Mitochondrial unfolded protein response gene <i>Clpp</i> is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre‐implantation embryos

Wang, Tianren; Babayev, Elnur; Jiang, Zongliang; Li, Guangxin; Zhang, Man; Esencan, Ecem; Horváth, Tamas L.; Seli, Emre

doi:10.1111/acel.12784

Cited by 83 publications

(115 citation statements)

References 43 publications

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“…As a result of deficient CLPP-1, cells were shown to have numerous alterations, such as a higher amount of ROS, decreased ATP production and downregulation of fusion markers, establishing a link between protease abnormalities, energy metabolism and mitochondrial dynamics [96,97]. In addition, CLPP-1-deficient aged cells were found to have an upregulation of mTORC1 signaling markers, suggesting that the increased activation of the mTORC1/PGC-1 axis in aged-AECII reported in our study could be a response to an upstream alteration in the mitochondrial matrix proteases [98,99].…”

Section: Mitochondria In Age-related Lung Fibrosissupporting

confidence: 57%

Mitochondrial Quality Control in Age-Related Pulmonary Fibrosis

Roque

Cuevas-Mora

Romero

2020

IJMS

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Idiopathic pulmonary fibrosis (IPF) is age-related interstitial lung disease of unknown etiology. About 100,000 people in the U.S have IPF, with a 3-year median life expectancy post-diagnosis. The development of an effective treatment for pulmonary fibrosis will require an improved understanding of its molecular pathogenesis and the “normal” and “pathological’ hallmarks of the aging lung. An important characteristic of the aging organism is its lowered capacity to adapt quickly to, and counteract, disturbances. While it is likely that DNA damage, chronic endoplasmic reticulum (ER) stress, and accumulation of heat shock proteins are capable of initiating tissue repair, recent studies point to a pathogenic role for mitochondrial dysfunction in the development of pulmonary fibrosis. These studies suggest that damage to the mitochondria induces fibrotic remodeling through a variety of mechanisms including the activation of apoptotic and inflammatory pathways. Mitochondrial quality control (MQC) has been demonstrated to play an important role in the maintenance of mitochondrial homeostasis. Different factors can induce MQC, including mitochondrial DNA damage, proteostasis dysfunction, and mitochondrial protein translational inhibition. MQC constitutes a complex signaling response that affects mitochondrial biogenesis, mitophagy, fusion/fission and the mitochondrial unfolded protein response (UPRmt) that, together, can produce new mitochondria, degrade the components of the oxidative complex or clearance the entire organelle. In pulmonary fibrosis, defects in mitophagy and mitochondrial biogenesis have been implicated in both cellular apoptosis and senescence during tissue repair. MQC has also been found to have a role in the regulation of other protein activity, inflammatory mediators, latent growth factors, and anti-fibrotic growth factors. In this review, we delineated the role of MQC in the pathogenesis of age-related pulmonary fibrosis.

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Section: Mitochondria In Age-related Lung Fibrosissupporting

confidence: 57%

Mitochondrial Quality Control in Age-Related Pulmonary Fibrosis

Roque

Cuevas-Mora

Romero

2020

IJMS

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“…Although this structure is conserved in vertebrates, there are several reports that CLPX has roles that are distinct from its function in CLPXP mediated proteolysis (Cheong et al, 2020;Kardon et al, 2015;Seo et al, 2016;Wang et al, 2018). This is most strikingly illustrated by the fact that Clpx -/-mouse embryos die by E8.5 with severe gastrulation defects (Cheong et al, 2020), while Clpp -/-mice survive to adulthood (Wang et al, 2018). Our data adds to studies that demonstrate that CLPX has roles that are independent of its function within the CLPXP proteolytic complex.…”

Section: Discussionmentioning

confidence: 58%

“…The CLPXP proteolytic complex, which has been extensively studied in bacteria, consists of an ATP-dependent CLPX subunit which unfolds and translocates protein substrates into a CLPP proteolytic barrel, which then degrades unfolded protein substrates (Olivares et al, 2016). Although this structure is conserved in vertebrates, there are several reports that CLPX has roles that are distinct from its function in CLPXP mediated proteolysis (Cheong et al, 2020;Kardon et al, 2015;Seo et al, 2016;Wang et al, 2018). This is most strikingly illustrated by the fact that Clpx -/-mouse embryos die by E8.5 with severe gastrulation defects (Cheong et al, 2020), while Clpp -/-mice survive to adulthood (Wang et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

