity, mediates signaling between tissues, and regulates development and organismal aging. In mammals, the UPRmt is embedded within the integrated stress response (ISR), a program that enables selective translation of transcripts harboring upstream open reading frames.In mammals, UPRmt induction is mediated by the transcription factors CHOP; ATF4; and a functional ortholog of ATFS-1, ATF5.The kinases responsible for activating the ISR have all been implicated in maintaining mitochondrial homeostasis or responding to mitochondrial dysfunction.
Mitochondrial diseases and aging are associated with defects in the oxidative phosphorylation machinery (OXPHOS), which are the only complexes composed of proteins encoded by separate genomes. To ...better understand genome coordination and OXPHOS recovery during mitochondrial dysfunction, we examined ATFS-1, a transcription factor that regulates mitochondria-to-nuclear communication during the mitochondrial UPR, via ChIP-sequencing. Surprisingly, in addition to regulating mitochondrial chaperone, OXPHOS complex assembly factor, and glycolysis genes, ATFS-1 bound directly to OXPHOS gene promoters in both the nuclear and mitochondrial genomes. Interestingly, atfs-1 was required to limit the accumulation of OXPHOS transcripts during mitochondrial stress, which required accumulation of ATFS-1 in the nucleus and mitochondria. Because balanced ATFS-1 accumulation promoted OXPHOS complex assembly and function, our data suggest that ATFS-1 stimulates respiratory recovery by fine-tuning OXPHOS expression to match the capacity of the suboptimal protein-folding environment in stressed mitochondria, while simultaneously increasing proteostasis capacity.
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•ATFS-1 ChIP-seq indicates the UPRmt includes both proteostasis and metabolism genes•ATFS-1 negatively regulates OXPHOS and TCA cycle mRNAs from the nuclear genome•Mitochondrial ATFS-1 binds mtDNA and limits accumulation of mtDNA-encoded mRNAs•ATFS-1 promotes OXPHOS recovery by matching biogenesis to proteostasis capacity
OXPHOS components are encoded by both the nuclear and mitochondrial genomes. Nargund et al. discover that, during mitochondrial stress, ATFS-1 regulates expression of mitochondrial proteostasis and multiple metabolic genes. By coordinating expression of nuclear and mitochondrial genome-encoded OXPHOS components, ATFS-1 matches OXPHOS complex biogenesis with mitochondrial proteostasis capacity.
Deterioration of adult stem cells accounts for much of aging-associated compromised tissue maintenance. How stem cells maintain metabolic homeostasis remains elusive. Here, we identified a regulatory ...branch of the mitochondrial unfolded protein response (UPRmt), which is mediated by the interplay of SIRT7 and NRF1 and is coupled to cellular energy metabolism and proliferation. SIRT7 inactivation caused reduced quiescence, increased mitochondrial protein folding stress (PFSmt), and compromised regenerative capacity of hematopoietic stem cells (HSCs). SIRT7 expression was reduced in aged HSCs, and SIRT7 up-regulation improved the regenerative capacity of aged HSCs. These findings define the deregulation of a UPRmt-mediated metabolic checkpoint as a reversible contributing factor for HSC aging.
Mitochondria are multifaceted and indispensable organelles required for cell performance. Accordingly, dysfunction to mitochondria can result in cellular decline and possibly the onset of disease. ...Cells use a variety of means to recover mitochondria and restore homeostasis, including the activation of retrograde pathways such as the mitochondrial unfolded protein response (UPRmt). In this Minireview, we will discuss how cells adapt to mitochondrial stress through UPRmt regulation. Furthermore, we will explore the current repertoire of biological functions that are associated with this essential stress-response pathway.
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