CLPX regulates erythroid heme synthesis by control of mitochondrial heme synthesis enzymes and iron utilization

Rondelli

Perfetto

Danoff

et al. 2020

Preprint

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Heme is a prosthetic group that plays a critical role in catalyzing life-essential redox reactions in all cells, including critical metabolic processes. Heme synthesis must be tightly co-regulated with cellular requirements in order to maximize utilization and minimize toxicity. Terminally differentiating erythroid cells have an extremely high demand for heme for hemoglobin synthesis. While the enzymatic reactions of heme synthesis are extremely well studied, the mechanisms by which the mitochondrial homeostatic machinery interacts with and regulates heme synthesis are poorly understood. Knowledge of these regulatory mechanisms are key to understanding how red cells couple heme production with heme demand. Heme synthesis is tightly regulated by the mitochondrial AAA+ unfoldase CLPX, which has been reported to promote heme synthesis by activation of yeast δ-aminolevulinate synthase (ALAS/Hem1). CLPX was also reported to mediate heme-induced turnover of ALAS1 in human cells. However, a mutation in the ATP binding domain of CLPX that abrogated ATP binding caused an increase in ALAS activity, contrary to previous predictions that CLPX activated ALAS. Using loss-of-function assays in murine cells and zebrafish, we interrogated the mechanisms by which CLPX regulates erythroid heme synthesis. We found that consistent with previous studies, CLPX is required for erythroid heme synthesis. We show that ALAS2 stability and activity were both increased in the absence of CLPX, suggesting that CLPX primarily regulates ALAS2 by control of its turnover. However, we also showed that CLPX is required for PPOX activity and maintenance of FECH levels, likely accounting for the heme deficiency in the absence of CLPX. Lastly, CLPX is required for iron metabolism during erythroid terminal differentiation. Our results show that the role of CLPX in heme synthesis is not conserved across eukaryotes. Our studies reveal a potential mechanism for the role of CLPX in anemia and porphyria, and reveal multiple nodes at which heme synthesis is regulated by the mitochondrial housekeeping machinery.

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“…The diagnosis of Perrault syndrome is molecularly confirmed by the presence of biallelic pathogenic variants in one of six genes, all involved in mitochondria functions: caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP), Era like 12S mitochondrial rRNA chaperone 1 (ERAL1), histidyl-tRNA synthetase 2, mitochondrial (HARS2), hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4), mitochondrial leucyl-tRNA synthetase 2 (LARS2), and twinkle mtDNA helicase (TWNK). Role of Clpp in oocyte quality was recently confirmed by analysis of ovarian phenotype in the mouse model, confirming defects in oocyte mitochondrial function and upregulated ovarian mTOR signalling [117].…”

Section: Genes Involved In the Replication And Maintenance Of Mitochomentioning

confidence: 72%

The Role of Mitochondria in Oocyte and Early Embryo Health

Kim¹,

Kenigsberg²,

Jurisicova³

et al. 2019

obm genet

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The mitochondria of the oocyte are a prominent source of energy metabolism as well as mitochondrial DNA that will later populate the cells of the offspring. Recent discoveries provided new insight into the physiology of the mitochondria and its unique genetics. The concept of heteroplasmy defined as the presence of more than one type of mitochondrial genome, is gaining increasing recognition as an important contributor to several complex morbidities, age-related reproductive dysfunction and aging. Understanding the changes caused by pathogenic mutations as well as identifying defects occurring during reproductive aging will enhance our knowledge of the role of mitochondria as organelles in germ cell biology. In this review, we summarize the current state of knowledge about the role of mitochondria in embryo and fetal development.

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Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre‐implantation embryos

Cited by 83 publications

References 43 publications

Mitochondrial Quality Control in Age-Related Pulmonary Fibrosis

Mitochondrial Quality Control in Age-Related Pulmonary Fibrosis

CLPX regulates erythroid heme synthesis by control of mitochondrial heme synthesis enzymes and iron utilization

The Role of Mitochondria in Oocyte and Early Embryo Health

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